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Biodegradable Harmonophores for Targeted High-Resolution In Vivo Tumor Imaging

  • Ali Yasin Sonay
    Ali Yasin Sonay
    Department of Biosystems Science and Engineering (D-BSSE), Eidgenössische Technische Hochschule (ETH) Zurich, 4058 Basel, Switzerland
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  • , 
  • Konstantinos Kalyviotis
    Konstantinos Kalyviotis
    Department of Bioengineering, Imperial College London, South Kensington Campus, London SW7 2AZ, U.K.
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  • , 
  • Sine Yaganoglu
    Sine Yaganoglu
    Department of Biosystems Science and Engineering (D-BSSE), Eidgenössische Technische Hochschule (ETH) Zurich, 4058 Basel, Switzerland
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  • , 
  • Aysen Unsal
    Aysen Unsal
    Department of Bioengineering, Imperial College London, South Kensington Campus, London SW7 2AZ, U.K.
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  • , 
  • Martina Konantz
    Martina Konantz
    Department of Biomedicine, University Hospital Basel and University of Basel, 4031 Basel, Switzerland
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  • , 
  • Claire Teulon
    Claire Teulon
    Laboratory for Fundamental BioPhotonics, Institute of Bioengineering, School of Engineering, École Polytechnique Fédérale de Lausanne, 1015 Lausanne, Switzerland
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  • , 
  • Ingo Lieberwirth
    Ingo Lieberwirth
    Max Planck Institute for Polymer Research, 55128 Mainz, Germany
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    Orcidhttp://orcid.org/0000-0003-1323-524X
  • , 
  • Sandro Sieber
    Sandro Sieber
    Division of Pharmaceutical Technology, Department of Pharmaceutical Sciences, University of Basel, 4031 Basel, Switzerland
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  • Shuai Jiang
    Shuai Jiang
    Max Planck Institute for Polymer Research, 55128 Mainz, Germany
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    Orcidhttp://orcid.org/0000-0002-8639-3495
  • , 
  • Shahed Behzadi
    Shahed Behzadi
    Max Planck Institute for Polymer Research, 55128 Mainz, Germany
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  • Daniel Crespy
    Daniel Crespy
    Max Planck Institute for Polymer Research, 55128 Mainz, Germany
    Department of Materials Science and Engineering, School of Molecular Science and Engineering, Vidyasirimedhi Institute of Science and Technology (VISTEC), Rayong 21210, Thailand
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  • Katharina Landfester
    Katharina Landfester
    Max Planck Institute for Polymer Research, 55128 Mainz, Germany
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  • Sylvie Roke
    Sylvie Roke
    Laboratory for Fundamental BioPhotonics, Institute of Bioengineering, School of Engineering, École Polytechnique Fédérale de Lausanne, 1015 Lausanne, Switzerland
    Institute of Materials Science and Engineering, School of Engineering, École Polytechnique Fédérale de Lausanne, 1015 Lausanne, Switzerland
    Lausanne Centre for Ultrafast Science, École Polytechnique Fédérale de Lausanne, 1015 Lausanne, Switzerland
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    Orcidhttp://orcid.org/0000-0002-6062-7871
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  • Claudia Lengerke
    Claudia Lengerke
    Department of Biomedicine, University Hospital Basel and University of Basel, 4031 Basel, Switzerland
    Division of Hematology, University Hospital Basel, 4031 Basel, Switzerland
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  • , and 
  • Periklis Pantazis*
    Periklis Pantazis
    Department of Biosystems Science and Engineering (D-BSSE), Eidgenössische Technische Hochschule (ETH) Zurich, 4058 Basel, Switzerland
    Department of Bioengineering, Imperial College London, South Kensington Campus, London SW7 2AZ, U.K.
    *Email: [email protected]
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    Orcidhttp://orcid.org/0000-0002-8367-9332
Cite this: ACS Nano 2021, 15, 3, 4144–4154
Publication Date (Web):February 25, 2021
https://doi.org/10.1021/acsnano.0c10634

Copyright © 2022 The Authors. Published by American Chemical Society. This publication is licensed under

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Abstract

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Optical imaging probes have played a major role in detecting and monitoring a variety of diseases. In particular, nonlinear optical imaging probes, such as second harmonic generating (SHG) nanoprobes, hold great promise as clinical contrast agents, as they can be imaged with little background signal and unmatched long-term photostability. As their chemical composition often includes transition metals, the use of inorganic SHG nanoprobes can raise long-term health concerns. Ideally, contrast agents for biomedical applications should be degraded in vivo without any long-term toxicological consequences to the organism. Here, we developed biodegradable harmonophores (bioharmonophores) that consist of polymer-encapsulated, self-assembling peptides that generate a strong SHG signal. When functionalized with tumor cell surface markers, these reporters can target single cancer cells with high detection sensitivity in zebrafish embryos in vivo. Thus, bioharmonophores will enable an innovative approach to cancer treatment using targeted high-resolution optical imaging for diagnostics and therapy.

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Clinical and preclinical imaging holds great potential in mapping disease progression and can provide diagnostic information (1) that may guide the choice of treatment strategies for disease. (2,3) Optical techniques using bioluminescent and fluorescent probes have emerged as promising modalities for molecular imaging in disease and therapy due to their ease of use and improved cellular resolution, capable of distinguishing boundaries between malignant and normal tissue. (4) A key challenge for optical imaging probes and instrumentation, particularly those aimed at eventual clinical applications, is to overcome the problem of autofluorescence, which often result in a low signal-to-noise ratio (SNR). (5) The relatively poor photostability of most imaging probes poses another challenge to provide reliable and sensitive imaging of tumors.
Previously, we introduced inorganic second harmonic generating (SHG) nanocrystals, SHG nanoprobes, (6) as a class of imaging probes that can be used for in vivo imaging. (7) Given that SHG imaging employs near-infrared (NIR) incident light for contrast generation, SHG nanoprobes can be utilized for deep tissue imaging. (8,9) Unlike commonly used fluorescent probes, SHG nanoprobes neither bleach nor blink, and their signal does not saturate with increasing illumination intensity, ensuring high probe sensitivity. (10) Since their signal profile is very narrow, they can be imaged with high SNR by excluding the broad emission of typical autofluorescence background. (6,11) Robust functionalization allows targeting to a wide variety of cells and proteins of interest, (12) allowing these imaging probes to be promising tools for both clinical and preclinical imaging applications. (13) Despite these advantages, the chemical structure of inorganic SHG nanoprobes makes them stable in the body, which may cause concerns for the long-term health of an organism that has been imaged with these reporters. (14)
To create a foundation for safe SHG nanoprobe-based clinical imaging, we set out to generate a nanoprobe that consists of biodegradable materials, capable of generating sufficient SHG signal that can be detected with high SNR. Our efforts were guided by the observation that peptides with a variable number of amino acid units can self-assemble into large, solid nanostructures of different morphologies and symmetries (Figure 1a). (15) It has been previously shown that such structures can be ferroelectric and give nonlinear optical contrast such as SHG (Figure 1c). (16,17) Since these peptides self-assemble in solution in an inherently sequential process, they form nanostructures in the micrometer range that are difficult to control in size and cannot be readily utilized for in vitro and in vivo imaging. Given that the SHG signal output is dependent on the size of the assembly and significantly decreases at the nanoscale, we set out to develop a synthesis method that would miniaturize these peptides assemblies and control their size into nanoparticles. Importantly, miniaturized peptide assemblies should not lose their crystalline structure and SHG signal, generating imaging agents that can be degraded over time without harming the body.

Figure 1

Figure 1. Synthesis and analysis of bioharmonophores. (a) Schematic of the self-assembling reaction of diphenylalanine peptides (FF) into large-scale nanotube structures from a concentrated solution. (b) Schematic of the emulsion–solvent evaporation method for the synthesis of bioharmonophores. Self-assembling peptides are dissolved in chloroform along with biodegradable poly(l-lactic acid) (PLLA) and emulsified with the surfactant sodium dodecyl sulfate (SDS) using sonication, followed by evaporation of chloroform. (c) SHG signal from diphenylalanine peptide nanotubes aggregated on top of the imaging chamber. Peptide nanotubes were illuminated with a 850 nm pulsed laser. Image composite of multiple stitched images. (d) SHG signal from encapsulated triphenylalanine peptide (FFF) bioharmonophores immobilized in 1% low melting agarose illuminated with 850 nm pulsed laser. (e) TEM image of synthesized FFF-based bioharmonophores showing uniform spherical nanoparticles. (f) DLS data showing the size distribution of synthesized bioharmonophores. Scale bar, 100 μm (c); 10 μm (d); 500 nm (e).

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Results and Discussion

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Synthesis of Bioharmonophores

To render these nanostructures suitable for biological applications, we evaluated methods for the encapsulation of self-assembling peptides in order (i) to hinder their macroscopic aggregation by confining their self-assembly in nanodroplets without affecting their ability to generate a strong SHG signal and (ii) to generate a nanoparticle that can be further functionalized without influencing the peptide assembly. To this end, we subjected several peptides that have been reported to self-assemble into complex nanostructures to the emulsion–solvent evaporation method, (18) a widely used procedure for the fabrication of monolithic and core–shell nanoparticles (Figure 1b, see the Experimental Methods).
We identified three peptides with different self-assembling properties (pentaalanine, (19) trileucine, (20) and triphenylalanine (21)) that could generate a detectable SHG signal when encapsulated in the biodegradable polymer (Figure 1d and Supplementary Figure 1). Transmission electron microscopy (TEM) analysis of the predominantly spherical nanoparticles, hereinafter referred to as bioharmonophores, revealed a diameter ranging from 50 to 150 nm (Supplementary Figure 2), which was confirmed by dynamic light scattering (DLS) measurements (Figure 1e,f).
SHG signal from bioharmonophores can stem from (i) the bulk of the self-assembling peptides that form noncentrosymmetric crystalline structures or (ii) the surface of the bioharmonophores where there is no inversion symmetry. To ascertain that the SHG signal originates from the crystalline peptide core, we performed X-ray diffraction (XRD) analysis of bioharmonophores with different peptide contents. In all cases, the peptides showed a high degree of internal order with distinct diffraction patterns associated with their individual crystalline phases and self-assembling behavior (Supplementary Figure 3a–d).

Optical Characterization of Bioharmonophores

Because bioharmonophores based on triphenylalanine (FFF) peptides yielded the strongest SHG signal compared to pentaalanine and trileucine, we subjected these bioharmonophores to detailed optical characterizations. The SHG signal of FFF-based bioharmonophores was spectrally well-defined (Figure 2a) and comparable with inorganic SHG nanoprobes (Supplementary Figure 4). Additionally, the SHG emission patterns of FFF-based bioharmonophores displayed a broad opening: one seemingly isotropic (Figure 2b, PSS polarization, blue data) and the other one displaying one lobe with a width of 60° centered around the forward direction (Figure 2b, PPP polarization, red data). These results indicate that bioharmonophores emit an SHG signal in multiple directions, which can be detected in an epi-detection setup (i.e., illumination and collection of SHG signal using the same objective lens), unlike the predominantly forward-directed SHG signal of large protein arrays, such as collagen and myosin that require a trans-detection approach (i.e., illumination and SHG signal traverses the sample to reach the detector). (10) This difference in detection geometry allows exclusion of a collagen-based SHG signal during imaging, leading to a high SNR bioharmonophore signal that can be distinguished from large-scale collagen arrays even in tissues with high SHG background. Moreover, the presence of a single lobe suggests that the observed SHG signal originates from the bulk (22) of the bioharmonophores and not from its surface, as described by nonlinear light scattering theory. (22,23) The high intensity emission in the PPP polarization combination further indicates that a coherent response originates from a noncentrosymmetric crystalline bulk.

Figure 2

Figure 2. Optical characterization of bioharmonophores and analysis of parameters influencing bioharmonophore formation. (a) Normalized SHG signal spectrum of FFF-based bioharmonophores (signal ranging from 400 to 600 nm) illuminated with 850 nm pulsed laser. The characteristic SHG peak is centered around 425 nm. (b) SHG emission pattern of Triphenylalanine based bioharmonophores. Orange arrow indicates excitation beam direction. Green arrow shows SHG collection direction, which rotates between −90° and +90°. The detected polarization is in the beams plane (P, black arrow). The red pattern shows PPP polarization configuration (excitation and detection polarizations in the plane of the beams), and the blue pattern shows PSS (excitation with a perpendicular polarization). (c) SHG intensity vs incident polarization angle for a bioharmonophore, highlighted by the solid white circle in Supplementary Figure 5. Red color shows detection along the X axis while green color shows detection along the Y axis. The experimental curve is a dotted line, the corresponding fitted curve, assuming C2 symmetry, is a solid line. (d) Influence of using different amounts of FFF peptide during bioharmonophore production on the SHG signal intensity. The optimal condition (33 wt %) is marked in green. The use of higher FFF peptide amount leads to aggregates (n = 5). (e) Influence of SDS concentration (wt % of disperse phase) on SHG intensity of generated bioharmonophores. The optimal condition (40 wt % SDS) with high bioharmonophore stability and less aggregation is marked in green (n = 5). (f) Influence of using different amounts of PLLA during bioharmonophore production on the SHG intensity of the generated bioharmonophores. The optimal condition (66 wt % PLLA) is marked in green (n = 5). Mean ± s.d. ****, P < 0.0001, **, P < 0.005, *, P < 0.05 (ordinary one-way ANOVA with Tukey’s multiple comparisons).

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Because SHG involves only virtual energy transitions, bioharmonophores did not display blinking and remained stable over extended periods of illumination, and their SHG signal intensity rose quadratically when the laser intensity shone on them was linearly increased (Supplementary Figure 5a,b). The measured polarimetric diagrams (Figure 2c and Supplementary Figure 5c–f) were consistent with the hypothesis that bioharmonophores have a self-assembling peptide core with a monoclinic (C2) symmetry. Indeed, the experimental curves were well fitted with the analytical expression calculated for this symmetry (see Supplementary Note 1). Taken together, bioharmonophores have the same photophysical advantages for biomedical imaging applications that have been previously described for inorganic SHG nanoprobes. (6)
To gain insight into the parameters influencing the bioharmonophore stability and signal intensity, we tested several reaction conditions to generate bioharmonophores. Given that the SHG signal originating from bioharmonophores is dependent on the amount of encapsulated peptide, we first tested whether varying the FFF peptide concentration during production would improve the SHG signal intensity of generated bioharmonophores (Figure 2d and Supplementary Figure 6). We found that an amount of 15 mg of FFF (33 wt %) peptide provided an optimal combination of intense SHG signal and bioharmonophore stability. Interestingly, while an FFF peptide amount of 20 mg (40 wt %) increased the overall SHG signal, it also led to bioharmonophore aggregation and decreased colloidal stability. Conversely, 10 mg (25 wt %) of FFF peptide generated little SHG signal.
Because surfactant concentration plays a crucial role in emulsification of chloroform droplets, (18) we reasoned that altering the surfactant concentration during the preparation of bioharmonophores would have a profound effect on their stability and signal strength (Figure 2e and Supplementary Figure 7). Bioharmonophores emulsified in an aqueous solution with 0.3% sodium dodecyl sulfate (SDS) (40 wt % of dispersed phase) yielded stable bioharmonophores with intense SHG signal, whereas compositions employing 0.1% SDS (18 wt %) yielded aggregated nanoparticles. Increasing the SDS concentration to 0.6% (57 wt %) diminished the SHG signal intensity, suggesting that the bioharmonophore size and hence the number of enclosed peptide molecules within each bioharmonophore is influenced by the concentration of surfactant.
Finally, we varied the polymer quantity that encapsulates and shields peptides from environmental changes and assessed its role in both SHG signal intensity and nanoparticle morphology (Figure 2f and Supplementary Figure 8). We identified that an amount of 30 mg of poly(l-lactic acid) (PLLA) (66 wt %) resulted in an optimal combination of intense SHG signal and bioharmonophore stability. A lower polymer amount of 10 mg (40 wt %) yielded a weaker SHG signal, whereas a higher polymer amount (90 mg, 86 wt %) led to elongated bioharmonophore morphologies. Taken together, we identified optimal experimental conditions to generate bioharmonophores providing a high SNR along with an excellent stability and size distribution for biological applications.

Biodegradation of Bioharmonophores

Clinical imaging probes that are biodegradable provide the significant advantage of being able to be broken down in the body and removed after they have served their function. To demonstrate that bioharmonophores are indeed biodegradable, we utilized the highly effective serine protease, proteinase K, which exhibits a broad cleavage specificity. (24) We incubated bioharmonophores with a proteinase K concentration that is routinely used for dissolving tissue structures (25) and probed the extent of degradation by monitoring the SHG signal at different time intervals (Figure 3a). We observed a decrease of SHG signal within 2 h of protease incubation. After 10 h, the SHG signal disappeared and the turbid bioharmonophore suspension became transparent (Figure 3b and Supplementary Figure 9), indicating a successful biodegradation of the bioharmonophore. When characterized by TEM imaging, the structural integrity of the bioharmonophore coat started to disintegrate within 4 h of Proteinase K treatment (Supplementary Figure 10).

Figure 3

Figure 3. Bioharmonophores can be degraded by proteases, cells, and cell-free lysate systems. (a) Schematic showing different degradation methods utilized to assess biodegradability of the bioharmonophores. (b) Graph displaying the change of SHG signal intensity over time of bioharmonophores incubating with proteinase K (n = 5). Mean values of data points were fitted for one-phase exponential decay. (c) Quantification of SHG signal/cell after overnight incubation of Tat-peptide functionalized bioharmonophores over time. SHG signal/cell is significantly reduced 30 h after reseeding. Mean ± s.d. ****, P < 0.0001, **, P < 0.005, *, P < 0.05 (nonparametric Kruskal–Wallis test with Dunn’s post hoc multiple comparison). (d) Graph showing the loss of SHG signal intensity when bioharmonophores are subjected to the cell-free reticulate lysate degradation system (n = 5). Mean values of data points were fitted using a one phase exponential decay. Scale bar, 10 μm (c); 10 μm (d).

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To evaluate bioharmonophore degradation under physiological conditions (Figure 3c), we functionalized bioharmonophores with Tat-derived cell penetrating peptides (26) using bioorthogonal click chemistry (Supplementary Figure 11) and incubated them with a model cancer cell line (see below) overnight. Adherent cells were then detached by trypsinization and centrifuged to remove excess bioharmonophores that did not enter the cancer cells. Following this procedure, cells were reseeded and fixed at specific time periods to monitor bioharmonophore degradation (i.e., the intracellular presence of SHG signal per cell) using nonlinear optical imaging. Thirty hours after cell reseeding, a pronounced decrease of intracellular SHG signal per cell was noticeable (Figure 3c). As bioharmonophores displayed long-term photostability even at low pH values (Supplementary Figure 12), the drop of signal was not due to their potential accumulation in acidic endolysosomal compartments over time. Immunostaining of uptaken bioharmonophores indeed revealed that bright SHG signal still persisted in lysosome-associated membrane protein 2 (LAMP2)-positive endocytic compartments prior to degradation (Supplementary Figure 13). In order to show that bioharmonophores can be degraded using intracellular proteolytic degradation, we tested whether the bioharmonophores could be degraded using a cell-free lysate system based on an established cell-free degradation assay. (27) We also observed reduced SHG signal, indicating that intracellular enzymatic degradation of bioharmonophores might account for the signal loss (Figure 3d and Supplementary Figure 14). Importantly, bioharmonophores did not exhibit any short-term toxicity in vitro and in vivo (Supplementary Figure 15) and did not induce protein aggregation (Supplementary Figure 16), (28) rendering them safe imaging probes.

In Vivo Cancer Imaging

Among various diagnostic applications, bioharmonophores could be ideal imaging probes for single-cell cancer detection due to their high SNR and photostability, which other intravital imaging modalities cannot achieve. (2) To demonstrate the optical features of bioharmonophores for cancer targeting and imaging, we employed xenograft zebrafish cancer models, which offer speed, cellular resolution, and the ability to perform large numbers of transplants for obtaining valuable information about several cancer types. (29,30)
To generate a highly aggressive cancer model that can be tracked over time, we injected a DsRed-expressing metastatic human melanoma cells (MDA-MB-435-DsRed) into the Duct of Cuvier (DoC) of zebrafish embryos at 2 dpf (days post fertilization) (Figure 4a). (29,30) By 3 days after the injection, the resulting tumors spread to various locations in the body and were found next to blood vessels, which likely support the tumors with nutrients (Figure 4b). (31)

Figure 4

Figure 4. Bioharmonophores can be specifically targeted to single cancer cells in vivo. (a) Schematic showing the generation of a zebrafish cancer model by injecting MDA-MB-435-DsRed cancer cells into the Duct of Cuvier (DoC) at 2 dpf, resulting in tumors spread to multiple locations of the zebrafish body at 5 dpf. (b) Composite image of the cancer model (left) in a 5 dpf old zebrafish embryo. Close-up image of one of the tumor sites (right) reveals DsRed-labeled tumors (magenta), adjacent to the eGFP-labeled vasculature (green). (c) Schematic showing cancer cell injection of 2 dpf zebrafish embryos followed by bioharmonophore injection into DoC of 3 dpf zebrafish embryos and subsequent fluorescence and SHG imaging at 5 dpf. Red rectangles labeled as c1–4 denote the regions of interest that are illustrated in more detail. Individual panels showing the images of labeled cancer cells with the details of bioharmonophore (white) labeling down to single cancer cells (magenta) in solid tumors (c1–4). Colored cell boundary reconstruction of targeted cancer cells using the bioharmonophore SHG signal (c1′–4′). Note that cellular bioharmonophore distribution can in most cases predict cell morphologies. Scale bar, left panel 200 μm, right panel 20 μm (b); 15 μm (c). (d) Quantification of the fraction of SHG-labeled tumors as the ratio of labeled tumors to all tumors in a given zebrafish embryo after PEG- and p32 peptide-coated bioharmonophore injection, respectively. Each data point signifies one zebrafish. Note that active targeting with p32-coated bioharmonophores significantly increases the labeling efficiency (approximately 4-fold). Mean ± s.d. ****, P < 0.0001, **, P = 0.0063, *, P = 0.0470 (nonparametric Kruskal–Wallis test with Dunn’s post hoc multiple comparison). N = 12, pooled from 3 independent experiments.

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To demonstrate the specificity and efficiency of bioharmonophores as contrast agents that can accomplish resolution down to the single cell in vivo, we targeted bioharmonophores to tumor sites by taking advantage of the surface protein p32/gC1qR as a characteristic molecular marker for MDA-MB-435-DsRed cells. (32) To this end, we functionalized bioharmonophores with a p32 targeting peptide, injected them into the DoC of zebrafish embryos at 3 dpf, 1 day after the embryos were injected with MDA-MB-435-DsRed cancer cells (Figure 4c), and assessed colocalization between cancer cells and bioharmonophore signal at 5 dpf (see Supplementary Note 2). In the absence of tumors, functionalized bioharmonophores did not cause clustering at the site of injection and were localized at different parts of injected zebrafish embryos (Supplementary Figure 17d–i), indicating good biodistribution. Without bioharmonophore injection, zebrafish as well as tumor sites did not produce any SHG background signal (Supplementary Figures 17a–c and 18a–c) with the exception of minimal endogenous SHG signal localized at the zebrafish tail, (33) which was excluded from assessing specificity of tumor targeting (Supplementary Figure 19). In the case of passive targeting, zebrafish injected with PEG-coated bioharmonophores revealed limited tumor labeling (Supplementary Figure 18d–f), stemming from leaky blood vessels and enhanced permeability and retention effect (EPR). (34) In contrast, we observed an increased accumulation of p32 peptide-targeted bioharmonophores within individual cancer cells at tumor sites throughout the zebrafish embryos (Figure 4c1–c4′), indicating that the tumor-labeling specificity and efficiency are highly dependent on the p32 targeting peptide. While p32 peptide-targeted bioharmonophores can extravasate to different tumor sites, not all the cancer cells were labeled (Figure 4c). This observation is potentially due to limited accessibility within densely packed solid tumors (35) and the continued proliferation and metastasis of cancer cells between bioharmonophore administration and imaging (see Supplementary Note 2).
In order to determine the extent of labeling of targeted bioharmonophores in the xenograft zebrafish cancer model, we measured the colocalization of cancer cells with bioharmonophores at each tumor site for noninjected zebrafish as well as for zebrafish that were injected with p32 peptide-targeted and PEG-coated bioharmonophores, respectively (see Supplementary Note 2 and Figure 4c,d). The number of tumors were not significantly different between data sets (Supplementary Figure 20). The zebrafish cancer model injected with p32 peptide-targeted bioharmonophores had a significantly higher fraction of labeled tumors compared with noninjected and PEG-coated bioharmonophores (Figure 4d) due to our active targeting strategy. Overall, these results demonstrate that bioharmonophores exhibit high SNR and outstanding photostability for efficient labeling of individual cancer cells at multiple tumor sites in vivo.

Conclusions

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In summary, we introduced bioharmonophores as a class of imaging probes that retain all the photophysical advantages of previously introduced inorganic SHG nanoprobes. Because bioharmonophores consist of a biodegradable peptide core and a polymer shell, they can be metabolized within cells. Our experiments indicated a degradation time between 24 and 48 h after injection, (36−38) which is similar to existing nanoparticle based and molecular imaging agents. Their relative stability before finding their target and degradation upon cellular entry could render bioharmonophores ideal contrast agent for clinical imaging applications. The straightforward implementation of robust functionalization strategies and a sufficiently high metabolic stability in vivo allowed us to target bioharmonophores with high detection sensitivity to individual tumor cells in live zebrafish embryos. With the recent development of nonlinear microendoscopes, (39,40) bioharmonophores have the potential to emerge as superior contrast agents during image-guided surgery to help surgeons perform safer and highly precise tumor removal procedures. Moreover, their ability to target single cells could be exploited for detecting cancer stem cells, a subpopulation of cells responsible for tumorigenicity, invasion, and metastasis. (41) Once successfully identified, the nonlinear signal of bioharmonophores could be used for light induced drug delivery or photodynamic therapy. (42) By employing pulsed lasers in the infrared wavelength range that permit deep tissue penetration, targeted bioharmonophore signal could trigger highly localized cancer stem cell death. (43) Finally, as the SHG signal intensity of bioharmonophore relies on the self-assembly behavior of each peptide, (44) we anticipate that a screen for alternative peptide sequences may yield even brighter bioharmonophores that will potentially permit diagnosis with deep-tissue single-molecule detection sensitivity.

Experimental Methods

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Formation of Large-Scale Peptide Nanotubes

Diphenylalanine (FF) and triphenylalanine (FFF) (Bachem) peptide assemblies were prepared as previously described. (45) Briefly, peptides were freshly dissolved in hexafluoroisopropanol (Sigma) at 100 mg/mL concentration prior to experiments and diluted to 5 mg/mL final concentration in deionized water.

Encapsulation of SHG-Active Peptide Assemblies

For the evaluation of different peptides and their SHG capabilities, 30 mg of PLLA was dissolved in 3 mL of chloroform (Sigma) along with 15 mg of triphenylalanine, 30 mg of pentalalanine (Bachem), and 30 mg of trileucine (Sigma) peptides in separate glass vials. The resulting suspension was mixed with aqueous SDS (Sigma) solution with a final 0.3% SDS concentration. A macroemulsion was obtained by stirring the samples at 1000 rpm for 1 h. Afterward, the samples were sonicated (Branson Sonifier) with a 1.5 in. tip at 70% power in a pulsed mode (30 s ON and 10 s OFF) for 2 min under ice cooling. The chloroform was evaporated from the obtained emulsions by stirring the samples at 500 rpm at 40 °C overnight. For the remaining experiments with triphenylalanine peptide containing bioharmonophores, the same protocol was followed unless stated otherwise. For probing the optimal conditions for nanoparticle formation, FFF peptide, PLLA, and SDS concentrations were varied as described in Supplementary Figures 6–8.

Characterization of Encapsulated SHG-Active Peptide Assemblies

Produced samples were characterized using dynamic light scattering. Nanoparticle morphology, aggregation tendency, and the SHG signal intensity were evaluated using nonlinear microscopy. XRD patterns were obtained using a PANalytical X’PERT Pro powder diffractometer in Bragg–Brentano geometry and with Cu K-α1 radiation in grazing incidence geometry between 2–60 using a step size of 0.0167. The samples were air-dried on silicon single crystals, and four identical scans were obtained from each sample and summed up.

SHG Polarimetry

The SHG polarimetry was performed on a wide-field SHG microscope (see the Supporting Information). A 1030 nm laser, pulse width 190 fs, and 200 kHz repetition rate (Pharos, Light Conversion), delivered 36 mW on the sample over a 150 μm fwhm diameter field-of-view (1 mJ·cm–2). Two non-colinear beams are incident on the sample, with a 30° opening angle. The SHG signal was detected in the phase matching direction (transmission). The image was recorded with an electron-multiplying intensified charge-coupled device (EM-ICCD) camera. Nonlinear polarimetry was performed by controlling and analyzing the polarization state of the illuminating and emitted beams. A polarization state generator, comprising a half- and a quarter-wave plate, was used. The polarization state of the emitted light was analyzed with a half-wave plate placed in the emission path, followed by a polarizing beam splitter.

Second-Harmonic Spectroscopy Patterns

SHG emission pattern measurement was performed on a custom-build setup for this purpose (see the Supporting Information). Excitation was performed with a 1030 nm laser, pulse width 190 fs, and 200 kHz repetition rate, which delivered 60 mW on the sample, a cylindrical cuvette containing the solution, over a 36 μm focal spot (30 mJ·cm–2). The signal was detected with a rotating PMT and a filter (515 + 10, Chroma) at angles between −90 and 90. Both incident and detection polarizations was controlled.

Stability of Biodegradable Bioharmonophores at Different pH Values

To evaluate how different pH values might influence the PLLA-coated peptide assemblies and their signal intensity, synthesized bioharmonophores were centrifuged for 3 min at 13500 rpm and resuspended in citric acid/Na2HPO4 buffer ranging from 4 to 7 pH values. The bioharmonophores were incubated for 72 h in the buffers containing 1% Tween 80 to prevent aggregation, and the signal intensity was monitored using nonlinear microscopy.

Biodegradation of Bioharmonophores in Vitro

Bioharmonophores were centrifuged for 3 min at 13500 rpm and resuspended in 1% Tween 80 in 1X PBS. In order to assess proteinase K (Sigma) degradation, 1 mL of bioharmonophore suspension was incubated with 100 μg/mL final proteinase K concentration at 37 °C and the SHG signal intensity was measured every 2 h. Similarly, in order to assess how bioharmonophores were degraded using cellular content, an ex vivo biodegradation protocol was adapted based on the Rabbit Reticulocyte Lysate system (Promega). In a typical setup, 1 mL of bioharmonophore in 1% Tween 80 in 1X PBS was mixed with 25 mM phosphocreatine (Sigma), 10 μg/mL phosphocreatine kinase (Sigma), 1 mM ATP (Sigma), and 50 μL Rabbit Reticulocyte Lysate. The mixture was incubated at 37 °C, and the SHG signal intensity was monitored every 2 h.

Biodegradable Bioharmonophore Functionalization

One milliliter of 1.5 mg/mL bioharmonophores was incubated with 1 mg of Candida antarctica Lipase B (Sigma) for 2 h, which hydrolyzes the PLLA polymer to increase the number of carboxyl groups. The bioharmonophore suspension was centrifuged at 13500 rpm for 3 min and resuspended in 1% Tween 80 in 1X PBS and mixed with 10 mg of N-(3-(dimethylamino)propyl)-N′-ethylcarbodiimide hydrochloride (EDC) (Sigma), 10 mg of N-hydroxysuccinimide (NHS) (Sigma), and 10 mg of methoxypolyethylene glycol amine 5000 Da (mPEG Amine) (Sigma) for 2 h. The suspension was centrifuged and resuspended in 1% Tween 80 in 1X PBS and stored at 4 °C prior to use.
For further functionalization experiments thiol-PEG-amine 2000 Da (SH-PEG-NH2) (Sigma) was used as a platform for bioorthogonal click chemistry. In a similar setup, 10 mg of EDC, 10 mg of NHS, and 10 mg of thiol-PEG-NH2 were incubated for 2 h. The suspension was centrifuged and resuspended in 1% Tween 80 in 1X PBS with methyltetrazine-PEG4-maleimide (Click Chemistry Tools) of 200 μM final concentration. The mixture was incubated for 2 h at room temperature, centrifuged, and resuspended in 1% Tween 80 in 1X PBS.
The other click chemistry pair trans-cyclooctene (TCO)-PEG3-maleimide (Click Chemistry Tools) (3 mM in 200 μL of PBS) was incubated for 2 h with cysteine-containing Tat or P32 targeting peptides (1 mM final concentration) depending on the application. The peptides were passed through Illustra Microspin G25 columns (GE Healthcare) to remove TCO-PEG3-maleimide.
A 200 μLportion of tetrazine-modified bioharmonophores was incubated with 20 μL of TCO-modified peptide for 2 h. The bioharmonophore suspension was washed with 1% Tween 80 in 1X PBS to remove unbound peptides and resuspended in 1X PBS to be immediately used for cell culture experiments.

Cellular Degradation and Toxicity

MDA-MB-435-DsRed cancer cells were kindly gifted by Prof. R. Klemke. The cells were cultured at 37 °C, 5% CO2, in high glucose DMEM with GlutaMAX (10569010, Thermo Fisher), supplemented with 10% FBS (P40–37500, Pan Biotech) and 1X penicillin–streptomycin solution (15140122, Thermo Fisher). The cells were cultured on six-well plates (140675, Thermo Fisher) until they reached ∼80% confluency and were incubated with 400 μL Tat-derived cell penetrating peptide coated bioharmonophores overnight. The cells were washed with 1X PBS twice and detached using 0.05% Trypsin-EDTA (25300054, Thermo Fisher) in order to remove bioharmonophores that did not enter the cancer cells. Detached cells were centrifuged for 5 min at 500g to remove excess bioharmonophores that were not taken up, reseeded or ibiTreat-coated on eight-well slides (80826, Ibidi GmbH), and fixed after 6, 30, 54, and 78 h to monitor bioharmonophores degradation. The samples were then washed three times with 1X PBS and stained with the CellMask Orange Membrane dye (Invitrogen). The samples were washed again and imaged subsequently. To determine cell viability after treatment with functionalized bioharmonophores, trypan blue exclusion method was used. Briefly, cells in triplicates seeded in 96-well tissue culture plates (167008, Thermo Fisher) were exposed to varying concentrations of functionalized bioharmonophores for 48 or 72 h. After incubation, cells were washed with 1X PBS twice and detached as described above. Ten microliters of the cell suspension was then mixed with 10 μL of 0.4% Trypan Blue, and 4 μL of this mixture was added to the cell-counting slide (C10228, Thermo Fisher) and measured using Countess II Automated cell counter (Thermo Fisher). The viability was expressed as a fold difference of the untreated samples for each time point.

Subcellular Localization of Bioharmonophores upon Cellular Uptake

HeLa cells were cultured at 37 °C, 5% CO2, in high glucose DMEM with GlutaMAX (10569010, Thermo Fisher), supplemented with 10% FBS (P40-37500, Pan Biotech) and 1× penicillin–streptomycin solution (15140122, Thermo Fisher). A 13 mm round coverslip was coated with 0.1% gelatin (G1393, Merck) for 1 h, and cells were seeded to reach around 70% confluency. The following day, 400 μL of freshly prepared thiol-PEG functionalized bioharmonophores (46,47) (2 mg/mL) or an equal volume of 1X PBS (control) was added to the cells and incubated for 24 h. The cells were washed with 1X DPBS (containing Ca2+ and Mg2+, 14040133, Gibco) to remove the excess of not internalized bioharmonophores, fixed with 4% PFA for 15 min, permeabilized with 1X PBST (1X PBS containing 0.01% Tween20) for 15 min, blocked with 10% goat serum in 1X PBST for at least 1 h, and incubated overnight with mouse anti-LAMP2 (ab25631, Abcam, 1:200) in 5% goat serum at 4 °C. The next day, cells were rinsed with 1X PBST and incubated for 1 h with the goat antimouse Alexa488 conjugated secondary antibody (A28175, Thermo Scientific, 1:1000), washed thoroughly with 1X PBST, and mounted in mowiol mounting medium containing 2.5% v/v DABCO (290734, Merck).

Toxicity Assay and Thioflavin T Staining

For toxicity assay, cells were grown in 96-well plates and were incubated with bioharmonophores at different concentrations for 48 and 72 h. After the incubation period, the cells were detached with trypsinization, and their viability was analyzed using Trypan Blue (Sigma) staining.
For thioflavin staining, cells were seeded in an eight-well chamber (ibidi) with 50% confluency. The cells were treated with either Amyloid Beta Peptide (Bachem) or 5 μL of bioharmonophores for 24 h and extensively washed with 1X PBS to remove excess peptides and bioharmonophores. To evaluate whether bioharmonophores induce fibril formation the cells were fixed with 4% PFA for 10 min and washed with 1X PBS three times. Afterward, 0.05% Thioflavin T (Sigma) solution was added to the sample for 8 min, and excess dye was washed with 80% ethanol for 5 min. The washing step was repeated three times, and the samples were imaged using confocal microscopy.

Zebrafish Cancer Model and Bioharmonophore Targeting

Animal experiments and zebrafish husbandry were approved by the “Kantonales Veterinaeramt Basel-Stadt”. MDA-MB-435-DsRed cancer cells were injected into the Duct of Cuvier of Tg(fli1:egfp) zebrafish embryos at 2 days post fertilization (dpf). After injection, embryos were incubated for 1 h at 29 °C for recovery and cell transfer then verified by fluorescence microscopy. Fish harboring red cells were incubated at 35 °C essentially as described before. (29,30) Fish were anaesthetized and embedded in low melting agarose as described previously (48) and were imaged at 5 dpf for assessing cancer cell localization.
For targeting experiments, p32/gC1qR ligand-functionalized bioharmonophores were injected into the zebrafish embryos 24 h after cancer cell injection following the same procedure. In vivo bioharmonophores targeting was evaluated at 5 dpf using nonlinear laser scanning microscopy.

Transmission Electron Microscopy

Bioharmonophore samples were spun down to remove aggregated nanoparticles at 3000 rpm for 3 min. Five microliters of the sample (i.e., the supernatant of the centrifuged solution) was placed on a carbon coated grid (Quantifoil, D) previously glow-discharged for 30 s (Emitech K100X, GB). The drop was allowed to remain for 60 s; after this interval, excess fluid was drained along the periphery using a piece of filter paper followed by staining with 2% uranyl acetate for 1 and 15 s, respectively. Excess moisture was drained after each step, and when dry, the grid was examined in an FEI Morgagni 268 TEM operated at 100 kV.

Nonlinear and Confocal Laser Scanning Microscopy

Bioharmonophores were immobilized in low melting agarose by mixing 200 μL of bioharmonophore with 100 μL of 1% SeaPlaque low melting agarose (Lonza) solution in eight-well imaging chambers (Lab-Tek). Imaging experiments were performed either on a Zeiss LSM 780 microscope (Carl Zeiss AG) equipped with a spectral GaAsP detector and a tunable two-photon laser source (Chameleon Ultra II, Coherent, Inc.) using an LD C-Apochromat 40×/1.1 water immersion objective lens (Carl Zeiss AG) or on a Leica SP5 microscope equipped with 2 Hybrid Detectors (HyD, Leica) and a tunable two-photon laser source (Mai-Tai 690-1020, Spectraphysics), using a HC PL Apochromat 63×/1.40 Oil immersion objective lens (Leica). Throughout the imaging experiments, bioharmonophores were illuminated with 850 nm incident wavelength, and the SHG signal was collected between 405 and 435 nm or with a GaAsP spectral wavelength detector for spectral measurements.

Statistical Analysis

All numerical values represent mean ± s.d. Sample sizes (n) are given in the figure legends for each experiment. Each experiment was repeated at least three times. Normal distribution of data sets was established using the D’Agostino & Pearson omnibus normality test where P > 0.05 indicated Gaussian distribution. When all of the data sets had Gaussian distribution, one-way Anova was used for multiple comparisons followed by Tukey’s multiple comparisons. When one or more data sets showed a non-Gaussian distribution or high degree of variance as in the case of zebrafish tumor models, a Kruskal–Wallis test was applied along with Dunn’s multiple comparisons. For all statistical tests, a P value was reported, n.s., P > 0.05, *, P < 0.05, **, P < 0.005, ***, P < 0.001, ****, P < 0.0001. Second-order polynomial fit and one phase exponential decay values were calculated, and graphs were drawn using GraphPad Prism 6.

Supporting Information

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The Supporting Information is available free of charge at https://pubs.acs.org/doi/10.1021/acsnano.0c10634.

  • Supplementary figures as described in the text (Figures 1–20) and supplementary notes describing optical characterization of bioharmonophores and determination of the fraction of bioharmonophore-labeled tumors in a zebrafish cancer model (PDF)

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Author Information

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  • Corresponding Author
    • Periklis Pantazis - Department of Biosystems Science and Engineering (D-BSSE), Eidgenössische Technische Hochschule (ETH) Zurich, 4058 Basel, Switzerland;  Department of Bioengineering, Imperial College London, South Kensington Campus, London SW7 2AZ, U.K.;  Orcidhttp://orcid.org/0000-0002-8367-9332;  Email: [email protected]
  • Authors
    • Ali Yasin Sonay - Department of Biosystems Science and Engineering (D-BSSE), Eidgenössische Technische Hochschule (ETH) Zurich, 4058 Basel, Switzerland;  Present Address: (A.Y.S.) Molecular Pharmacology Program, Memorial Sloan Kettering Cancer Center, 10065 New York, NY 10065
    • Konstantinos Kalyviotis - Department of Bioengineering, Imperial College London, South Kensington Campus, London SW7 2AZ, U.K.
    • Sine Yaganoglu - Department of Biosystems Science and Engineering (D-BSSE), Eidgenössische Technische Hochschule (ETH) Zurich, 4058 Basel, Switzerland
    • Aysen Unsal - Department of Bioengineering, Imperial College London, South Kensington Campus, London SW7 2AZ, U.K.
    • Martina Konantz - Department of Biomedicine, University Hospital Basel and University of Basel, 4031 Basel, Switzerland
    • Claire Teulon - Laboratory for Fundamental BioPhotonics, Institute of Bioengineering, School of Engineering, École Polytechnique Fédérale de Lausanne, 1015 Lausanne, Switzerland
    • Ingo Lieberwirth - Max Planck Institute for Polymer Research, 55128 Mainz, Germany;  Orcidhttp://orcid.org/0000-0003-1323-524X
    • Sandro Sieber - Division of Pharmaceutical Technology, Department of Pharmaceutical Sciences, University of Basel, 4031 Basel, Switzerland
    • Shuai Jiang - Max Planck Institute for Polymer Research, 55128 Mainz, Germany;  Orcidhttp://orcid.org/0000-0002-8639-3495
    • Shahed Behzadi - Max Planck Institute for Polymer Research, 55128 Mainz, Germany
    • Daniel Crespy - Max Planck Institute for Polymer Research, 55128 Mainz, Germany;  Department of Materials Science and Engineering, School of Molecular Science and Engineering, Vidyasirimedhi Institute of Science and Technology (VISTEC), Rayong 21210, Thailand
    • Katharina Landfester - Max Planck Institute for Polymer Research, 55128 Mainz, Germany
    • Sylvie Roke - Laboratory for Fundamental BioPhotonics, Institute of Bioengineering, School of Engineering, École Polytechnique Fédérale de Lausanne, 1015 Lausanne, Switzerland;  Institute of Materials Science and Engineering, School of Engineering, École Polytechnique Fédérale de Lausanne, 1015 Lausanne, Switzerland;  Lausanne Centre for Ultrafast Science, École Polytechnique Fédérale de Lausanne, 1015 Lausanne, Switzerland;  Orcidhttp://orcid.org/0000-0002-6062-7871
    • Claudia Lengerke - Department of Biomedicine, University Hospital Basel and University of Basel, 4031 Basel, Switzerland;  Division of Hematology, University Hospital Basel, 4031 Basel, Switzerland;  Present Address: (C.L.) Internal Medicine II, University Hospital Tübingen, 72076 Tübingen, Germany
  • Notes
    The authors declare the following competing financial interest(s): A patent application has been filed relating to aspects of the work described in this manuscript. Authors listed on the patent: P.P., A.Y.S., K.L., and D.C.

    This publication was previously submitted to a preprint server: Sonay, A. Y.; Yaganoglu, S.; Konantz, M.; Teulon, C.; Sieber, S.; Jiang, S.; Behzadi, S.; Crespy, D.; Landfester, K.; Roke, S.; Langerke, C.; Pantazis, P. Biodegradable Harmonophores for Targeted High-Resolution In Vivo Tumor Imaging. bioRxiv2019, 694760, https://www.biorxiv.org/content/10.1101/694760v1 (accessed 2021-02-02).

Acknowledgments

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We thank members of the Pantazis group for discussion and feedback. We thank W. P. Dempsey for feedback on the manuscript. We thank the Scientific Center for Optical and Electron Microscopy (ScopeM) for their help in imaging bioharmonophores. We also thank T. Weber of the Crystallography Laboratory of ETH Zurich for his help with the XRD analysis. We thank R. Klemke for kindly providing the MDA-MB-435-DsRed cell line. We thank M. Affolter and H. G. Belting for providing some of the zebrafish eggs. The Facility for Imaging by Light Microscopy (FILM) at Imperial College London is partially supported by funding from the Wellcome Trust (Grant No. 104931/Z/14/Z). This work was supported by the Swiss National Science Foundation (SNF Grant No. 31003A_144048), the European Union Seventh Framework Program (Marie Curie Career Integration Grant (CIG) No. 334552), and the Swiss National Center of Competence in Research (NCCR) “Nanoscale Science”, which were awarded to P.P. who is a Royal Society Wolfson Research Merit Award holder.

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    In order to assess the therapeutic potential of cell-based strategies, it is of paramount importance to elaborate and validate tools for monitoring the behavior of injected cells in terms of tissue dissemination and engraftment properties. Here, we apply bismuth ferrite harmonic nanoparticles (BFO HNPs) to in vitro expanded human skeletal muscle-derived stem cells (hMuStem cells), an attractive therapeutic avenue for patients suffering from Duchenne muscular dystrophy (DMD). We demonstrate the possibility of stem cell labeling with HNPs. We also show that the simultaneous acquisition of second- and third-harmonic generation (SHG and THG) from BFO HNPs helps sep. their response from tissue background, with a net increase in imaging selectivity, which could be particularly important in pathol. context that is defined by a highly remodelling tissue. We demonstrate the possibility of identifying <100 nm HNPs in depth of muscle tissue at more than 1 mm from the surface, taking full advantage of the extended imaging penetration depth allowed by multiphoton microscopy in the second near-IR window (NIR-II). Based on this successful assessment, we monitor over 14 days any modification on proliferation and morphol. features of hMuStem cells upon exposure to PEG-coated BFO HNPs at different concns., revealing their high biocompatibility. Successively, we succeed in detecting individual HNP-labeled hMuStem cells in skeletal muscle tissue after their i.m. injection.
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  10. 10
    Dempsey, W. P.; Fraser, S. E.; Pantazis, P. SHG Nanoprobes: Advancing Harmonic Imaging in Biology. BioEssays 2012, 34 (5), 351– 360,  DOI: 10.1002/bies.201100106
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    10
    SHG nanoprobes: Advancing harmonic imaging in biology
    Dempsey, William P.; Fraser, Scott E.; Pantazis, Periklis
    BioEssays (2012), 34 (5), 351-360CODEN: BIOEEJ; ISSN:0265-9247. (Wiley-Blackwell)
    A review. Second harmonic generating (SHG) nanoprobes have recently emerged as versatile and durable labels suitable for in vivo imaging, circumventing many of the inherent drawbacks encountered with classical fluorescent probes. Since their nanocryst. structure lacks a central point of symmetry, they are capable of generating second harmonic signal under intense illumination - converting two photons into one photon of half the incident wavelength - and can be detected by conventional two-photon microscopy. Because the optical signal of SHG nanoprobes is based on scattering, rather than absorption as in the case of fluorescent probes, they neither bleach nor blink, and the signal does not sat. with increasing illumination intensity. When SHG nanoprobes are used to image live tissue, the SHG signal can be detected with little background signal, and they are physiol. inert, showing excellent long-term photostability. Because of their photophys. properties, SHG nanoprobes provide unique advantages for mol. imaging of living cells and tissues with unmatched sensitivity and temporal resoln.
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  11. 11
    Magouroux, T.; Extermann, J.; Hoffmann, P.; Mugnier, Y.; Le Dantec, R.; Jaconi, M. E.; Kasparian, C.; Ciepielewski, D.; Bonacina, L.; Wolf, J.-P. High-Speed Tracking of Murine Cardiac Stem Cells by Harmonic Nanodoublers. Small 2012, 8 (17), 2752– 2756,  DOI: 10.1002/smll.201200366
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    11
    High-Speed Tracking of Murine Cardiac Stem Cells by Harmonic Nanodoublers
    Magouroux, Thibaud; Extermann, Jerome; Hoffmann, Pernilla; Mugnier, Yannick; Le Dantec, Ronan; Jaconi, Marisa E.; Kasparian, Christelle; Ciepielewski, Daniel; Bonacina, Luigi; Wolf, Jean-Pierre
    Small (2012), 8 (17), 2752-2756, S2752/1-S2752/2CODEN: SMALBC; ISSN:1613-6810. (Wiley-VCH Verlag GmbH & Co. KGaA)
    Potassium niobate nonlinear nanoparticles are used for the first time to monitor the evolution of embryonic stem cells (ESC) by second harmonic microscopy. These particles feature the complete absence of photo-bleaching and unlimited excitation wavelength flexibility. The potential of this approach is made evident for tissue-regeneration studies and applications, by capturing a high-speed movie of ESC-derived cardiomyocytes autonomously beating within a cluster. Time-resolved data are analyzed to retrieve 3D information of the contraction pattern at the cellular level.
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  12. 12
    Culic-Viskota, J.; Dempsey, W. P; Fraser, S. E; Pantazis, P. Surface Functionalization of Barium Titanate SHG Nanoprobes for in Vivo Imaging in Zebrafish. Nat. Protoc. 2012, 7 (9), 1618– 1633,  DOI: 10.1038/nprot.2012.087
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    12
    Surface functionalization of barium titanate SHG nanoprobes for in vivo imaging in zebrafish
    Culic-Viskota, Jelena; Dempsey, William P.; Fraser, Scott E.; Pantazis, Periklis
    Nature Protocols (2012), 7 (9), 1618-1633CODEN: NPARDW; ISSN:1750-2799. (Nature Publishing Group)
    To address the need for a bright, photostable labeling tool that allows long-term in vivo imaging in whole organisms, we recently introduced second harmonic generating (SHG) nanoprobes. Here we present a protocol for the prepn. and use of a particular SHG nanoprobe label, barium titanate (BT), for in vivo imaging in living zebrafish embryos. Chem. treatment of the BT nanoparticles results in surface coating with amine-terminal groups, which act as a platform for a variety of chem. modifications for biol. applications. Here we describe crosslinking of BT to a biotin-linked moiety using click chem. methods and coating of BT with nonreactive poly(ethylene glycol) (PEG). We also provide details for injecting PEG-coated SHG nanoprobes into zygote-stage zebrafish embryos, and in vivo imaging of SHG nanoprobes during gastrulation and segmentation. Implementing the PROCEDURE requires a basic understanding of laser-scanning microscopy, experience with handling zebrafish embryos and chem. lab. experience. Functionalization of the SHG nanoprobes takes ∼3 d, whereas zebrafish prepn., injection and imaging setup should take approx. 2-4 h.
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  13. 13
    Sugiyama, N.; Sonay, A. Y.; Tussiwand, R.; Cohen, B. E.; Pantazis, P. Effective Labeling of Primary Somatic Stem Cells with BaTiO3 Nanocrystals for Second Harmonic Generation Imaging. Small 2018, 14 (8), 1703386,  DOI: 10.1002/smll.201703386
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    Staedler, D.; Magouroux, T.; Hadji, R.; Joulaud, C.; Extermann, J.; Schwung, S.; Passemard, S.; Kasparian, C.; Clarke, G.; Gerrmann, M.; Le Dantec, R.; Mugnier, Y.; Rytz, D.; Ciepielewski, D.; Galez, C.; Gerber-Lemaire, S.; Juillerat-Jeanneret, L.; Bonacina, L.; Wolf, J.-P. Harmonic Nanocrystals for Biolabeling: A Survey of Optical Properties and Biocompatibility. ACS Nano 2012, 6 (3), 2542– 2549,  DOI: 10.1021/nn204990n
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    14
    Harmonic Nanocrystals for Biolabeling: A Survey of Optical Properties and Biocompatibility
    Staedler, Davide; Magouroux, Thibaud; Hadji, Rachid; Joulaud, Cecile; Extermann, Jerome; Schwung, Sebastian; Passemard, Solene; Kasparian, Christelle; Clarke, Gareth; Gerrmann, Mathias; Le Dantec, Ronan; Mugnier, Yannick; Rytz, Daniel; Ciepielewski, Daniel; Galez, Christine; Gerber-Lemaire, Sandrine; Juillerat-Jeanneret, Lucienne; Bonacina, Luigi; Wolf, Jean-Pierre
    ACS Nano (2012), 6 (3), 2542-2549CODEN: ANCAC3; ISSN:1936-0851. (American Chemical Society)
    Nonlinear optical nanocrystals have been recently introduced as a promising alternative to fluorescent probes for multiphoton microscopy. The authors present for the first time a complete survey of the properties of five nanomaterials (KNbO3, LiNbO3, BaTiO3, KTP, and ZnO), describing their prepn. and stabilization and providing quant. estns. of their nonlinear optical response. In the light of their prospective use as biol. and clin. markers, the authors assess their biocompatibility on human healthy and cancerous cell lines. Finally, the authors demonstrate the great potential for cell imaging of these inherently nonlinear probes in terms of optical contrast, wavelength flexibility, and signal photostability.
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  15. 15
    Lakshmanan, A.; Zhang, S.; Hauser, C. A. E. Short Self-Assembling Peptides as Building Blocks for Modern Nanodevices. Trends Biotechnol. 2012, 30 (3), 155– 165,  DOI: 10.1016/j.tibtech.2011.11.001
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    15
    Short self-assembling peptides as building blocks for modern nanodevices
    Lakshmanan, Anupama; Zhang, Shuguang; Hauser, Charlotte A. E.
    Trends in Biotechnology (2012), 30 (3), 155-165CODEN: TRBIDM; ISSN:0167-7799. (Elsevier Ltd.)
    A review. Short, self-assembling peptides form a variety of stable nanostructures used for the rational design of functional devices. Peptides serve as org. templates for conjugating biorecognition elements, and assembling ordered nanoparticle arrays and hybrid supramol. structures. We are witnessing the emergence of a new phase of bionanotechnol., particularly towards electronic, photonic and plasmonic applications. Recent advances include self-assembly of photoluminescent semiconducting nanowires and peptide-conjugated systems for sensing, catalysis and energy storage. Concurrently, methods and tools have been developed to control and manipulate the self-assembled nanostructures. Furthermore, there is growing knowledge on nanostructure properties such as piezoelectricity, dipolar elec. field and stability. This review focuses on the emerging role of short, linear self-assembling peptides as simple and versatile building blocks for nanodevices.
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  16. 16
    Kholkin, A.; Amdursky, N.; Bdikin, I.; Gazit, E.; Rosenman, G. Strong Piezoelectricity in Bioinspired Peptide Nanotubes. ACS Nano 2010, 4 (2), 610– 614,  DOI: 10.1021/nn901327v
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    16
    Strong Piezoelectricity in Bioinspired Peptide Nanotubes
    Kholkin, Andrei; Amdursky, Nadav; Bdikin, Igor; Gazit, Ehud; Rosenman, Gil
    ACS Nano (2010), 4 (2), 610-614CODEN: ANCAC3; ISSN:1936-0851. (American Chemical Society)
    We show anomalously strong shear piezoelec. activity in self-assembled diphenylalanine peptide nanotubes (PNTs), indicating elec. polarization directed along the tube axis. Comparison with well-known piezoelec. LiNbO3 and lateral signal calibration yields sufficiently high effective piezoelec. coeff. values of at least 60 pm/V (shear response for tubes of ≈200 nm in diam.). PNTs demonstrate linear deformation without irreversible degrdn. in a broad range of driving voltages. The results open up a wide avenue for developing new generations of "green" piezoelec. materials and piezonanodevices based on bioactive tubular nanostructures potentially compatible with human tissue.
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  17. 17
    Handelman, A.; Beker, P.; Amdursky, N.; Rosenman, G. Physics and Engineering of Peptide Supramolecular Nanostructures. Phys. Chem. Chem. Phys. 2012, 14 (18), 6391– 6408,  DOI: 10.1039/c2cp40157f
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    17
    Physics and engineering of peptide supramolecular nanostructures
    Handelman Amir; Beker Peter; Amdursky Nadav; Rosenman Gil
    Physical chemistry chemical physics : PCCP (2012), 14 (18), 6391-408 ISSN:.
    The emerging "bottom-up" nanotechnology reveals a new field of bioinspired nanomaterials composed of chemically synthesized biomolecules. They are formed from elementary constituents in supramolecular structures by the use of a developed nature self-assembly mechanism. The focus of this perspective paper is on intrinsic fundamental physical properties of bioinspired peptide nanostructures and their small building units linked by weak noncovalent bonds. The observed exceptional optical properties indicate a phenomenon of quantum confinement in these supramolecular structures, which originates from nanoscale size of their elementary building blocks. The dimensionality of the confinement gives insight into intrinsic packing of peptide supramolecular nanomaterials. QC regions, revealed in bioinspired nanostructures, were found by us in amyloid fibrils formed from insulin protein. We describe ferroelectric and related properties found at the nanoscale based on original crystalline asymmetry of the nanoscale building blocks, packing these structures. In this context, we reveal a classic solid state physics phenomenon such as reconstructive phase transition observed in bioorganic peptide nanotubes. This irreversible phase transformation leads to drastic reshaping of their quantum structure from quantum dots to quantum wells, which is followed by variation of their space group symmetry from asymmetric to symmetric. We show that the supramolecular origin of these bioinspired nanomaterials provides them a unique chance to be disassembled into elementary building block peptide nanodots of 1-2 nm size possessing unique electronic, optical and ferroelectric properties. These multifunctional nanounits could lead to a new future step in nanotechnology and nanoscale advanced devices in the fields of nanophotonics, nanobiomedicine, nanobiopiezotronics, etc.
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  18. 18
    Staff, R. H.; Schaeffel, D.; Turshatov, A.; Donadio, D.; Butt, H.-J.; Landfester, K.; Koynov, K.; Crespy, D. Particle Formation in the Emulsion-Solvent Evaporation Process. Small 2013, 9 (20), 3514– 3522,  DOI: 10.1002/smll.201300372
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    18
    Particle Formation in the Emulsion-Solvent Evaporation Process
    Staff, Roland H.; Schaeffel, David; Turshatov, Andrey; Donadio, Davide; Butt, Hans-Juergen; Landfester, Katharina; Koynov, Kaloian; Crespy, Daniel
    Small (2013), 9 (20), 3514-3522CODEN: SMALBC; ISSN:1613-6810. (Wiley-VCH Verlag GmbH & Co. KGaA)
    The mechanism of particle formation from submicrometer emulsion droplets by solvent evapn. is revisited. A combination of dynamic light scattering, fluorescence resonance energy transfer, zeta potential measurements, and fluorescence cross-correlation spectroscopy is used to analyze the colloids during the evapn. process. It is shown that a combination of different methods yields reliable and quant. data for describing the fate of the droplets during the process. The results indicate that coalescence plays a minor role during the process; the relatively large size distribution of the obtained polymer colloids can be explained by the droplet distribution after their formation.
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  19. 19
    Rabotyagova, O. S.; Cebe, P.; Kaplan, D. L. Role of Polyalanine Domains in β-Sheet Formation in Spider Silk Block Copolymers. Macromol. Biosci. 2010, 10 (1), 49– 59,  DOI: 10.1002/mabi.200900203
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    19
    Role of Polyalanine Domains in β-Sheet Formation in Spider Silk Block Copolymers
    Rabotyagova, Olena S.; Cebe, Peggy; Kaplan, David L.
    Macromolecular Bioscience (2010), 10 (1), 49-59CODEN: MBAIBU; ISSN:1616-5187. (Wiley-VCH Verlag GmbH & Co. KGaA)
    Genetically engineered spider silk-like block copolymers were studied to det. the influence of polyalanine domain size on secondary structure. The role of polyalanine block distribution on β-sheet formation was explored using FT-IR and WAXS. The no. of polyalanine blocks had a direct effect on the formation of cryst. β-sheets, reflected in the change in crystallinity index as the blocks of polyalanines increased. WAXS anal. confirmed the cryst. nature of the sample with the largest no. of polyalanine blocks. This approach provides a platform for further exploration of the role of specific amino acid chemistries in regulating the assembly of β-sheet secondary structures, leading to options to regulate material properties through manipulation of this key component in spider silks.
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  20. 20
    Handelman, A.; Kuritz, N.; Natan, A.; Rosenman, G. Reconstructive Phase Transition in Ultrashort Peptide Nanostructures and Induced Visible Photoluminescence. Langmuir 2016, 32 (12), 2847– 2862,  DOI: 10.1021/acs.langmuir.5b02784
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    20
    Reconstructive Phase Transition in Ultrashort Peptide Nanostructures and Induced Visible Photoluminescence
    Handelman, Amir; Kuritz, Natalia; Natan, Amir; Rosenman, Gil
    Langmuir (2016), 32 (12), 2847-2862CODEN: LANGD5; ISSN:0743-7463. (American Chemical Society)
    A reconstructive phase transition has been found and studied in ultrashort di- and tripeptide nanostructures, self-assembled from biomols. of different compns. and origin such as arom., aliph., linear, and cyclic (linear FF-diphenylalanine, linear LL-dileucine, FFF-triphenylalanine, and cyclic FF-diphenylalanine). The native linear arom. FF, FFF and aliph. LL peptide nanoensembles of various shapes (nanotubes and nanospheres) have asym. elementary structure and demonstrate nonlinear optical and piezoelec. effects. At elevated temp., 140-180 °C, these native supramol. structures (except for native Cyc-FF nanofibers) undergo an irreversible thermally induced transformation via reassembling into a completely new thermodynamically stable phase having nanowire morphol. similar to those of amyloid fibrils. This reconstruction process is followed by deep and similar modification at all levels: macroscopic (morphol.), mol., peptide secondary, and electronic structures. However, original Cyc-FF nanofibers preserve their native phys. properties. The self-fabricated supramol. fibrillar ensembles exhibit the FTIR and CD signatures of new antiparallel β-sheet secondary folding with intermol. hydrogen bonds and centrosym. structure. In this phase, the β-sheet nanofibers, irresp. of their native biomol. origin, do not reveal nonlinear optical and piezoelec. effects, but do exhibit similar profound modification of optoelectronic properties followed by the appearance of visible (blue and green) photoluminescence (PL), which is not obsd. in the original peptides and their native nanostructures. The obsd. visible PL effect, ascribed to hydrogen bonds of thermally induced β-sheet secondary structures, has the same phys. origin as that of the fluorescence found recently in amyloid fibrils and can be considered to be an optical signature of β-sheet structures in both biol. and bioinspired materials. Such PL centers represent a new class of self-assembled dyes and can be used as intrinsic optical labels in biomedical microscopy as well as for a new generation of novel optoelectronic nanomaterials for emerging nanophotonic applications, such as biolasers, biocompatible markers, and integrated optics.
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    Handelman, A.; Lavrov, S.; Kudryavtsev, A.; Khatchatouriants, A.; Rosenberg, Y.; Mishina, E.; Rosenman, G. Nonlinear Optical Bioinspired Peptide Nanostructures. Adv. Opt. Mater. 2013, 1 (11), 875– 884,  DOI: 10.1002/adom.201300282
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    de Beer, A. G. F.; de Aguiar, H. B.; Nijsen, J. F. W.; Roke, S. Detection of Buried Microstructures by Nonlinear Light Scattering Spectroscopy. Phys. Rev. Lett. 2009, 102 (9), 095502,  DOI: 10.1103/PhysRevLett.102.095502
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    Detection of Buried Microstructures by Nonlinear Light Scattering Spectroscopy
    de Beer, A. G. F.; de Aguiar, H. B.; Nijsen, J. F. W.; Roke, S.
    Physical Review Letters (2009), 102 (9), 095502/1-095502/4CODEN: PRLTAO; ISSN:0031-9007. (American Physical Society)
    Many processes in chem. and physics rely on the structure, growth or change of material buried in solids. The impenetrable surrounding medium often prohibits the study of such material in situ. Nonlinear light scattering can be used to observe the internal structure of a cryst. state embedded inside another solid state. Vibrational sum frequency scattering patterns of polymer microspheres, consisting of both amorphous and cryst. material, reveal the size of the buried microstructure and the optical components of the 2nd-order susceptibility of the material. The vibrational spectra reveal the mol. structure.
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    Roke, S.; Gonella, G. Nonlinear Light Scattering and Spectroscopy of Particles and Droplets in Liquids. Annu. Rev. Phys. Chem. 2012, 63 (1), 353– 378,  DOI: 10.1146/annurev-physchem-032511-143748
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    23
    Nonlinear light scattering and spectroscopy of particles and droplets in liquids
    Roke, Sylvie; Gonella, Grazia
    Annual Review of Physical Chemistry (2012), 63 (), 353-378CODEN: ARPLAP; ISSN:0066-426X. (Annual Reviews Inc.)
    A review. Nano- and microparticles have optical, structural, and chem. properties that differ from both their building blocks and the bulk materials themselves. These different phys. and chem. properties are induced by the high surface-to-vol. ratio. As a logical consequence, to understand the properties of nano- and microparticles, it is of fundamental importance to characterize the particle surfaces and their interactions with the surrounding medium. Recent developments of nonlinear light scattering techniques have resulted in a deeper insight of the underlying light-matter interactions. They have shed new light on the mol. mechanism of surface kinetics in soln., properties of interfacial water in contact with hydrophilic and hydrophobic particles and droplets, mol. orientation distribution of mols. at particle surfaces in soln., interfacial structure of surfactants at droplet interfaces, acid-base chem. on particles in soln., and vesicle structure and transport properties.
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    Tsuji, H.; Ogiwara, M.; Saha, S. K.; Sakaki, T. Enzymatic, Alkaline, and Autocatalytic Degradation of Poly-L-Lactic Acid: Effects of Biaxial Orientation. Biomacromolecules 2006, 7 (1), 380– 387,  DOI: 10.1021/bm0507453
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    24
    Enzymatic, Alkaline, and Autocatalytic Degradation of Poly(L-lactic acid): Effects of Biaxial Orientation
    Tsuji, Hideto; Ogiwara, Miyuki; Saha, Swapan Kumar; Sakaki, Takuya
    Biomacromolecules (2006), 7 (1), 380-387CODEN: BOMAF6; ISSN:1525-7797. (American Chemical Society)
    The hydrolytic degrdn. of biaxially oriented and de-oriented (melt-crystd.) poly(L-lactic acid) (PLLA) films was investigated in Tris-HCl-buffered soln. (pH 8.6) with proteinase K, alk. soln., and phosphate-buffered soln. (pH 7.4) by the use of gravimetry, gel permeation chromatog., differential scanning calorimetry, and SEM. Biaxial orientation disturbed the proteinase K-catalyzed enzymic degrdn. of PLLA films and the effects of biaxial orientation overcame those of crystallinity. The former may be due to the fact the enzyme cannot attach to the extended (strained) chains in the amorphous regions of the biaxially oriented PLLA film or cannot catalyze the cleavage of the strained chains. Another probable cause is that the enzyme can act only at the film surface of the biaxially oriented PLLA film, in marked contrast with the case of the de-oriented PLLA films where enzymic degrdn. can proceed beneath the spherulitic cryst. residues. The effects of biaxial orientation on the alk. and autocatalytic degrdn. of the PLLA films were insignificant for the periods studied here. The crystallinity rather than the biaxial orientation seems to det. the alk. and autocatalytic degrdn. rates of the PLLA films. The accumulation of cryst. residues formed as a result of selective cleavage and removal of the amorphous chains was obsd. for the de-oriented PLLA films, but not for the biaxially oriented PLLA film, when degraded in the presence of proteinase K. This means the facile release of formed cryst. residues from the surface of the biaxially oriented PLLA film during enzymic degrdn., due to the fact that the cryst. regions of the biaxially oriented PLLA film were oriented with their c axis parallel to the film surface.
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    Sepp, R.; Szabo, I.; Uda, H.; Sakamoto, H. Rapid Techniques for DNA Extraction from Routinely Processed Archival Tissue for Use in PCR. J. Clin. Pathol. 1994, 47 (4), 318– 323,  DOI: 10.1136/jcp.47.4.318
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    25
    Rapid techniques for DNA extraction from routinely processed archival tissue for use in PCR
    Sepp R; Szabo I; Uda H; Sakamoto H
    Journal of clinical pathology (1994), 47 (4), 318-23 ISSN:0021-9746.
    AIMS: To evaluate the ability of four rapid DNA extraction methods to provide DNA for the polymerase chain reaction (PCR) from routinely fixed, paraffin wax embedded archival tissues. METHODS: Eighteen blocks of various tissues, 18 blocks of cervical cancer specimens, and nine blocks of B cell lymphomas were investigated. Both normal and biopsy specimen sized tissues were studied. DNA was extracted using four methods: boiling for 20 minutes in distilled water; boiling for 20 minutes in 5% Chelex-100 resin solution; 3-hour proteinase K digestion; and 3-hour proteinase K digestion, followed by boiling in 5% Chelex-100. Different exons of the p53 gene, human papillomavirus type 16 (HPV 16) sequence, and immunoglobulin heavy chain (IgH) gene rearrangement were amplified from the extracts. RESULTS: The Chelex boiling, proteinase K digestion, and proteinase K digestion-Chelex boiling methods produced DNA suitable for amplification in all of the 45 samples. Boiling in water yielded insufficient template for the PCR in three of the 45 cases (7%), and in six of 42 positive cases (14%) much fainter bands were observed, mostly when the processed material was either biopsy specimen sized or a B cell lymphoma sample. Fragments of the p53 gene were successfully amplified up to 408 base pairs in water boiled extracts, up to 647 in Chelex boiled preparates, and up to 984 in proteinase K digested and proteinase K digested-Chelex boiled samples, although with decreased sensitivity in the last case. All of the templates were reusable after 3 months of storage at -20 degrees C. CONCLUSIONS: Chelex boiling, proteinase K digestion, and proteinase K digestion followed by Chelex boiling produce suitable templates for the PCR from a large variety of paraffin wax embedded tissues. As the simple 20 minute boiling method in 5% Chelex-100 solution requires minimal manipulation and time, it could be useful, especially in the routine processing of large amounts of material.
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  26. 26
    Lewin, M.; Carlesso, N.; Tung, C.-H.; Tang, X.-W.; Cory, D.; Scadden, D. T.; Weissleder, R. Tat Peptide-Derivatized Magnetic Nanoparticles Allow in Vivo Tracking and Recovery of Progenitor Cells. Nat. Biotechnol. 2000, 18 (4), 410– 414,  DOI: 10.1038/74464
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    Tat peptide-derivatized magnetic nanoparticles allow in vivo tracking and recovery of progenitor cells
    Lewin, Maite; Carlesso, Nadia; Tung, Ching-Hsuan; Tang, Xiao-Wu; Cory, David; Scadden, David T.; Weissleder, Ralph
    Nature Biotechnology (2000), 18 (4), 410-414CODEN: NABIF9; ISSN:1087-0156. (Nature America)
    The ability to track the distribution and differentiation of progenitor and stem cells by high-resoln. in vivo imaging techniques would have significant clin. and research implications. We have developed a cell labeling approach using short HIV-Tat peptides to derivatize superparamagnetic nanoparticles. The particles are efficiently internalized into hematopoietic and neural progenitor cells in quantities up to 10-30 pg of superparamagnetic iron per cell. Iron incorporation did not affect cell viability, differentiation, or proliferation of CD34+ cells. Following i.v. injection into immunodeficient mice, 4% of magnetically CD34+ cells homed to bone marrow per g of tissue, and single cells could be detected by magnetic resonance (MR) imaging in tissue samples. In addn., magnetically labeled cells that had homed to bone marrow could be recovered by magnetic sepn. columns. Localization and retrieval of cell populations in vivo enable detailed anal. of specific stem cell and organ interactions crit. for advancing the therapeutic use of stem cells.
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    Nguyen, H.; Gitig, D. M.; Koff, A. Cell-Free Degradation of p27 kip1, a G1 Cyclin-Dependent Kinase Inhibitor, Is Dependent on CDK2 Activity and the Proteasome. Mol. Cell. Biol. 1999, 19 (2), 1190– 1201,  DOI: 10.1128/MCB.19.2.1190
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    Cell-free degradation of p27kip1, a G1 cyclin-dependent kinase inhibitor, is dependent on CDK2 activity and the proteasome
    Nguyen, Hoang; Gitig, Diana M.; Koff, Andrew
    Molecular and Cellular Biology (1999), 19 (2), 1190-1201CODEN: MCEBD4; ISSN:0270-7306. (American Society for Microbiology)
    Entry into S phase is dependent on the coordinated activation of CDK4,6 and CDK2 kinases. Once a cell commits to S phase, there must be a mechanism to ensure the irreversibility of this decision. The activity of these kinases is inhibited by their assocn. with p27. In many cells, p27 plays a major role in the withdrawal from the cell cycle in response to environmental cues. Thus, it is likely that p27 is a target of the machinery required to ensure the irreversibility of S-phase entry. We have been interested in understanding the mechanisms regulating p27 at the G1/S transition. In this report, we define a cell-free degrdn. system which faithfully recapitulates the cell cycle phase-specific degrdn. of p27. We show that this reaction is dependent on active CDK2 activity, suggesting that CDK2 activity is directly required for p27 degrdn. In addn. to CDK2, other S-phase-specific factors are required for p27 degrdn. At least some of these factors are ubiquitin and proteasome dependent. We discuss the relationships between CDK2 activity, ubiquitin-dependent, and possibly ubiquitin-independent proteasomal activities in S-phase exts. as related to p27.
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    Lee, H.-J.; Shin, S. Y.; Choi, C.; Lee, Y. H.; Lee, S.-J. Formation and Removal of Alpha-Synuclein Aggregates in Cells Exposed to Mitochondrial Inhibitors. J. Biol. Chem. 2002, 277 (7), 5411– 5417,  DOI: 10.1074/jbc.M105326200
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    Formation and removal of α-synuclein aggregates in cells exposed to mitochondrial inhibitors
    Lee, He-Jin; Shin, Soon Young; Choi, Chan; Lee, Young Han; Lee, Seung-Jae
    Journal of Biological Chemistry (2002), 277 (7), 5411-5417CODEN: JBCHA3; ISSN:0021-9258. (American Society for Biochemistry and Molecular Biology)
    Mitochondrial dysfunction has been assocd. with Parkinson's disease. However, the role of mitochondrial defects in the formation of Lewy bodies, a pathol. hallmark of Parkinson's disease has not been addressed directly. In this report, we investigated the effects of inhibitors of the mitochondrial electron-transport chain on the aggregation of α-synuclein, a major protein component of Lewy bodies. Treatment with rotenone, an inhibitor of complex I, resulted in an increase of detergent-resistant α-synuclein aggregates and a redn. in ATP level. Another inhibitor of the electron-transport chain, oligomycin, also showed temporal correlation between the formation of aggregates and ATP redn. Microscopic analyses showed a progressive evolution of small aggregates of α-synuclein to a large perinuclear inclusion body. The inclusions were co-stained with ubiquitin, 20 S proteasome, γ-tubulin, and vimentin. The perinuclear inclusion bodies, but not the small cytoplasmic aggregates, were thioflavin S-pos., suggesting the amyloid-like conformation. Interestingly, the aggregates disappeared when the cells were replenished with inhibitor-free medium. Disappearance of aggregates coincided with the recovery of mitochondrial metab. and was partially inhibited by proteasome inhibitors. These results suggest that the formation of α-synuclein inclusions could be initiated by an impaired mitochondrial function and be reversed by restoring normal mitochondrial metab.
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    Konantz, M.; Balci, T. B.; Hartwig, U. F.; Dellaire, G.; André, M. C.; Berman, J. N.; Lengerke, C. Zebrafish Xenografts as a Tool for in Vivo Studies on Human Cancer. Ann. N. Y. Acad. Sci. 2012, 1266 (1), 124– 137,  DOI: 10.1111/j.1749-6632.2012.06575.x
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    Zebrafish xenografts as a tool for in vivo studies on human cancer
    Konantz Martina; Balci Tugce B; Hartwig Udo F; Dellaire Graham; Andre Maya C; Berman Jason N; Lengerke Claudia
    Annals of the New York Academy of Sciences (2012), 1266 (), 124-37 ISSN:.
    The zebrafish has become a powerful vertebrate model for genetic studies of embryonic development and organogenesis and increasingly for studies in cancer biology. Zebrafish facilitate the performance of reverse and forward genetic approaches, including mutagenesis and small molecule screens. Moreover, several studies report the feasibility of xenotransplanting human cells into zebrafish embryos and adult fish. This model provides a unique opportunity to monitor tumor-induced angiogenesis, invasiveness, and response to a range of treatments in vivo and in real time. Despite the high conservation of gene function between fish and humans, concern remains that potential differences in zebrafish tissue niches and/or missing microenvironmental cues could limit the relevance and translational utility of data obtained from zebrafish human cancer cell xenograft models. Here, we summarize current data on xenotransplantation of human cells into zebrafish, highlighting the advantages and limitations of this model in comparison to classical murine models of xenotransplantation.
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    Stoletov, K.; Kato, H.; Zardouzian, E.; Kelber, J.; Yang, J.; Shattil, S.; Klemke, R. Visualizing Extravasation Dynamics of Metastatic Tumor Cells. J. Cell Sci. 2010, 123 (13), 2332– 2341,  DOI: 10.1242/jcs.069443
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    Visualizing extravasation dynamics of metastatic tumor cells
    Stoletov, Konstantin; Kato, Hisashi; Zardouzian, Erin; Kelber, Jonathan; Yang, Jing; Shattil, Sanford; Klemke, Richard
    Journal of Cell Science (2010), 123 (13), 2332-2341CODEN: JNCSAI; ISSN:0021-9533. (Company of Biologists Ltd.)
    Little is known about how metastatic cancer cells arrest in small capillaries and traverse the vascular wall during extravasation in vivo. Using real-time intravital imaging of human tumor cells transplanted into transparent zebrafish, we show here that extravasation of cancer cells is a highly dynamic process that involves the modulation of tumor cell adhesion to the endothelium and intravascular cell migration along the luminal surface of the vascular wall. Tumor cells do not damage or induce vascular leak at the site of extravasation, but rather induce local vessel remodeling characterized by clustering of endothelial cells and cell-cell junctions. Intravascular locomotion of tumor cells is independent of the direction of blood flow and requires β1-integrin-mediated adhesion to the blood-vessel wall. Interestingly, the expression of the pro-metastatic gene Twist in tumor cells increases their intravascular migration and extravasation through the vessel wall. However, in this case, Twist expression causes the tumor cells to switch to a β1-integrin-independent mode of extravasation that is assocd. with the formation of large dynamic rounded membrane protrusions. Our results demonstrate that extravasation of tumor cells is a highly dynamic process influenced by metastatic genes that target adhesion and intravascular migration of tumor cells, and induce endothelial remodeling.
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    Stoletov, K.; Montel, V.; Lester, R. D.; Gonias, S. L.; Klemke, R. High-Resolution Imaging of the Dynamic Tumor Cell-Vascular Interface in Transparent Zebrafish. Proc. Natl. Acad. Sci. U. S. A. 2007, 104 (44), 17406– 17411,  DOI: 10.1073/pnas.0703446104
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    High-resolution imaging of the dynamic tumor cell-vascular interface in transparent zebrafish
    Stoletov, Konstantin; Montel, Valerie; Lester, Robin D.; Gonias, Steven L.; Klemke, Richard
    Proceedings of the National Academy of Sciences of the United States of America (2007), 104 (44), 17406-17411CODEN: PNASA6; ISSN:0027-8424. (National Academy of Sciences)
    Cell metastasis is a highly dynamic process that occurs in multiple steps. Understanding this process has been limited by the inability to visualize tumor cell behavior in real time by using animal models. Here, we employ translucent zebrafish and high-resoln. confocal microscopy to study how human cancer cells invade in tissues, induce angiogenesis, and interact with newly formed vessels. We use this system to study how the human metastatic gene RhoC promotes the initial steps of metastasis. We find that RhoC expression induces a primitive amoeboid-like cell invasion characterized by the formation of dynamic membrane protrusions and blebs. Surprisingly, these structures penetrate the blood vessel wall exclusively at sites of vascular remodeling and not at regions of existing intact vessels. This process requires tumor cells to secrete VEGF, which induces vascular openings, which in turn, serve as portholes allowing access of RhoC-expressing cells to the blood system. Our results support a model in which the early steps in intravasation and metastasis require two independent events: (i) dynamic regulation of the actin/myosin cytoskeleton within the tumor cell to form protrusive structures and (ii) vascular permeabilization and vessel remodeling. The integration of zebrafish transgenic technol. with human cancer biol. may aid in the development of cancer models that target specific organs, tissues, or cell types within the tumors. Zebrafish could also provide a cost-effective means for the rapid development of therapeutic agents directed at blocking human cancer progression and tumor-induced angiogenesis.
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    Agemy, L.; Kotamraju, V. R.; Friedmann-Morvinski, D.; Sharma, S.; Sugahara, K. N.; Ruoslahti, E. Proapoptotic Peptide-Mediated Cancer Therapy Targeted to Cell Surface p32. Mol. Ther. 2013, 21 (12), 2195– 2204,  DOI: 10.1038/mt.2013.191
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    Proapoptotic Peptide-Mediated Cancer Therapy Targeted to Cell Surface p32
    Agemy, Lilach; Kotamraju, Venkata R.; Friedmann-Morvinski, Dinorah; Sharma, Shweta; Sugahara, Kazuki N.; Ruoslahti, Erkki
    Molecular Therapy (2013), 21 (12), 2195-2204CODEN: MTOHCK; ISSN:1525-0016. (Nature Publishing Group)
    Antiangiogenic therapy is a promising new treatment modality for cancer, but it generally produces only transient tumor regression. We have previously devised a tumor-targeted nanosystem, in which a pentapeptide, CGKRK, delivers a proapoptotic peptide into the mitochondria of tumor blood vessel endothelial cells and tumor cells. The treatment was highly effective in glioblastoma mouse models completely refractory to other antiangiogenic treatments. Here, we identify p32/gC1qR/HABP, a mitochondrial protein that is also expressed at the cell surface of activated (angiogenic) endothelial cells and tumor cells, as a receptor for the CGKRK peptide. The results demonstrate the ability of p32 to cause internalization of a payload bound to p32 into the cytoplasm. We also show that nardilysin, a protease capable of cleaving CGKRK, plays a role in the internalization of a p32-bound payload. As p32 is overexpressed and surface displayed in breast cancers, we studied the efficacy of the nanosystem in this cancer. We show highly significant treatment results in an orthotopic model of breast cancer. The specificity of cell surface p32 for tumor-assocd. cells, its ability to carry payloads to mitochondria, and the efficacy of the system in important types of cancer make the nanosystem a promising candidate for further development.
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    LeBert, D. C.; Squirrell, J. M.; Huttenlocher, A.; Eliceiri, K. W. Second Harmonic Generation Microscopy in Zebrafish. Methods Cell Biol. 2016, 133, 55– 68,  DOI: 10.1016/bs.mcb.2016.01.005
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    Second harmonic generation microscopy in zebrafish
    LeBert, D. C.; Squirrell, J. M.; Huttenlocher, A.; Eliceiri, K. W.
    Methods in Cell Biology (2016), 133 (Zebrafish: Cellular and Developmental Biology, Part A), 55-68CODEN: MCBLAG; ISSN:0091-679X. (Elsevier Inc.)
    Modem optical imaging has progressed rapidly with the ability to noninvasively image cellular and subcellular phenomena with high spatial and temporal resoln. In particular, emerging techniques such as second harmonic generation (SHG) microscopy can allow for the monitoring of intrinsic contrast, such as that from collagen, in live and fixed samples. When coupled with multiphoton fluorescence microscopy, SHG can be used to image interactions between cells and the surrounding extracellular environment. There is recent interest in using these approaches to study inflammation and wound healing in zebrafish, an important model for studying these processes. In this chapter we present the practical aspects of using second harmonic generation to image interactions between leukocytes and collagen during wound healing in zebrafish.
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    Nakamura, Y.; Mochida, A.; Choyke, P. L.; Kobayashi, H. Nanodrug Delivery: Is the Enhanced Permeability and Retention Effect Sufficient for Curing Cancer?. Bioconjugate Chem. 2016, 27 (10), 2225– 2238,  DOI: 10.1021/acs.bioconjchem.6b00437
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    Nanodrug Delivery: Is the Enhanced Permeability and Retention Effect Sufficient for Curing Cancer?
    Nakamura, Yuko; Mochida, Ai; Choyke, Peter L.; Kobayashi, Hisataka
    Bioconjugate Chemistry (2016), 27 (10), 2225-2238CODEN: BCCHES; ISSN:1043-1802. (American Chemical Society)
    A review. Nanotechnol. offers several attractive design features that have prompted its exploration for cancer diagnosis and treatment. Nano-sized drugs have a large loading capacity, the ability to protect the payload from degrdn., a large surface on which to conjugate targeting ligands and controlled or sustained release. Nano-sized drugs also leak preferentially into tumor tissue through permeable tumor vessels and are then retained in the tumor bed due to reduced lymphatic drainage. This process is known as 'the enhanced permeability and retention (EPR) effect'. However, while the EPR effect is widely held to improve delivery of nano-drugs to tumors, it in fact offers less than a 2-fold increase in nano-drug delivery compared with crit. normal organs, resulting in drug concns. that are not sufficient for curing most of cancers. In this review, we first overview various barriers for nano-sized drug delivery with an emphasis on the capillary wall's resistance, the main obstacle to delivering drugs. Then, we discuss current regulatory issues facing nanomedicine. Finally, we discuss how to make the delivery of nano-sized drugs to tumors more effective by building on the EPR effect.
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    Jain, R. K.; Stylianopoulos, T. Delivering Nanomedicine to Solid Tumors. Nat. Rev. Clin. Oncol. 2010, 7 (11), 653– 664,  DOI: 10.1038/nrclinonc.2010.139
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    Delivering nanomedicine to solid tumors
    Jain, Rakesh K.; Stylianopoulos, Triantafyllos
    Nature Reviews Clinical Oncology (2010), 7 (11), 653-664CODEN: NRCOAA; ISSN:1759-4774. (Nature Publishing Group)
    A review. Nanotechnol. offers great promise for the detection, prevention and treatment of cancer. Current limitations of this technol. include the heterogeneous distribution of nanoparticles to tumors, caused in part by the physiol. barriers presented by the abnormal tumor vasculature and interstitial matrix. This Review discusses these barriers and summarizes strategies that have been developed to overcome them. It addnl. examines design considerations for the optimization of delivery of nanoparticles to tumors. Recent advances in nanotechnol. have offered new hope for cancer detection, prevention, and treatment. While the enhanced permeability and retention effect has served as a key rationale for using nanoparticles to treat solid tumors, it does not enable uniform delivery of these particles to all regions of tumors in sufficient quantities. This heterogeneous distribution of therapeutics is a result of physiol. barriers presented by the abnormal tumor vasculature and interstitial matrix. These barriers are likely to be responsible for the modest survival benefit offered by many FDA-approved nanotherapeutics and must be overcome for the promise of nanomedicine in patients to be realized. Here, we review these barriers to the delivery of cancer therapeutics and summarize strategies that have been developed to overcome these barriers. Finally, we discuss design considerations for optimizing the delivery of nanoparticles to tumors.
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    Schädlich, A.; Caysa, H.; Mueller, T.; Tenambergen, F.; Rose, C.; Göpferich, A.; Kuntsche, J.; Mäder, K. Tumor Accumulation of NIR Fluorescent PEG-PLA Nanoparticles: Impact of Particle Size and Human Xenograft Tumor Model. ACS Nano 2011, 5 (11), 8710– 8720,  DOI: 10.1021/nn2026353
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    Tumor Accumulation of NIR Fluorescent PEG-PLA Nanoparticles: Impact of Particle Size and Human Xenograft Tumor Model
    Schadlich, Andreas; Caysa, Henrike; Mueller, Thomas; Tenambergen, Frederike; Rose, Cornelia; Gopferich, Achim; Kuntsche, Judith; Mader, Karsten
    ACS Nano (2011), 5 (11), 8710-8720CODEN: ANCAC3; ISSN:1936-0851. (American Chemical Society)
    Cancer therapies are often terminated due to serious side effects of the drugs. The cause is the nonspecific distribution of chemotherapeutic agents to both cancerous and normal cells. Therefore, drug carriers which deliver their toxic cargo specific to cancer cells are needed. Size is one key parameter for the nanoparticle accumulation in tumor tissues. In the present study the influence of the size of biodegradable nanoparticles was investigated in detail, combining in vivo and ex vivo anal. with comprehensive particle size characterizations. Polyethylene glycol-polyesters poly(lactide) block polymers were synthesized and used for the prodn. of three defined, stable, and nontoxic near-IR (NIR) dye-loaded nanoparticle batches. Size anal. based on asym. field flow field fractionation coupled with multiangle laser light scattering and photon correlation spectroscopy (PCS) revealed narrow size distribution and permitted accurate size evaluations. Furthermore, this study demonstrates the constraints of particle size data only obtained by PCS. By the multispectral anal. of the Maestro in vivo imaging system the in vivo fate of the nanoparticles next to their accumulation in special red fluorescent DsRed2 expressing HT29 xenografts could be followed. This simultaneous imaging in addn. to confocal microscopy studies revealed information about the accumulation characteristics of nanoparticles inside the tumor tissues. This knowledge was further combined with extended size-dependent fluorescence imaging studies at two different xenograft tumor types, the HT29 (colorectal carcinoma) and the A2780 (ovarian carcinoma) cell lines. The combination of two different size measurement methods allowed the characterization of the dependence of nanoparticle accumulation in the tumor on even rather small differences in the nanoparticle size. While two nanoparticle batches (111 and 141 nm in diam.) accumulated efficiently in the human xenograft tumor tissue, the slightly bigger nanoparticles (diam. 166 nm) were rapidly eliminated by the liver.
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    Perry, J. L.; Reuter, K. G.; Luft, J. C.; Pecot, C. V.; Zamboni, W.; DeSimone, J. M. Mediating Passive Tumor Accumulation through Particle Size, Tumor Type, and Location. Nano Lett. 2017, 17 (5), 2879– 2886,  DOI: 10.1021/acs.nanolett.7b00021
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    Mediating Passive Tumor Accumulation through Particle Size, Tumor Type, and Location
    Perry, Jillian L.; Reuter, Kevin G.; Luft, J. Christopher; Pecot, Chad V.; Zamboni, William; DeSimone, Joseph M.
    Nano Letters (2017), 17 (5), 2879-2886CODEN: NALEFD; ISSN:1530-6984. (American Chemical Society)
    As the enhanced permeation and retention (EPR) effect continues to be a controversial topic in nanomedicine, we sought to examine EPR as a function of nanoparticle size, tumor model, and tumor location, while also evaluating tumors for EPR mediating factors such as microvessel d., vascular permeability, lymphatics, stromal content, and tumor-assocd. immune cells. Tumor accumulation was evaluated for 55 × 60, 80 × 180, and 80 × 320 nm PRINT particles in four s.c. flank tumor models (SKOV3 human ovarian, 344SQ murine nonsmall cell lung, A549 human nonsmall cell lung, and A431 human epidermoid cancer). Each tumor model revealed specific particle accumulation trends with evident particle size dependence. Immuno-histochem. staining revealed differences in tumor microvessel densities that correlated with overall tumor accumulation. Immunofluorescence images displayed size-mediated tumor penetration with signal from the larger particles concd. close to the blood vessels, while signal from the smaller particle was obsd. throughout the tissue. Differences were also obsd. for the 55 × 60 nm particle tumor penetration across flank tumor models as a function of stromal content. The 55 × 60 nm particles were further evaluated in three orthotopic, metastatic tumor models (344SQ, A549, and SKOV3), revealing preferential accumulation in primary tumors and metastases over healthy tissue. Moreover, we obsd. higher tumor accumulation in the orthotopic lung cancer models than in the flank lung cancer models, whereas tumor accumulation was const. for both orthotopic and flank ovarian cancer models, further demonstrating the variability in the EPR effect as a function of tumor model and location.
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    Zhou, Z.; Lu, Z.-R. Molecular Imaging of the Tumor Microenvironment. Adv. Drug Delivery Rev. 2017, 113, 24– 48,  DOI: 10.1016/j.addr.2016.07.012
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    Molecular imaging of the tumor microenvironment
    Zhou, Zhuxian; Lu, Zheng-Rong
    Advanced Drug Delivery Reviews (2017), 113 (), 24-48CODEN: ADDREP; ISSN:0169-409X. (Elsevier B.V.)
    The tumor microenvironment plays a crit. role in tumor initiation, progression, metastasis, and resistance to therapy. It is different from normal tissue in the extracellular matrix, vascular and lymphatic networks, as well as physiol. conditions. Mol. imaging of the tumor microenvironment provides a better understanding of its function in cancer biol., and thus allowing for the design of new diagnostics and therapeutics for early cancer diagnosis and treatment. The clin. translation of cancer mol. imaging is often hampered by the high cost of commercialization of targeted imaging agents as well as the limited clin. applications and small market size of some of the agents. Because many different cancer types share similar tumor microenvironment features, the ability to target these biomarkers has the potential to provide clin. translatable mol. imaging technologies for a spectrum of cancers and broad clin. applications. There has been significant progress in targeting the tumor microenvironment for cancer mol. imaging. In this review, we summarize the principles and strategies of recent advances made in mol. imaging of the tumor microenvironment, using various imaging modalities for early detection and diagnosis of cancer.
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    König, K.; Ehlers, A.; Riemann, I.; Schenkl, S.; Bückle, R.; Kaatz, M. Clinical Two-Photon Microendoscopy. Microsc. Res. Tech. 2007, 70 (5), 398– 402,  DOI: 10.1002/jemt.20445
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    Clinical two-photon microendoscopy
    Konig K; Ehlers A; Riemann I; Schenkl S; Buckle R; Kaatz M
    Microscopy research and technique (2007), 70 (5), 398-402 ISSN:1059-910X.
    Two-photon medical imaging has found its way into dermatology as an excellent method for noninvasive skin cancer detection without need of contrast agents as well as for in situ drug screening of topically-applied cosmetical and pharmaceutical components. There is an increasing demand to apply the multiphoton technology also for deep-tissue skin imaging as well as for intracorporal imaging. We report on the first clinical use of multiphoton endoscopes, in particular of a miniaturized rigid two-photon GRIN lens endoscope. The microendoscope was attached to the multiphoton tomograph DermaInspect and employed to detect the extracellular matrix proteins collagen and elastin in the human dermis of volunteers and patients with ulcera by in vivo second harmonic generation and in vivo two-photon autofluorescence.
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    Nature Photonics (2014), 8 (6), 455-461CODEN: NPAHBY; ISSN:1749-4885. (Nature Publishing Group)
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  • Abstract

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    Figure 1

    Figure 1. Synthesis and analysis of bioharmonophores. (a) Schematic of the self-assembling reaction of diphenylalanine peptides (FF) into large-scale nanotube structures from a concentrated solution. (b) Schematic of the emulsion–solvent evaporation method for the synthesis of bioharmonophores. Self-assembling peptides are dissolved in chloroform along with biodegradable poly(l-lactic acid) (PLLA) and emulsified with the surfactant sodium dodecyl sulfate (SDS) using sonication, followed by evaporation of chloroform. (c) SHG signal from diphenylalanine peptide nanotubes aggregated on top of the imaging chamber. Peptide nanotubes were illuminated with a 850 nm pulsed laser. Image composite of multiple stitched images. (d) SHG signal from encapsulated triphenylalanine peptide (FFF) bioharmonophores immobilized in 1% low melting agarose illuminated with 850 nm pulsed laser. (e) TEM image of synthesized FFF-based bioharmonophores showing uniform spherical nanoparticles. (f) DLS data showing the size distribution of synthesized bioharmonophores. Scale bar, 100 μm (c); 10 μm (d); 500 nm (e).

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    Figure 2. Optical characterization of bioharmonophores and analysis of parameters influencing bioharmonophore formation. (a) Normalized SHG signal spectrum of FFF-based bioharmonophores (signal ranging from 400 to 600 nm) illuminated with 850 nm pulsed laser. The characteristic SHG peak is centered around 425 nm. (b) SHG emission pattern of Triphenylalanine based bioharmonophores. Orange arrow indicates excitation beam direction. Green arrow shows SHG collection direction, which rotates between −90° and +90°. The detected polarization is in the beams plane (P, black arrow). The red pattern shows PPP polarization configuration (excitation and detection polarizations in the plane of the beams), and the blue pattern shows PSS (excitation with a perpendicular polarization). (c) SHG intensity vs incident polarization angle for a bioharmonophore, highlighted by the solid white circle in Supplementary Figure 5. Red color shows detection along the X axis while green color shows detection along the Y axis. The experimental curve is a dotted line, the corresponding fitted curve, assuming C2 symmetry, is a solid line. (d) Influence of using different amounts of FFF peptide during bioharmonophore production on the SHG signal intensity. The optimal condition (33 wt %) is marked in green. The use of higher FFF peptide amount leads to aggregates (n = 5). (e) Influence of SDS concentration (wt % of disperse phase) on SHG intensity of generated bioharmonophores. The optimal condition (40 wt % SDS) with high bioharmonophore stability and less aggregation is marked in green (n = 5). (f) Influence of using different amounts of PLLA during bioharmonophore production on the SHG intensity of the generated bioharmonophores. The optimal condition (66 wt % PLLA) is marked in green (n = 5). Mean ± s.d. ****, P < 0.0001, **, P < 0.005, *, P < 0.05 (ordinary one-way ANOVA with Tukey’s multiple comparisons).

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    Figure 3. Bioharmonophores can be degraded by proteases, cells, and cell-free lysate systems. (a) Schematic showing different degradation methods utilized to assess biodegradability of the bioharmonophores. (b) Graph displaying the change of SHG signal intensity over time of bioharmonophores incubating with proteinase K (n = 5). Mean values of data points were fitted for one-phase exponential decay. (c) Quantification of SHG signal/cell after overnight incubation of Tat-peptide functionalized bioharmonophores over time. SHG signal/cell is significantly reduced 30 h after reseeding. Mean ± s.d. ****, P < 0.0001, **, P < 0.005, *, P < 0.05 (nonparametric Kruskal–Wallis test with Dunn’s post hoc multiple comparison). (d) Graph showing the loss of SHG signal intensity when bioharmonophores are subjected to the cell-free reticulate lysate degradation system (n = 5). Mean values of data points were fitted using a one phase exponential decay. Scale bar, 10 μm (c); 10 μm (d).

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    Figure 4

    Figure 4. Bioharmonophores can be specifically targeted to single cancer cells in vivo. (a) Schematic showing the generation of a zebrafish cancer model by injecting MDA-MB-435-DsRed cancer cells into the Duct of Cuvier (DoC) at 2 dpf, resulting in tumors spread to multiple locations of the zebrafish body at 5 dpf. (b) Composite image of the cancer model (left) in a 5 dpf old zebrafish embryo. Close-up image of one of the tumor sites (right) reveals DsRed-labeled tumors (magenta), adjacent to the eGFP-labeled vasculature (green). (c) Schematic showing cancer cell injection of 2 dpf zebrafish embryos followed by bioharmonophore injection into DoC of 3 dpf zebrafish embryos and subsequent fluorescence and SHG imaging at 5 dpf. Red rectangles labeled as c1–4 denote the regions of interest that are illustrated in more detail. Individual panels showing the images of labeled cancer cells with the details of bioharmonophore (white) labeling down to single cancer cells (magenta) in solid tumors (c1–4). Colored cell boundary reconstruction of targeted cancer cells using the bioharmonophore SHG signal (c1′–4′). Note that cellular bioharmonophore distribution can in most cases predict cell morphologies. Scale bar, left panel 200 μm, right panel 20 μm (b); 15 μm (c). (d) Quantification of the fraction of SHG-labeled tumors as the ratio of labeled tumors to all tumors in a given zebrafish embryo after PEG- and p32 peptide-coated bioharmonophore injection, respectively. Each data point signifies one zebrafish. Note that active targeting with p32-coated bioharmonophores significantly increases the labeling efficiency (approximately 4-fold). Mean ± s.d. ****, P < 0.0001, **, P = 0.0063, *, P = 0.0470 (nonparametric Kruskal–Wallis test with Dunn’s post hoc multiple comparison). N = 12, pooled from 3 independent experiments.

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      4
      Tumor-Specific Uptake of Fluorescent Bevacizumab-IRDye800CW Microdosing in Patients with Primary Breast Cancer: A Phase I Feasibility Study
      Lamberts, Laetitia E.; Koch, Maximillian; de Jong, Johannes S.; Adams, Arthur L. L.; Glatz, Jurgen; Kranendonk, Mariette E. G.; Terwisscha van Scheltinga, Anton G. T.; Jansen, Liesbeth; de Vries, Jakob; Lub-de Hooge, Marjolijn N.; Schroder, Carolien P.; Jorritsma-Smit, Annelies; Linssen, Matthijs D.; de Boer, Esther; van der Vegt, Bert; Nagengast, Wouter B.; Elias, Sjoerd G.; Oliveira, Sabrina; Witkamp, Arjen J.; Mali, Willem P. Th. M.; Van der Wall, Elsken; van Diest, Paul J.; de Vries, Elisabeth G. E.; Ntziachristos, Vasilis; van Dam, Gooitzen M.
      Clinical Cancer Research (2017), 23 (11), 2730-2741CODEN: CCREF4; ISSN:1078-0432. (American Association for Cancer Research)
      Purpose: To provide proof of principle of safety, breast tumor-specific uptake, and pos. tumor margin assessment of the systemically administered near-IR fluorescent tracer bevacizumab-IRDye800CW targeting VEGF-A in patients with breast cancer. Exptl. Design: Twenty patients with primary invasive breast cancer eligible for primary surgery received 4.5 mg bevacizumab-IRDye800CW as i.v. bolus injection. Safety aspects were assessed as well as tracer uptake and tumor delineation during surgery and ex vivo in surgical specimens using an optical imaging system. Ex vivo multiplexed histopathol. analyses were performed for evaluation of biodistribution of tracer uptake and coregistration of tumor tissue and healthy tissue. Results: None of the patients experienced adverse events. Tracer levels in primary tumor tissue were higher compared with those in the tumor margin (P < 0.05) and healthy tissue (P < 0.0001). VEGF-A tumor levels also correlated with tracer levels (r = 0.63, P < 0.0002). All but one tumor showed specific tracer uptake. Two of 20 surgically excised lumps contained microscopic pos. margins detected ex vivo by fluorescent macro- and microscopy and confirmed at the cellular level. Conclusions: Our study shows that systemic administration of the bevacizumab-IRDye800CW tracer is safe for breast cancer guidance and confirms tumor and tumor margin uptake as evaluated by a systematic validation methodol. The findings are a step toward a phase II dose-finding study aimed at in vivo margin assessment and point to a novel drug assessment tool that provides a detailed picture of drug distribution in the tumor tissue.
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    5. 5
      Billinton, N.; Knight, A. W. Seeing the Wood through the Trees: A Review of Techniques for Distinguishing Green Fluorescent Protein from Endogenous Autofluorescence. Anal. Biochem. 2001, 291 (2), 175– 197,  DOI: 10.1006/abio.2000.5006
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      5
      Seeing the Wood through the Trees: A Review of Techniques for Distinguishing Green Fluorescent Protein from Endogenous Autofluorescence
      Billinton, Nicholas; Knight, Andrew W.
      Analytical Biochemistry (2001), 291 (2), 175-197CODEN: ANBCA2; ISSN:0003-2697. (Academic Press)
      A review, with 119 refs., is given on the main sources of autofluorescence and highlighted a wide range of varied techniques for removing interfering autofluorescence from measurements of green fluorescent protein (GFP). Those methods that are likely to be most appealing are those which do not negate the exquisite advantages of using GFP in the first place, namely the ability for nondestructive, in vivo, expression and measurement. These are non-invasive methods such as dual wavelength differential fluorescence correction, fluorescence polarization, and time-resolved techniques, all of which rely on different inherent spectroscopic properties of GFP and the autofluorescence species. (c) 2001 Academic Press.
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    6. 6
      Pantazis, P.; Maloney, J.; Wu, D.; Fraser, S. E. Second Harmonic Generating (SHG) Nanoprobes for in Vivo Imaging. Proc. Natl. Acad. Sci. U. S. A. 2010, 107 (33), 14535– 14540,  DOI: 10.1073/pnas.1004748107
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      6
      Second harmonic generating (SHG) nanoprobes for in vivo imaging
      Pantazis, Periklis; Maloney, James; Wu, David; Fraser, Scott E.
      Proceedings of the National Academy of Sciences of the United States of America (2010), 107 (33), 14535-14540, S14535/1-S14535/8CODEN: PNASA6; ISSN:0027-8424. (National Academy of Sciences)
      Fluorescence microscopy has profoundly changed cell and mol. biol. studies by permitting tagged gene products to be followed as they function and interact. The ability of a fluorescent dye to absorb and emit light of different wavelengths allows it to generate startling contrast that, in the best cases, can permit single mol. detection and tracking. However, in many exptl. settings, fluorescent probes fall short of their potential due to dye bleaching, dye signal satn., and tissue autofluorescence. Here, we demonstrate that second harmonic generating (SHG) nanoprobes can be used for in vivo imaging, circumventing many of the limitations of classical fluorescence probes. Under intense illumination, such as at the focus of a laser-scanning microscope, these SHG nanocrystals convert two photons into one photon of half the wavelength; thus, when imaged by conventional two-photon microscopy, SHG nanoprobes appear to generate a signal with an inverse Stokes shift like a fluorescent dye, but with a narrower emission. Unlike commonly used fluorescent probes, SHG nanoprobes neither bleach nor blink, and the signal they generate does not sat. with increasing illumination intensity. The resulting contrast and detectability of SHG nanoprobes provide unique advantages for mol. imaging of living cells and tissues.
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    7. 7
      Rogov, A.; Mugnier, Y.; Bonacina, L. Harmonic Nanoparticles: Noncentrosymmetric Metal Oxides for Nonlinear Optics. J. Opt. 2015, 17 (3), 033001,  DOI: 10.1088/2040-8978/17/3/033001
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      7
      Harmonic nanoparticles: noncentrosymmetric metal oxides for nonlinear optics
      Rogov, Andrii; Mugnier, Yannick; Bonacina, Luigi
      Journal of Optics (Bristol, United Kingdom) (2015), 17 (3), 033001/1-033001/12CODEN: JOOPCA; ISSN:2040-8978. (IOP Publishing Ltd.)
      The combination of nonlinear optics and nanotechnol. is an extremely rich scientific domain yet widely unexplored. We present here a review of recent optical investigations on noncentrosym. oxide nanoparticles with a large χ(2) response, often referred to as harmonic nanoparticles (HNPs). HNPs feature a series of properties which distinguish them from other photonics nanoprobes (quantum dots, up-conversion nanoparticles, noble metal particles). HNPs emission is inherently nonlinear and based on the efficient generation of harmonics as opposed to fluorescence or surface plasmon scattering. In addn., the fully coherent signal emitted by HNPs together with their polarization sensitive response and absence of resonant interaction make them appealing for several applications ranging from multi-photon (IR) microscopy and holog., to cell tracking and sensing.
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    8. 8
      Extermann, J.; Bonacina, L.; Cuña, E.; Kasparian, C.; Mugnier, Y.; Feurer, T.; Wolf, J.-P. Nanodoublers as Deep Imaging Markers for Multi-Photon Microscopy. Opt. Express 2009, 17 (17), 15342– 15349,  DOI: 10.1364/OE.17.015342
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      8
      Nanodoublers as deep imaging markers for multi-photon microscopy
      Extermann, Jerome; Bonacina, Luigi; Cuna, Enrique; Kasparian, Christelle; Mugnier, Yannick; Feurer, Thomas; Wolf, Jean-Pierre
      Optics Express (2009), 17 (17), 15342-15349CODEN: OPEXFF; ISSN:1094-4087. (Optical Society of America)
      We demonstrate the possibility to excite second-harmonic (SH) active Fe(IO3)3 nanocrystals with two distinct laser sources at 800 and 1550 nm, and we show, by a complementary exptl. and numerical study, how the wavelength flexibility inherent to non-phase-matched SH nanoparticles can be efficiently exploited to increase imaging penetration depth of markers embedded in biol. samples.
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    9. 9
      Dubreil, L.; Leroux, I.; Ledevin, M.; Schleder, C.; Lagalice, L.; Lovo, C.; Fleurisson, R.; Passemard, S.; Kilin, V.; Gerber-Lemaire, S.; Colle, M.-A.; Bonacina, L.; Rouger, K. Multi-Harmonic Imaging in the Second Near-Infrared Window of Nanoparticle-Labeled Stem Cells as a Monitoring Tool in Tissue Depth. ACS Nano 2017, 11 (7), 6672– 6681,  DOI: 10.1021/acsnano.7b00773
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      9
      Multi-harmonic Imaging in the Second Near-Infrared Window of Nanoparticle-Labeled Stem Cells as a Monitoring Tool in Tissue Depth
      Dubreil, Laurence; Leroux, Isabelle; Ledevin, Mireille; Schleder, Cindy; Lagalice, Lydie; Lovo, Claire; Fleurisson, Romain; Passemard, Solene; Kilin, Vasyl; Gerber-Lemaire, Sandrine; Colle, Marie-Anne; Bonacina, Luigi; Rouger, Karl
      ACS Nano (2017), 11 (7), 6672-6681CODEN: ANCAC3; ISSN:1936-0851. (American Chemical Society)
      In order to assess the therapeutic potential of cell-based strategies, it is of paramount importance to elaborate and validate tools for monitoring the behavior of injected cells in terms of tissue dissemination and engraftment properties. Here, we apply bismuth ferrite harmonic nanoparticles (BFO HNPs) to in vitro expanded human skeletal muscle-derived stem cells (hMuStem cells), an attractive therapeutic avenue for patients suffering from Duchenne muscular dystrophy (DMD). We demonstrate the possibility of stem cell labeling with HNPs. We also show that the simultaneous acquisition of second- and third-harmonic generation (SHG and THG) from BFO HNPs helps sep. their response from tissue background, with a net increase in imaging selectivity, which could be particularly important in pathol. context that is defined by a highly remodelling tissue. We demonstrate the possibility of identifying <100 nm HNPs in depth of muscle tissue at more than 1 mm from the surface, taking full advantage of the extended imaging penetration depth allowed by multiphoton microscopy in the second near-IR window (NIR-II). Based on this successful assessment, we monitor over 14 days any modification on proliferation and morphol. features of hMuStem cells upon exposure to PEG-coated BFO HNPs at different concns., revealing their high biocompatibility. Successively, we succeed in detecting individual HNP-labeled hMuStem cells in skeletal muscle tissue after their i.m. injection.
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    10. 10
      Dempsey, W. P.; Fraser, S. E.; Pantazis, P. SHG Nanoprobes: Advancing Harmonic Imaging in Biology. BioEssays 2012, 34 (5), 351– 360,  DOI: 10.1002/bies.201100106
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      10
      SHG nanoprobes: Advancing harmonic imaging in biology
      Dempsey, William P.; Fraser, Scott E.; Pantazis, Periklis
      BioEssays (2012), 34 (5), 351-360CODEN: BIOEEJ; ISSN:0265-9247. (Wiley-Blackwell)
      A review. Second harmonic generating (SHG) nanoprobes have recently emerged as versatile and durable labels suitable for in vivo imaging, circumventing many of the inherent drawbacks encountered with classical fluorescent probes. Since their nanocryst. structure lacks a central point of symmetry, they are capable of generating second harmonic signal under intense illumination - converting two photons into one photon of half the incident wavelength - and can be detected by conventional two-photon microscopy. Because the optical signal of SHG nanoprobes is based on scattering, rather than absorption as in the case of fluorescent probes, they neither bleach nor blink, and the signal does not sat. with increasing illumination intensity. When SHG nanoprobes are used to image live tissue, the SHG signal can be detected with little background signal, and they are physiol. inert, showing excellent long-term photostability. Because of their photophys. properties, SHG nanoprobes provide unique advantages for mol. imaging of living cells and tissues with unmatched sensitivity and temporal resoln.
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    11. 11
      Magouroux, T.; Extermann, J.; Hoffmann, P.; Mugnier, Y.; Le Dantec, R.; Jaconi, M. E.; Kasparian, C.; Ciepielewski, D.; Bonacina, L.; Wolf, J.-P. High-Speed Tracking of Murine Cardiac Stem Cells by Harmonic Nanodoublers. Small 2012, 8 (17), 2752– 2756,  DOI: 10.1002/smll.201200366
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      11
      High-Speed Tracking of Murine Cardiac Stem Cells by Harmonic Nanodoublers
      Magouroux, Thibaud; Extermann, Jerome; Hoffmann, Pernilla; Mugnier, Yannick; Le Dantec, Ronan; Jaconi, Marisa E.; Kasparian, Christelle; Ciepielewski, Daniel; Bonacina, Luigi; Wolf, Jean-Pierre
      Small (2012), 8 (17), 2752-2756, S2752/1-S2752/2CODEN: SMALBC; ISSN:1613-6810. (Wiley-VCH Verlag GmbH & Co. KGaA)
      Potassium niobate nonlinear nanoparticles are used for the first time to monitor the evolution of embryonic stem cells (ESC) by second harmonic microscopy. These particles feature the complete absence of photo-bleaching and unlimited excitation wavelength flexibility. The potential of this approach is made evident for tissue-regeneration studies and applications, by capturing a high-speed movie of ESC-derived cardiomyocytes autonomously beating within a cluster. Time-resolved data are analyzed to retrieve 3D information of the contraction pattern at the cellular level.
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    12. 12
      Culic-Viskota, J.; Dempsey, W. P; Fraser, S. E; Pantazis, P. Surface Functionalization of Barium Titanate SHG Nanoprobes for in Vivo Imaging in Zebrafish. Nat. Protoc. 2012, 7 (9), 1618– 1633,  DOI: 10.1038/nprot.2012.087
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      12
      Surface functionalization of barium titanate SHG nanoprobes for in vivo imaging in zebrafish
      Culic-Viskota, Jelena; Dempsey, William P.; Fraser, Scott E.; Pantazis, Periklis
      Nature Protocols (2012), 7 (9), 1618-1633CODEN: NPARDW; ISSN:1750-2799. (Nature Publishing Group)
      To address the need for a bright, photostable labeling tool that allows long-term in vivo imaging in whole organisms, we recently introduced second harmonic generating (SHG) nanoprobes. Here we present a protocol for the prepn. and use of a particular SHG nanoprobe label, barium titanate (BT), for in vivo imaging in living zebrafish embryos. Chem. treatment of the BT nanoparticles results in surface coating with amine-terminal groups, which act as a platform for a variety of chem. modifications for biol. applications. Here we describe crosslinking of BT to a biotin-linked moiety using click chem. methods and coating of BT with nonreactive poly(ethylene glycol) (PEG). We also provide details for injecting PEG-coated SHG nanoprobes into zygote-stage zebrafish embryos, and in vivo imaging of SHG nanoprobes during gastrulation and segmentation. Implementing the PROCEDURE requires a basic understanding of laser-scanning microscopy, experience with handling zebrafish embryos and chem. lab. experience. Functionalization of the SHG nanoprobes takes ∼3 d, whereas zebrafish prepn., injection and imaging setup should take approx. 2-4 h.
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    13. 13
      Sugiyama, N.; Sonay, A. Y.; Tussiwand, R.; Cohen, B. E.; Pantazis, P. Effective Labeling of Primary Somatic Stem Cells with BaTiO3 Nanocrystals for Second Harmonic Generation Imaging. Small 2018, 14 (8), 1703386,  DOI: 10.1002/smll.201703386
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    14. 14
      Staedler, D.; Magouroux, T.; Hadji, R.; Joulaud, C.; Extermann, J.; Schwung, S.; Passemard, S.; Kasparian, C.; Clarke, G.; Gerrmann, M.; Le Dantec, R.; Mugnier, Y.; Rytz, D.; Ciepielewski, D.; Galez, C.; Gerber-Lemaire, S.; Juillerat-Jeanneret, L.; Bonacina, L.; Wolf, J.-P. Harmonic Nanocrystals for Biolabeling: A Survey of Optical Properties and Biocompatibility. ACS Nano 2012, 6 (3), 2542– 2549,  DOI: 10.1021/nn204990n
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      14
      Harmonic Nanocrystals for Biolabeling: A Survey of Optical Properties and Biocompatibility
      Staedler, Davide; Magouroux, Thibaud; Hadji, Rachid; Joulaud, Cecile; Extermann, Jerome; Schwung, Sebastian; Passemard, Solene; Kasparian, Christelle; Clarke, Gareth; Gerrmann, Mathias; Le Dantec, Ronan; Mugnier, Yannick; Rytz, Daniel; Ciepielewski, Daniel; Galez, Christine; Gerber-Lemaire, Sandrine; Juillerat-Jeanneret, Lucienne; Bonacina, Luigi; Wolf, Jean-Pierre
      ACS Nano (2012), 6 (3), 2542-2549CODEN: ANCAC3; ISSN:1936-0851. (American Chemical Society)
      Nonlinear optical nanocrystals have been recently introduced as a promising alternative to fluorescent probes for multiphoton microscopy. The authors present for the first time a complete survey of the properties of five nanomaterials (KNbO3, LiNbO3, BaTiO3, KTP, and ZnO), describing their prepn. and stabilization and providing quant. estns. of their nonlinear optical response. In the light of their prospective use as biol. and clin. markers, the authors assess their biocompatibility on human healthy and cancerous cell lines. Finally, the authors demonstrate the great potential for cell imaging of these inherently nonlinear probes in terms of optical contrast, wavelength flexibility, and signal photostability.
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    15. 15
      Lakshmanan, A.; Zhang, S.; Hauser, C. A. E. Short Self-Assembling Peptides as Building Blocks for Modern Nanodevices. Trends Biotechnol. 2012, 30 (3), 155– 165,  DOI: 10.1016/j.tibtech.2011.11.001
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      15
      Short self-assembling peptides as building blocks for modern nanodevices
      Lakshmanan, Anupama; Zhang, Shuguang; Hauser, Charlotte A. E.
      Trends in Biotechnology (2012), 30 (3), 155-165CODEN: TRBIDM; ISSN:0167-7799. (Elsevier Ltd.)
      A review. Short, self-assembling peptides form a variety of stable nanostructures used for the rational design of functional devices. Peptides serve as org. templates for conjugating biorecognition elements, and assembling ordered nanoparticle arrays and hybrid supramol. structures. We are witnessing the emergence of a new phase of bionanotechnol., particularly towards electronic, photonic and plasmonic applications. Recent advances include self-assembly of photoluminescent semiconducting nanowires and peptide-conjugated systems for sensing, catalysis and energy storage. Concurrently, methods and tools have been developed to control and manipulate the self-assembled nanostructures. Furthermore, there is growing knowledge on nanostructure properties such as piezoelectricity, dipolar elec. field and stability. This review focuses on the emerging role of short, linear self-assembling peptides as simple and versatile building blocks for nanodevices.
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    16. 16
      Kholkin, A.; Amdursky, N.; Bdikin, I.; Gazit, E.; Rosenman, G. Strong Piezoelectricity in Bioinspired Peptide Nanotubes. ACS Nano 2010, 4 (2), 610– 614,  DOI: 10.1021/nn901327v
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      16
      Strong Piezoelectricity in Bioinspired Peptide Nanotubes
      Kholkin, Andrei; Amdursky, Nadav; Bdikin, Igor; Gazit, Ehud; Rosenman, Gil
      ACS Nano (2010), 4 (2), 610-614CODEN: ANCAC3; ISSN:1936-0851. (American Chemical Society)
      We show anomalously strong shear piezoelec. activity in self-assembled diphenylalanine peptide nanotubes (PNTs), indicating elec. polarization directed along the tube axis. Comparison with well-known piezoelec. LiNbO3 and lateral signal calibration yields sufficiently high effective piezoelec. coeff. values of at least 60 pm/V (shear response for tubes of ≈200 nm in diam.). PNTs demonstrate linear deformation without irreversible degrdn. in a broad range of driving voltages. The results open up a wide avenue for developing new generations of "green" piezoelec. materials and piezonanodevices based on bioactive tubular nanostructures potentially compatible with human tissue.
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    17. 17
      Handelman, A.; Beker, P.; Amdursky, N.; Rosenman, G. Physics and Engineering of Peptide Supramolecular Nanostructures. Phys. Chem. Chem. Phys. 2012, 14 (18), 6391– 6408,  DOI: 10.1039/c2cp40157f
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      17
      Physics and engineering of peptide supramolecular nanostructures
      Handelman Amir; Beker Peter; Amdursky Nadav; Rosenman Gil
      Physical chemistry chemical physics : PCCP (2012), 14 (18), 6391-408 ISSN:.
      The emerging "bottom-up" nanotechnology reveals a new field of bioinspired nanomaterials composed of chemically synthesized biomolecules. They are formed from elementary constituents in supramolecular structures by the use of a developed nature self-assembly mechanism. The focus of this perspective paper is on intrinsic fundamental physical properties of bioinspired peptide nanostructures and their small building units linked by weak noncovalent bonds. The observed exceptional optical properties indicate a phenomenon of quantum confinement in these supramolecular structures, which originates from nanoscale size of their elementary building blocks. The dimensionality of the confinement gives insight into intrinsic packing of peptide supramolecular nanomaterials. QC regions, revealed in bioinspired nanostructures, were found by us in amyloid fibrils formed from insulin protein. We describe ferroelectric and related properties found at the nanoscale based on original crystalline asymmetry of the nanoscale building blocks, packing these structures. In this context, we reveal a classic solid state physics phenomenon such as reconstructive phase transition observed in bioorganic peptide nanotubes. This irreversible phase transformation leads to drastic reshaping of their quantum structure from quantum dots to quantum wells, which is followed by variation of their space group symmetry from asymmetric to symmetric. We show that the supramolecular origin of these bioinspired nanomaterials provides them a unique chance to be disassembled into elementary building block peptide nanodots of 1-2 nm size possessing unique electronic, optical and ferroelectric properties. These multifunctional nanounits could lead to a new future step in nanotechnology and nanoscale advanced devices in the fields of nanophotonics, nanobiomedicine, nanobiopiezotronics, etc.
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    18. 18
      Staff, R. H.; Schaeffel, D.; Turshatov, A.; Donadio, D.; Butt, H.-J.; Landfester, K.; Koynov, K.; Crespy, D. Particle Formation in the Emulsion-Solvent Evaporation Process. Small 2013, 9 (20), 3514– 3522,  DOI: 10.1002/smll.201300372
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      18
      Particle Formation in the Emulsion-Solvent Evaporation Process
      Staff, Roland H.; Schaeffel, David; Turshatov, Andrey; Donadio, Davide; Butt, Hans-Juergen; Landfester, Katharina; Koynov, Kaloian; Crespy, Daniel
      Small (2013), 9 (20), 3514-3522CODEN: SMALBC; ISSN:1613-6810. (Wiley-VCH Verlag GmbH & Co. KGaA)
      The mechanism of particle formation from submicrometer emulsion droplets by solvent evapn. is revisited. A combination of dynamic light scattering, fluorescence resonance energy transfer, zeta potential measurements, and fluorescence cross-correlation spectroscopy is used to analyze the colloids during the evapn. process. It is shown that a combination of different methods yields reliable and quant. data for describing the fate of the droplets during the process. The results indicate that coalescence plays a minor role during the process; the relatively large size distribution of the obtained polymer colloids can be explained by the droplet distribution after their formation.
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    19. 19
      Rabotyagova, O. S.; Cebe, P.; Kaplan, D. L. Role of Polyalanine Domains in β-Sheet Formation in Spider Silk Block Copolymers. Macromol. Biosci. 2010, 10 (1), 49– 59,  DOI: 10.1002/mabi.200900203
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      19
      Role of Polyalanine Domains in β-Sheet Formation in Spider Silk Block Copolymers
      Rabotyagova, Olena S.; Cebe, Peggy; Kaplan, David L.
      Macromolecular Bioscience (2010), 10 (1), 49-59CODEN: MBAIBU; ISSN:1616-5187. (Wiley-VCH Verlag GmbH & Co. KGaA)
      Genetically engineered spider silk-like block copolymers were studied to det. the influence of polyalanine domain size on secondary structure. The role of polyalanine block distribution on β-sheet formation was explored using FT-IR and WAXS. The no. of polyalanine blocks had a direct effect on the formation of cryst. β-sheets, reflected in the change in crystallinity index as the blocks of polyalanines increased. WAXS anal. confirmed the cryst. nature of the sample with the largest no. of polyalanine blocks. This approach provides a platform for further exploration of the role of specific amino acid chemistries in regulating the assembly of β-sheet secondary structures, leading to options to regulate material properties through manipulation of this key component in spider silks.
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    20. 20
      Handelman, A.; Kuritz, N.; Natan, A.; Rosenman, G. Reconstructive Phase Transition in Ultrashort Peptide Nanostructures and Induced Visible Photoluminescence. Langmuir 2016, 32 (12), 2847– 2862,  DOI: 10.1021/acs.langmuir.5b02784
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      20
      Reconstructive Phase Transition in Ultrashort Peptide Nanostructures and Induced Visible Photoluminescence
      Handelman, Amir; Kuritz, Natalia; Natan, Amir; Rosenman, Gil
      Langmuir (2016), 32 (12), 2847-2862CODEN: LANGD5; ISSN:0743-7463. (American Chemical Society)
      A reconstructive phase transition has been found and studied in ultrashort di- and tripeptide nanostructures, self-assembled from biomols. of different compns. and origin such as arom., aliph., linear, and cyclic (linear FF-diphenylalanine, linear LL-dileucine, FFF-triphenylalanine, and cyclic FF-diphenylalanine). The native linear arom. FF, FFF and aliph. LL peptide nanoensembles of various shapes (nanotubes and nanospheres) have asym. elementary structure and demonstrate nonlinear optical and piezoelec. effects. At elevated temp., 140-180 °C, these native supramol. structures (except for native Cyc-FF nanofibers) undergo an irreversible thermally induced transformation via reassembling into a completely new thermodynamically stable phase having nanowire morphol. similar to those of amyloid fibrils. This reconstruction process is followed by deep and similar modification at all levels: macroscopic (morphol.), mol., peptide secondary, and electronic structures. However, original Cyc-FF nanofibers preserve their native phys. properties. The self-fabricated supramol. fibrillar ensembles exhibit the FTIR and CD signatures of new antiparallel β-sheet secondary folding with intermol. hydrogen bonds and centrosym. structure. In this phase, the β-sheet nanofibers, irresp. of their native biomol. origin, do not reveal nonlinear optical and piezoelec. effects, but do exhibit similar profound modification of optoelectronic properties followed by the appearance of visible (blue and green) photoluminescence (PL), which is not obsd. in the original peptides and their native nanostructures. The obsd. visible PL effect, ascribed to hydrogen bonds of thermally induced β-sheet secondary structures, has the same phys. origin as that of the fluorescence found recently in amyloid fibrils and can be considered to be an optical signature of β-sheet structures in both biol. and bioinspired materials. Such PL centers represent a new class of self-assembled dyes and can be used as intrinsic optical labels in biomedical microscopy as well as for a new generation of novel optoelectronic nanomaterials for emerging nanophotonic applications, such as biolasers, biocompatible markers, and integrated optics.
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    21. 21
      Handelman, A.; Lavrov, S.; Kudryavtsev, A.; Khatchatouriants, A.; Rosenberg, Y.; Mishina, E.; Rosenman, G. Nonlinear Optical Bioinspired Peptide Nanostructures. Adv. Opt. Mater. 2013, 1 (11), 875– 884,  DOI: 10.1002/adom.201300282
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      de Beer, A. G. F.; de Aguiar, H. B.; Nijsen, J. F. W.; Roke, S. Detection of Buried Microstructures by Nonlinear Light Scattering Spectroscopy. Phys. Rev. Lett. 2009, 102 (9), 095502,  DOI: 10.1103/PhysRevLett.102.095502
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      Detection of Buried Microstructures by Nonlinear Light Scattering Spectroscopy
      de Beer, A. G. F.; de Aguiar, H. B.; Nijsen, J. F. W.; Roke, S.
      Physical Review Letters (2009), 102 (9), 095502/1-095502/4CODEN: PRLTAO; ISSN:0031-9007. (American Physical Society)
      Many processes in chem. and physics rely on the structure, growth or change of material buried in solids. The impenetrable surrounding medium often prohibits the study of such material in situ. Nonlinear light scattering can be used to observe the internal structure of a cryst. state embedded inside another solid state. Vibrational sum frequency scattering patterns of polymer microspheres, consisting of both amorphous and cryst. material, reveal the size of the buried microstructure and the optical components of the 2nd-order susceptibility of the material. The vibrational spectra reveal the mol. structure.
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      Roke, S.; Gonella, G. Nonlinear Light Scattering and Spectroscopy of Particles and Droplets in Liquids. Annu. Rev. Phys. Chem. 2012, 63 (1), 353– 378,  DOI: 10.1146/annurev-physchem-032511-143748
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      Nonlinear light scattering and spectroscopy of particles and droplets in liquids
      Roke, Sylvie; Gonella, Grazia
      Annual Review of Physical Chemistry (2012), 63 (), 353-378CODEN: ARPLAP; ISSN:0066-426X. (Annual Reviews Inc.)
      A review. Nano- and microparticles have optical, structural, and chem. properties that differ from both their building blocks and the bulk materials themselves. These different phys. and chem. properties are induced by the high surface-to-vol. ratio. As a logical consequence, to understand the properties of nano- and microparticles, it is of fundamental importance to characterize the particle surfaces and their interactions with the surrounding medium. Recent developments of nonlinear light scattering techniques have resulted in a deeper insight of the underlying light-matter interactions. They have shed new light on the mol. mechanism of surface kinetics in soln., properties of interfacial water in contact with hydrophilic and hydrophobic particles and droplets, mol. orientation distribution of mols. at particle surfaces in soln., interfacial structure of surfactants at droplet interfaces, acid-base chem. on particles in soln., and vesicle structure and transport properties.
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      Tsuji, H.; Ogiwara, M.; Saha, S. K.; Sakaki, T. Enzymatic, Alkaline, and Autocatalytic Degradation of Poly-L-Lactic Acid: Effects of Biaxial Orientation. Biomacromolecules 2006, 7 (1), 380– 387,  DOI: 10.1021/bm0507453
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      24
      Enzymatic, Alkaline, and Autocatalytic Degradation of Poly(L-lactic acid): Effects of Biaxial Orientation
      Tsuji, Hideto; Ogiwara, Miyuki; Saha, Swapan Kumar; Sakaki, Takuya
      Biomacromolecules (2006), 7 (1), 380-387CODEN: BOMAF6; ISSN:1525-7797. (American Chemical Society)
      The hydrolytic degrdn. of biaxially oriented and de-oriented (melt-crystd.) poly(L-lactic acid) (PLLA) films was investigated in Tris-HCl-buffered soln. (pH 8.6) with proteinase K, alk. soln., and phosphate-buffered soln. (pH 7.4) by the use of gravimetry, gel permeation chromatog., differential scanning calorimetry, and SEM. Biaxial orientation disturbed the proteinase K-catalyzed enzymic degrdn. of PLLA films and the effects of biaxial orientation overcame those of crystallinity. The former may be due to the fact the enzyme cannot attach to the extended (strained) chains in the amorphous regions of the biaxially oriented PLLA film or cannot catalyze the cleavage of the strained chains. Another probable cause is that the enzyme can act only at the film surface of the biaxially oriented PLLA film, in marked contrast with the case of the de-oriented PLLA films where enzymic degrdn. can proceed beneath the spherulitic cryst. residues. The effects of biaxial orientation on the alk. and autocatalytic degrdn. of the PLLA films were insignificant for the periods studied here. The crystallinity rather than the biaxial orientation seems to det. the alk. and autocatalytic degrdn. rates of the PLLA films. The accumulation of cryst. residues formed as a result of selective cleavage and removal of the amorphous chains was obsd. for the de-oriented PLLA films, but not for the biaxially oriented PLLA film, when degraded in the presence of proteinase K. This means the facile release of formed cryst. residues from the surface of the biaxially oriented PLLA film during enzymic degrdn., due to the fact that the cryst. regions of the biaxially oriented PLLA film were oriented with their c axis parallel to the film surface.
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      Sepp, R.; Szabo, I.; Uda, H.; Sakamoto, H. Rapid Techniques for DNA Extraction from Routinely Processed Archival Tissue for Use in PCR. J. Clin. Pathol. 1994, 47 (4), 318– 323,  DOI: 10.1136/jcp.47.4.318
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      25
      Rapid techniques for DNA extraction from routinely processed archival tissue for use in PCR
      Sepp R; Szabo I; Uda H; Sakamoto H
      Journal of clinical pathology (1994), 47 (4), 318-23 ISSN:0021-9746.
      AIMS: To evaluate the ability of four rapid DNA extraction methods to provide DNA for the polymerase chain reaction (PCR) from routinely fixed, paraffin wax embedded archival tissues. METHODS: Eighteen blocks of various tissues, 18 blocks of cervical cancer specimens, and nine blocks of B cell lymphomas were investigated. Both normal and biopsy specimen sized tissues were studied. DNA was extracted using four methods: boiling for 20 minutes in distilled water; boiling for 20 minutes in 5% Chelex-100 resin solution; 3-hour proteinase K digestion; and 3-hour proteinase K digestion, followed by boiling in 5% Chelex-100. Different exons of the p53 gene, human papillomavirus type 16 (HPV 16) sequence, and immunoglobulin heavy chain (IgH) gene rearrangement were amplified from the extracts. RESULTS: The Chelex boiling, proteinase K digestion, and proteinase K digestion-Chelex boiling methods produced DNA suitable for amplification in all of the 45 samples. Boiling in water yielded insufficient template for the PCR in three of the 45 cases (7%), and in six of 42 positive cases (14%) much fainter bands were observed, mostly when the processed material was either biopsy specimen sized or a B cell lymphoma sample. Fragments of the p53 gene were successfully amplified up to 408 base pairs in water boiled extracts, up to 647 in Chelex boiled preparates, and up to 984 in proteinase K digested and proteinase K digested-Chelex boiled samples, although with decreased sensitivity in the last case. All of the templates were reusable after 3 months of storage at -20 degrees C. CONCLUSIONS: Chelex boiling, proteinase K digestion, and proteinase K digestion followed by Chelex boiling produce suitable templates for the PCR from a large variety of paraffin wax embedded tissues. As the simple 20 minute boiling method in 5% Chelex-100 solution requires minimal manipulation and time, it could be useful, especially in the routine processing of large amounts of material.
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    26. 26
      Lewin, M.; Carlesso, N.; Tung, C.-H.; Tang, X.-W.; Cory, D.; Scadden, D. T.; Weissleder, R. Tat Peptide-Derivatized Magnetic Nanoparticles Allow in Vivo Tracking and Recovery of Progenitor Cells. Nat. Biotechnol. 2000, 18 (4), 410– 414,  DOI: 10.1038/74464
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      26
      Tat peptide-derivatized magnetic nanoparticles allow in vivo tracking and recovery of progenitor cells
      Lewin, Maite; Carlesso, Nadia; Tung, Ching-Hsuan; Tang, Xiao-Wu; Cory, David; Scadden, David T.; Weissleder, Ralph
      Nature Biotechnology (2000), 18 (4), 410-414CODEN: NABIF9; ISSN:1087-0156. (Nature America)
      The ability to track the distribution and differentiation of progenitor and stem cells by high-resoln. in vivo imaging techniques would have significant clin. and research implications. We have developed a cell labeling approach using short HIV-Tat peptides to derivatize superparamagnetic nanoparticles. The particles are efficiently internalized into hematopoietic and neural progenitor cells in quantities up to 10-30 pg of superparamagnetic iron per cell. Iron incorporation did not affect cell viability, differentiation, or proliferation of CD34+ cells. Following i.v. injection into immunodeficient mice, 4% of magnetically CD34+ cells homed to bone marrow per g of tissue, and single cells could be detected by magnetic resonance (MR) imaging in tissue samples. In addn., magnetically labeled cells that had homed to bone marrow could be recovered by magnetic sepn. columns. Localization and retrieval of cell populations in vivo enable detailed anal. of specific stem cell and organ interactions crit. for advancing the therapeutic use of stem cells.
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      Nguyen, H.; Gitig, D. M.; Koff, A. Cell-Free Degradation of p27 kip1, a G1 Cyclin-Dependent Kinase Inhibitor, Is Dependent on CDK2 Activity and the Proteasome. Mol. Cell. Biol. 1999, 19 (2), 1190– 1201,  DOI: 10.1128/MCB.19.2.1190
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      Cell-free degradation of p27kip1, a G1 cyclin-dependent kinase inhibitor, is dependent on CDK2 activity and the proteasome
      Nguyen, Hoang; Gitig, Diana M.; Koff, Andrew
      Molecular and Cellular Biology (1999), 19 (2), 1190-1201CODEN: MCEBD4; ISSN:0270-7306. (American Society for Microbiology)
      Entry into S phase is dependent on the coordinated activation of CDK4,6 and CDK2 kinases. Once a cell commits to S phase, there must be a mechanism to ensure the irreversibility of this decision. The activity of these kinases is inhibited by their assocn. with p27. In many cells, p27 plays a major role in the withdrawal from the cell cycle in response to environmental cues. Thus, it is likely that p27 is a target of the machinery required to ensure the irreversibility of S-phase entry. We have been interested in understanding the mechanisms regulating p27 at the G1/S transition. In this report, we define a cell-free degrdn. system which faithfully recapitulates the cell cycle phase-specific degrdn. of p27. We show that this reaction is dependent on active CDK2 activity, suggesting that CDK2 activity is directly required for p27 degrdn. In addn. to CDK2, other S-phase-specific factors are required for p27 degrdn. At least some of these factors are ubiquitin and proteasome dependent. We discuss the relationships between CDK2 activity, ubiquitin-dependent, and possibly ubiquitin-independent proteasomal activities in S-phase exts. as related to p27.
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      Lee, H.-J.; Shin, S. Y.; Choi, C.; Lee, Y. H.; Lee, S.-J. Formation and Removal of Alpha-Synuclein Aggregates in Cells Exposed to Mitochondrial Inhibitors. J. Biol. Chem. 2002, 277 (7), 5411– 5417,  DOI: 10.1074/jbc.M105326200
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      28
      Formation and removal of α-synuclein aggregates in cells exposed to mitochondrial inhibitors
      Lee, He-Jin; Shin, Soon Young; Choi, Chan; Lee, Young Han; Lee, Seung-Jae
      Journal of Biological Chemistry (2002), 277 (7), 5411-5417CODEN: JBCHA3; ISSN:0021-9258. (American Society for Biochemistry and Molecular Biology)
      Mitochondrial dysfunction has been assocd. with Parkinson's disease. However, the role of mitochondrial defects in the formation of Lewy bodies, a pathol. hallmark of Parkinson's disease has not been addressed directly. In this report, we investigated the effects of inhibitors of the mitochondrial electron-transport chain on the aggregation of α-synuclein, a major protein component of Lewy bodies. Treatment with rotenone, an inhibitor of complex I, resulted in an increase of detergent-resistant α-synuclein aggregates and a redn. in ATP level. Another inhibitor of the electron-transport chain, oligomycin, also showed temporal correlation between the formation of aggregates and ATP redn. Microscopic analyses showed a progressive evolution of small aggregates of α-synuclein to a large perinuclear inclusion body. The inclusions were co-stained with ubiquitin, 20 S proteasome, γ-tubulin, and vimentin. The perinuclear inclusion bodies, but not the small cytoplasmic aggregates, were thioflavin S-pos., suggesting the amyloid-like conformation. Interestingly, the aggregates disappeared when the cells were replenished with inhibitor-free medium. Disappearance of aggregates coincided with the recovery of mitochondrial metab. and was partially inhibited by proteasome inhibitors. These results suggest that the formation of α-synuclein inclusions could be initiated by an impaired mitochondrial function and be reversed by restoring normal mitochondrial metab.
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    29. 29
      Konantz, M.; Balci, T. B.; Hartwig, U. F.; Dellaire, G.; André, M. C.; Berman, J. N.; Lengerke, C. Zebrafish Xenografts as a Tool for in Vivo Studies on Human Cancer. Ann. N. Y. Acad. Sci. 2012, 1266 (1), 124– 137,  DOI: 10.1111/j.1749-6632.2012.06575.x
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      29
      Zebrafish xenografts as a tool for in vivo studies on human cancer
      Konantz Martina; Balci Tugce B; Hartwig Udo F; Dellaire Graham; Andre Maya C; Berman Jason N; Lengerke Claudia
      Annals of the New York Academy of Sciences (2012), 1266 (), 124-37 ISSN:.
      The zebrafish has become a powerful vertebrate model for genetic studies of embryonic development and organogenesis and increasingly for studies in cancer biology. Zebrafish facilitate the performance of reverse and forward genetic approaches, including mutagenesis and small molecule screens. Moreover, several studies report the feasibility of xenotransplanting human cells into zebrafish embryos and adult fish. This model provides a unique opportunity to monitor tumor-induced angiogenesis, invasiveness, and response to a range of treatments in vivo and in real time. Despite the high conservation of gene function between fish and humans, concern remains that potential differences in zebrafish tissue niches and/or missing microenvironmental cues could limit the relevance and translational utility of data obtained from zebrafish human cancer cell xenograft models. Here, we summarize current data on xenotransplantation of human cells into zebrafish, highlighting the advantages and limitations of this model in comparison to classical murine models of xenotransplantation.
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      Stoletov, K.; Kato, H.; Zardouzian, E.; Kelber, J.; Yang, J.; Shattil, S.; Klemke, R. Visualizing Extravasation Dynamics of Metastatic Tumor Cells. J. Cell Sci. 2010, 123 (13), 2332– 2341,  DOI: 10.1242/jcs.069443
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      Visualizing extravasation dynamics of metastatic tumor cells
      Stoletov, Konstantin; Kato, Hisashi; Zardouzian, Erin; Kelber, Jonathan; Yang, Jing; Shattil, Sanford; Klemke, Richard
      Journal of Cell Science (2010), 123 (13), 2332-2341CODEN: JNCSAI; ISSN:0021-9533. (Company of Biologists Ltd.)
      Little is known about how metastatic cancer cells arrest in small capillaries and traverse the vascular wall during extravasation in vivo. Using real-time intravital imaging of human tumor cells transplanted into transparent zebrafish, we show here that extravasation of cancer cells is a highly dynamic process that involves the modulation of tumor cell adhesion to the endothelium and intravascular cell migration along the luminal surface of the vascular wall. Tumor cells do not damage or induce vascular leak at the site of extravasation, but rather induce local vessel remodeling characterized by clustering of endothelial cells and cell-cell junctions. Intravascular locomotion of tumor cells is independent of the direction of blood flow and requires β1-integrin-mediated adhesion to the blood-vessel wall. Interestingly, the expression of the pro-metastatic gene Twist in tumor cells increases their intravascular migration and extravasation through the vessel wall. However, in this case, Twist expression causes the tumor cells to switch to a β1-integrin-independent mode of extravasation that is assocd. with the formation of large dynamic rounded membrane protrusions. Our results demonstrate that extravasation of tumor cells is a highly dynamic process influenced by metastatic genes that target adhesion and intravascular migration of tumor cells, and induce endothelial remodeling.
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      Stoletov, K.; Montel, V.; Lester, R. D.; Gonias, S. L.; Klemke, R. High-Resolution Imaging of the Dynamic Tumor Cell-Vascular Interface in Transparent Zebrafish. Proc. Natl. Acad. Sci. U. S. A. 2007, 104 (44), 17406– 17411,  DOI: 10.1073/pnas.0703446104
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      High-resolution imaging of the dynamic tumor cell-vascular interface in transparent zebrafish
      Stoletov, Konstantin; Montel, Valerie; Lester, Robin D.; Gonias, Steven L.; Klemke, Richard
      Proceedings of the National Academy of Sciences of the United States of America (2007), 104 (44), 17406-17411CODEN: PNASA6; ISSN:0027-8424. (National Academy of Sciences)
      Cell metastasis is a highly dynamic process that occurs in multiple steps. Understanding this process has been limited by the inability to visualize tumor cell behavior in real time by using animal models. Here, we employ translucent zebrafish and high-resoln. confocal microscopy to study how human cancer cells invade in tissues, induce angiogenesis, and interact with newly formed vessels. We use this system to study how the human metastatic gene RhoC promotes the initial steps of metastasis. We find that RhoC expression induces a primitive amoeboid-like cell invasion characterized by the formation of dynamic membrane protrusions and blebs. Surprisingly, these structures penetrate the blood vessel wall exclusively at sites of vascular remodeling and not at regions of existing intact vessels. This process requires tumor cells to secrete VEGF, which induces vascular openings, which in turn, serve as portholes allowing access of RhoC-expressing cells to the blood system. Our results support a model in which the early steps in intravasation and metastasis require two independent events: (i) dynamic regulation of the actin/myosin cytoskeleton within the tumor cell to form protrusive structures and (ii) vascular permeabilization and vessel remodeling. The integration of zebrafish transgenic technol. with human cancer biol. may aid in the development of cancer models that target specific organs, tissues, or cell types within the tumors. Zebrafish could also provide a cost-effective means for the rapid development of therapeutic agents directed at blocking human cancer progression and tumor-induced angiogenesis.
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    32. 32
      Agemy, L.; Kotamraju, V. R.; Friedmann-Morvinski, D.; Sharma, S.; Sugahara, K. N.; Ruoslahti, E. Proapoptotic Peptide-Mediated Cancer Therapy Targeted to Cell Surface p32. Mol. Ther. 2013, 21 (12), 2195– 2204,  DOI: 10.1038/mt.2013.191
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      Proapoptotic Peptide-Mediated Cancer Therapy Targeted to Cell Surface p32
      Agemy, Lilach; Kotamraju, Venkata R.; Friedmann-Morvinski, Dinorah; Sharma, Shweta; Sugahara, Kazuki N.; Ruoslahti, Erkki
      Molecular Therapy (2013), 21 (12), 2195-2204CODEN: MTOHCK; ISSN:1525-0016. (Nature Publishing Group)
      Antiangiogenic therapy is a promising new treatment modality for cancer, but it generally produces only transient tumor regression. We have previously devised a tumor-targeted nanosystem, in which a pentapeptide, CGKRK, delivers a proapoptotic peptide into the mitochondria of tumor blood vessel endothelial cells and tumor cells. The treatment was highly effective in glioblastoma mouse models completely refractory to other antiangiogenic treatments. Here, we identify p32/gC1qR/HABP, a mitochondrial protein that is also expressed at the cell surface of activated (angiogenic) endothelial cells and tumor cells, as a receptor for the CGKRK peptide. The results demonstrate the ability of p32 to cause internalization of a payload bound to p32 into the cytoplasm. We also show that nardilysin, a protease capable of cleaving CGKRK, plays a role in the internalization of a p32-bound payload. As p32 is overexpressed and surface displayed in breast cancers, we studied the efficacy of the nanosystem in this cancer. We show highly significant treatment results in an orthotopic model of breast cancer. The specificity of cell surface p32 for tumor-assocd. cells, its ability to carry payloads to mitochondria, and the efficacy of the system in important types of cancer make the nanosystem a promising candidate for further development.
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      LeBert, D. C.; Squirrell, J. M.; Huttenlocher, A.; Eliceiri, K. W. Second Harmonic Generation Microscopy in Zebrafish. Methods Cell Biol. 2016, 133, 55– 68,  DOI: 10.1016/bs.mcb.2016.01.005
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      Second harmonic generation microscopy in zebrafish
      LeBert, D. C.; Squirrell, J. M.; Huttenlocher, A.; Eliceiri, K. W.
      Methods in Cell Biology (2016), 133 (Zebrafish: Cellular and Developmental Biology, Part A), 55-68CODEN: MCBLAG; ISSN:0091-679X. (Elsevier Inc.)
      Modem optical imaging has progressed rapidly with the ability to noninvasively image cellular and subcellular phenomena with high spatial and temporal resoln. In particular, emerging techniques such as second harmonic generation (SHG) microscopy can allow for the monitoring of intrinsic contrast, such as that from collagen, in live and fixed samples. When coupled with multiphoton fluorescence microscopy, SHG can be used to image interactions between cells and the surrounding extracellular environment. There is recent interest in using these approaches to study inflammation and wound healing in zebrafish, an important model for studying these processes. In this chapter we present the practical aspects of using second harmonic generation to image interactions between leukocytes and collagen during wound healing in zebrafish.
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      Nakamura, Y.; Mochida, A.; Choyke, P. L.; Kobayashi, H. Nanodrug Delivery: Is the Enhanced Permeability and Retention Effect Sufficient for Curing Cancer?. Bioconjugate Chem. 2016, 27 (10), 2225– 2238,  DOI: 10.1021/acs.bioconjchem.6b00437
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      Nanodrug Delivery: Is the Enhanced Permeability and Retention Effect Sufficient for Curing Cancer?
      Nakamura, Yuko; Mochida, Ai; Choyke, Peter L.; Kobayashi, Hisataka
      Bioconjugate Chemistry (2016), 27 (10), 2225-2238CODEN: BCCHES; ISSN:1043-1802. (American Chemical Society)
      A review. Nanotechnol. offers several attractive design features that have prompted its exploration for cancer diagnosis and treatment. Nano-sized drugs have a large loading capacity, the ability to protect the payload from degrdn., a large surface on which to conjugate targeting ligands and controlled or sustained release. Nano-sized drugs also leak preferentially into tumor tissue through permeable tumor vessels and are then retained in the tumor bed due to reduced lymphatic drainage. This process is known as 'the enhanced permeability and retention (EPR) effect'. However, while the EPR effect is widely held to improve delivery of nano-drugs to tumors, it in fact offers less than a 2-fold increase in nano-drug delivery compared with crit. normal organs, resulting in drug concns. that are not sufficient for curing most of cancers. In this review, we first overview various barriers for nano-sized drug delivery with an emphasis on the capillary wall's resistance, the main obstacle to delivering drugs. Then, we discuss current regulatory issues facing nanomedicine. Finally, we discuss how to make the delivery of nano-sized drugs to tumors more effective by building on the EPR effect.
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      Jain, R. K.; Stylianopoulos, T. Delivering Nanomedicine to Solid Tumors. Nat. Rev. Clin. Oncol. 2010, 7 (11), 653– 664,  DOI: 10.1038/nrclinonc.2010.139
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      Delivering nanomedicine to solid tumors
      Jain, Rakesh K.; Stylianopoulos, Triantafyllos
      Nature Reviews Clinical Oncology (2010), 7 (11), 653-664CODEN: NRCOAA; ISSN:1759-4774. (Nature Publishing Group)
      A review. Nanotechnol. offers great promise for the detection, prevention and treatment of cancer. Current limitations of this technol. include the heterogeneous distribution of nanoparticles to tumors, caused in part by the physiol. barriers presented by the abnormal tumor vasculature and interstitial matrix. This Review discusses these barriers and summarizes strategies that have been developed to overcome them. It addnl. examines design considerations for the optimization of delivery of nanoparticles to tumors. Recent advances in nanotechnol. have offered new hope for cancer detection, prevention, and treatment. While the enhanced permeability and retention effect has served as a key rationale for using nanoparticles to treat solid tumors, it does not enable uniform delivery of these particles to all regions of tumors in sufficient quantities. This heterogeneous distribution of therapeutics is a result of physiol. barriers presented by the abnormal tumor vasculature and interstitial matrix. These barriers are likely to be responsible for the modest survival benefit offered by many FDA-approved nanotherapeutics and must be overcome for the promise of nanomedicine in patients to be realized. Here, we review these barriers to the delivery of cancer therapeutics and summarize strategies that have been developed to overcome these barriers. Finally, we discuss design considerations for optimizing the delivery of nanoparticles to tumors.
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    36. 36
      Schädlich, A.; Caysa, H.; Mueller, T.; Tenambergen, F.; Rose, C.; Göpferich, A.; Kuntsche, J.; Mäder, K. Tumor Accumulation of NIR Fluorescent PEG-PLA Nanoparticles: Impact of Particle Size and Human Xenograft Tumor Model. ACS Nano 2011, 5 (11), 8710– 8720,  DOI: 10.1021/nn2026353
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      Tumor Accumulation of NIR Fluorescent PEG-PLA Nanoparticles: Impact of Particle Size and Human Xenograft Tumor Model
      Schadlich, Andreas; Caysa, Henrike; Mueller, Thomas; Tenambergen, Frederike; Rose, Cornelia; Gopferich, Achim; Kuntsche, Judith; Mader, Karsten
      ACS Nano (2011), 5 (11), 8710-8720CODEN: ANCAC3; ISSN:1936-0851. (American Chemical Society)
      Cancer therapies are often terminated due to serious side effects of the drugs. The cause is the nonspecific distribution of chemotherapeutic agents to both cancerous and normal cells. Therefore, drug carriers which deliver their toxic cargo specific to cancer cells are needed. Size is one key parameter for the nanoparticle accumulation in tumor tissues. In the present study the influence of the size of biodegradable nanoparticles was investigated in detail, combining in vivo and ex vivo anal. with comprehensive particle size characterizations. Polyethylene glycol-polyesters poly(lactide) block polymers were synthesized and used for the prodn. of three defined, stable, and nontoxic near-IR (NIR) dye-loaded nanoparticle batches. Size anal. based on asym. field flow field fractionation coupled with multiangle laser light scattering and photon correlation spectroscopy (PCS) revealed narrow size distribution and permitted accurate size evaluations. Furthermore, this study demonstrates the constraints of particle size data only obtained by PCS. By the multispectral anal. of the Maestro in vivo imaging system the in vivo fate of the nanoparticles next to their accumulation in special red fluorescent DsRed2 expressing HT29 xenografts could be followed. This simultaneous imaging in addn. to confocal microscopy studies revealed information about the accumulation characteristics of nanoparticles inside the tumor tissues. This knowledge was further combined with extended size-dependent fluorescence imaging studies at two different xenograft tumor types, the HT29 (colorectal carcinoma) and the A2780 (ovarian carcinoma) cell lines. The combination of two different size measurement methods allowed the characterization of the dependence of nanoparticle accumulation in the tumor on even rather small differences in the nanoparticle size. While two nanoparticle batches (111 and 141 nm in diam.) accumulated efficiently in the human xenograft tumor tissue, the slightly bigger nanoparticles (diam. 166 nm) were rapidly eliminated by the liver.
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      Perry, J. L.; Reuter, K. G.; Luft, J. C.; Pecot, C. V.; Zamboni, W.; DeSimone, J. M. Mediating Passive Tumor Accumulation through Particle Size, Tumor Type, and Location. Nano Lett. 2017, 17 (5), 2879– 2886,  DOI: 10.1021/acs.nanolett.7b00021
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      37
      Mediating Passive Tumor Accumulation through Particle Size, Tumor Type, and Location
      Perry, Jillian L.; Reuter, Kevin G.; Luft, J. Christopher; Pecot, Chad V.; Zamboni, William; DeSimone, Joseph M.
      Nano Letters (2017), 17 (5), 2879-2886CODEN: NALEFD; ISSN:1530-6984. (American Chemical Society)
      As the enhanced permeation and retention (EPR) effect continues to be a controversial topic in nanomedicine, we sought to examine EPR as a function of nanoparticle size, tumor model, and tumor location, while also evaluating tumors for EPR mediating factors such as microvessel d., vascular permeability, lymphatics, stromal content, and tumor-assocd. immune cells. Tumor accumulation was evaluated for 55 × 60, 80 × 180, and 80 × 320 nm PRINT particles in four s.c. flank tumor models (SKOV3 human ovarian, 344SQ murine nonsmall cell lung, A549 human nonsmall cell lung, and A431 human epidermoid cancer). Each tumor model revealed specific particle accumulation trends with evident particle size dependence. Immuno-histochem. staining revealed differences in tumor microvessel densities that correlated with overall tumor accumulation. Immunofluorescence images displayed size-mediated tumor penetration with signal from the larger particles concd. close to the blood vessels, while signal from the smaller particle was obsd. throughout the tissue. Differences were also obsd. for the 55 × 60 nm particle tumor penetration across flank tumor models as a function of stromal content. The 55 × 60 nm particles were further evaluated in three orthotopic, metastatic tumor models (344SQ, A549, and SKOV3), revealing preferential accumulation in primary tumors and metastases over healthy tissue. Moreover, we obsd. higher tumor accumulation in the orthotopic lung cancer models than in the flank lung cancer models, whereas tumor accumulation was const. for both orthotopic and flank ovarian cancer models, further demonstrating the variability in the EPR effect as a function of tumor model and location.
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      Zhou, Z.; Lu, Z.-R. Molecular Imaging of the Tumor Microenvironment. Adv. Drug Delivery Rev. 2017, 113, 24– 48,  DOI: 10.1016/j.addr.2016.07.012
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      Molecular imaging of the tumor microenvironment
      Zhou, Zhuxian; Lu, Zheng-Rong
      Advanced Drug Delivery Reviews (2017), 113 (), 24-48CODEN: ADDREP; ISSN:0169-409X. (Elsevier B.V.)
      The tumor microenvironment plays a crit. role in tumor initiation, progression, metastasis, and resistance to therapy. It is different from normal tissue in the extracellular matrix, vascular and lymphatic networks, as well as physiol. conditions. Mol. imaging of the tumor microenvironment provides a better understanding of its function in cancer biol., and thus allowing for the design of new diagnostics and therapeutics for early cancer diagnosis and treatment. The clin. translation of cancer mol. imaging is often hampered by the high cost of commercialization of targeted imaging agents as well as the limited clin. applications and small market size of some of the agents. Because many different cancer types share similar tumor microenvironment features, the ability to target these biomarkers has the potential to provide clin. translatable mol. imaging technologies for a spectrum of cancers and broad clin. applications. There has been significant progress in targeting the tumor microenvironment for cancer mol. imaging. In this review, we summarize the principles and strategies of recent advances made in mol. imaging of the tumor microenvironment, using various imaging modalities for early detection and diagnosis of cancer.
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      König, K.; Ehlers, A.; Riemann, I.; Schenkl, S.; Bückle, R.; Kaatz, M. Clinical Two-Photon Microendoscopy. Microsc. Res. Tech. 2007, 70 (5), 398– 402,  DOI: 10.1002/jemt.20445
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      Clinical two-photon microendoscopy
      Konig K; Ehlers A; Riemann I; Schenkl S; Buckle R; Kaatz M
      Microscopy research and technique (2007), 70 (5), 398-402 ISSN:1059-910X.
      Two-photon medical imaging has found its way into dermatology as an excellent method for noninvasive skin cancer detection without need of contrast agents as well as for in situ drug screening of topically-applied cosmetical and pharmaceutical components. There is an increasing demand to apply the multiphoton technology also for deep-tissue skin imaging as well as for intracorporal imaging. We report on the first clinical use of multiphoton endoscopes, in particular of a miniaturized rigid two-photon GRIN lens endoscope. The microendoscope was attached to the multiphoton tomograph DermaInspect and employed to detect the extracellular matrix proteins collagen and elastin in the human dermis of volunteers and patients with ulcera by in vivo second harmonic generation and in vivo two-photon autofluorescence.
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      Sanchez, G. N.; Sinha, S.; Liske, H.; Chen, X.; Nguyen, V.; Delp, S. L.; Schnitzer, M. J. In Vivo Imaging of Human Sarcomere Twitch Dynamics in Individual Motor Units. Neuron 2015, 88 (6), 1109– 1120,  DOI: 10.1016/j.neuron.2015.11.022
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      In Vivo Imaging of Human Sarcomere Twitch Dynamics in Individual Motor Units
      Sanchez, Gabriel N.; Sinha, Supriyo; Liske, Holly; Chen, Xuefeng; Nguyen, Viet; Delp, Scott L.; Schnitzer, Mark J.
      Neuron (2015), 88 (6), 1109-1120CODEN: NERNET; ISSN:0896-6273. (Cell Press)
      Motor units comprise a pre-synaptic motor neuron and multiple post-synaptic muscle fibers. Many movement disorders disrupt motor unit contractile dynamics and the structure of sarcomeres, skeletal muscle's contractile units. Despite the motor unit's centrality to neuromuscular physiol., no extant technol. can image sarcomere twitch dynamics in live humans. We created a wearable microscope equipped with a microendoscope for minimally invasive observation of sarcomere lengths and contractile dynamics in any major skeletal muscle. By elec. stimulating twitches via the microendoscope and visualizing the sarcomere displacements, we monitored single motor unit contractions in soleus and vastus lateralis muscles of healthy individuals. Control expts. verified that these evoked twitches involved neuromuscular transmission and faithfully reported muscle force generation. In post-stroke patients with spasticity of the biceps brachii, we found involuntary microscopic contractions and sarcomere length abnormalities. The wearable microscope facilitates exploration of many basic and disease-related neuromuscular phenomena never visualized before in live humans.
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      Yu, Z.; Pestell, T. G.; Lisanti, M. P.; Pestell, R. G. Cancer Stem Cells. Int. J. Biochem. Cell Biol. 2012, 44 (12), 2144– 51,  DOI: 10.1016/j.biocel.2012.08.022
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      Cancer stem cells
      Yu, Zuoren; Pestell, Timothy G.; Lisanti, Michael P.; Pestell, Richard G.
      International Journal of Biochemistry & Cell Biology (2012), 44 (12), 2144-2151CODEN: IJBBFU; ISSN:1357-2725. (Elsevier Ltd.)
      A review. Cancer stem cells (CSCs) are a small subpopulation of cells within tumors with capabilities of self-renewal, differentiation, and tumorigenicity when transplanted into an animal host. A no. of cell surface markers such as CD44, CD24, and CD133 are often used to identify and enrich CSCs. A regulatory network consisting of microRNAs and Wnt/β-catenin, Notch, and Hedgehog signaling pathways controls CSC properties. The clin. relevance of CSCs has been strengthened by emerging evidence, demonstrating that CSCs are resistant to conventional chemotherapy and radiation treatment and that CSCs are very likely to be the origin of cancer metastasis. CSCs are believed to be an important target for novel anti-cancer drug discovery. Herein the authors summarize the current understanding of CSCs, with a focus on the role of miRNA and epithelial-mesenchymal transition (EMT), and discuss the clin. application of targeting CSCs for cancer treatment.
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      Kachynski, A. V.; Pliss, A.; Kuzmin, A. N.; Ohulchanskyy, T. Y.; Baev, A.; Qu, J.; Prasad, P. N. Photodynamic Therapy by in Situ Nonlinear Photon Conversion. Nat. Photonics 2014, 8, 455,  DOI: 10.1038/nphoton.2014.90
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      Photodynamic therapy by in situ nonlinear photon conversion
      Kachynski, A. V.; Pliss, A.; Kuzmin, A. N.; Ohulchanskyy, T. Y.; Baev, A.; Qu, J.; Prasad, P. N.
      Nature Photonics (2014), 8 (6), 455-461CODEN: NPAHBY; ISSN:1749-4885. (Nature Publishing Group)
      In photodynamic therapy, light is absorbed by a therapy agent (photosensitizer) to generate reactive oxygen, which then locally kills diseased cells. Here, we report a new form of photodynamic therapy in which nonlinear optical interactions of near-IR laser radiation with a biol. medium in situ produce light that falls within the absorption band of the photosensitizer. The use of near-IR radiation, followed by upconversion to visible or UV light, provides deep tissue penetration, thus overcoming a major hurdle in treatment. By modeling and expt., we demonstrate activation of a known photosensitizer, chlorin e6, by in situ nonlinear optical upconversion of near-IR laser radiation using second-harmonic generation in collagen and four-wave mixing, including coherent anti-Stokes Raman scattering, produced by cellular biomols. The introduction of coherent anti-Stokes Raman scattering/four-wave mixing to photodynamic therapy in vitro increases the efficiency by a factor of two compared to two-photon photodynamic therapy alone, while second-harmonic generation provides a fivefold increase.
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      Costa, D. F.; Mendes, L. P.; Torchilin, V. P. The Effect of Low- and High-Penetration Light on Localized Cancer Therapy. Adv. Drug Delivery Rev. 2019, 138, 105,  DOI: 10.1016/j.addr.2018.09.004
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      The effect of low- and high-penetration light on localized cancer therapy
      Costa, Daniel F.; Mendes, Livia P.; Torchilin, Vladimir P.
      Advanced Drug Delivery Reviews (2019), 138 (), 105-116CODEN: ADDREP; ISSN:0169-409X. (Elsevier B.V.)
      The design of a delivery system allowing targeted and controlled drug release has been considered one of the main strategies used to provide individualized cancer therapy, to improve survival statistics, and to enhance quality-of-life. External stimuli including low- and high-penetration light have been shown to have the ability to turn drug delivery on and off in a non-invasive remotely-controlled fashion. The success of this approach has been closely related to the development of a variety of drug delivery systems - from photosensitive liposomes to gold nanocages - and relies on multiple mechanisms of drug release activation. In this review, we make ref. to the two extremes of the light spectrum and their potential as triggers for the delivery of antitumor drugs, along with the most recent achievements in preclin. trials and the challenges to an efficient translation of this technol. to the clin. setting.
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      Adler-Abramovich, L.; Gazit, E. The Physical Properties of Supramolecular Peptide Assemblies: From Building Block Association to Technological Applications. Chem. Soc. Rev. 2014, 43 (20), 6881– 6893,  DOI: 10.1039/C4CS00164H
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      The physical properties of supramolecular peptide assemblies: from building block association to technological applications
      Adler-Abramovich, Lihi; Gazit, Ehud
      Chemical Society Reviews (2014), 43 (20), 6881-6893CODEN: CSRVBR; ISSN:0306-0012. (Royal Society of Chemistry)
      A review. Bio-inspired nanomaterials can be formed by the ordered assembly of elementary building blocks using recognition modules and structural elements. Among the biol. sources, peptides and proteins are of special interest due to their role as major structural elements in all living systems, ranging from bacteria to humans in a continuum of magnitudes, from the nano-scale to the macro-scale. Peptides, as short as dipeptides, contain all the mol. information needed to form well-ordered structures at the nanoscale. Here, in light of the significant advancements in the field of peptide nanostructures in the last few years, the authors provide an updated overview of this subject. The use of these nanostructures was indeed recently demonstrated in various fields including the design of mol. motors based on nanostructure complexation with a metal-org. framework, the delivery of therapeutic agents, the development of energy storage devices and the fabrication of piezoelec.-based sensors.
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      Reches, M.; Gazit, E. Controlled Patterning of Aligned Self-Assembled Peptide Nanotubes. Nat. Nanotechnol. 2006, 1 (3), 195– 200,  DOI: 10.1038/nnano.2006.139
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      Controlled patterning of aligned self-assembled peptide nanotubes
      Reches, Meital; Gazit, Ehud
      Nature Nanotechnology (2006), 1 (3), 195-200CODEN: NNAABX; ISSN:1748-3387. (Nature Publishing Group)
      Controlling the spatial organization of objects at the nanoscale is a key challenge in enabling their technol. application. Biomol. assemblies are attractive nanostructures owing to their biocompatibility, straightforward chem. modifiability, inherent mol. recognition properties and their availability for bottom-up fabrication. Arom. peptide nanotubes are self-assembled nanostructures with unique phys. and chem. stability and remarkable mech. rigidity. Their application in the fabrication of metallic nanowires and in the improvement of the sensitivity of electrochem. biosensors have already been demonstrated. Here we show the formation of a vertically aligned nanoforest by axial unidirectional growth of a dense array of these peptide tubes. We also achieved horizontal alignment of the tubes through noncovalent coating of the tubes with a ferrofluid and the application of an external magnetic field. Taken together, our results demonstrate the ability to form a two-dimensional dense array of nanotube assemblies with either vertical or horizontal patterns.
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      Loretz, B.; Thaler, M.; Bernkop-Schnürch, A. Role of Sulfhydryl Groups in Transfection? A Case Study with Chitosan-NAC Nanoparticles. Bioconjugate Chem. 2007, 18 (4), 1028– 35,  DOI: 10.1021/bc0603079
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      Role of Sulfhydryl Groups in Transfection? A Case Study with Chitosan-N-acetylcysteine Nanoparticles
      Loretz, Brigitta; Thaler, Marlene; Bernkop-Schnuerch, Andreas
      Bioconjugate Chemistry (2007), 18 (4), 1028-1035CODEN: BCCHES; ISSN:1043-1802. (American Chemical Society)
      This study investigated the use of chitosan-N-acetylcysteine (NAC) as a non-viral gene carrier. In particular, we aimed to elucidate whether the advantage of thiolation was more pronounced in the stabilization of particles or in the effect of nonspecific sulfhydryl redn. of the target cells. Low-viscosity chitosan was modified by covalent binding of NAC. The resulting conjugate displayed 1.35 mM SH/g polymer. Particles produced via self-assembly of chitosan conjugate and pDNA had a mean particle size of 113.7 nm and a pos. ζ-potential. Sulfhydryl group content on the particle surface was investigated by Ellman's test and papain reactivation assay, with the result of about 100 nM SH groups/mL nanoparticle suspension. An oxidn. step was performed to stabilize polyplexes via disulfide bonds. The enhanced stability of oxidized particles against both polyanion heparin and alk. pH was proven by a gel retardation assay. The stabilization was demonstrated to be reversible by treatment with glutathione. Further, the effect of immobilized SH groups and of supplementation with free NAC on transfection efficacy on Caco-2 cells was investigated. The expression of the transgene was raised 2.5-fold and 10-fold with nonoxidized thiomer polyplexes in comparison to polyplexes of unmodified chitosan and oxidized chitosan-NAC, resp. The impact of sulfhydryl redn. on transfection was assessed via thiol group inactivation with 5,5'-dithiobis-(2-nitrobenzoic acid) (DNTB). This inactivation resulted in a decrease of transfection efficacy. In conclusion, chitosan-NAC conjugate was demonstrated to be beneficial for transfection, either for stabilization via disulfide bonds or for raising the expression of transgene via shifting the redox potential of the target cells.
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      Gasparini, G.; Sargsyan, G.; Bang, E. K.; Sakai, N.; Matile, S. Ring Tension Applied to Thiol-Mediated Cellular Uptake. Angew. Chem., Int. Ed. 2015, 54 (25), 7328– 31,  DOI: 10.1002/anie.201502358
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      Ring Tension Applied to Thiol-Mediated Cellular Uptake
      Gasparini, Giulio; Sargsyan, Gevorg; Bang, Eun-Kyoung; Sakai, Naomi; Matile, Stefan
      Angewandte Chemie, International Edition (2015), 54 (25), 7328-7331CODEN: ACIEF5; ISSN:1433-7851. (Wiley-VCH Verlag GmbH & Co. KGaA)
      The objective of the study was to explore the potential of ring tension in cyclic disulfides for thiol-mediated cellular uptake. Fluorescent probes that cannot enter cells were equipped with cyclic disulfides of gradually increasing ring tension. As demonstrated by flow cytometry expts., uptake into HeLa Kyoto cells increased with increasing tension. Differences in carbon-sulfur-sulfur-carbon (CSSC) dihedral angles as small as 8° caused significant changes in uptake efficiency. Uptake with high ring tension was better than with inactivated or activated linear disulfides or with thiols. Conversion of thiols on the cell surface into sulfides and disulfides decreased the uptake. Redn. of exofacial disulfides into thiols increased the uptake of transporters with disulfides and inactivated controls with thiols. These results confirm the occurrence of dynamic covalent disulfide-exchange chem. on cell surfaces. Mechanistic and colocalization studies indicate that endocytosis does not fully account for this cellular uptake with ring tension.
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      Dempsey, W. P.; Fraser, S. E.; Pantazis, P. PhOTO Zebrafish: A Transgenic Resource for in Vivo Lineage Tracing during Development and Regeneration. PLoS One 2012, 7 (3), e32888  DOI: 10.1371/journal.pone.0032888
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      PhOTO zebrafish: a transgenic resource for in vivo lineage tracing during development and regeneration
      Dempsey, William P.; Fraser, Scott E.; Pantazis, Periklis
      PLoS One (2012), 7 (3), e32888CODEN: POLNCL; ISSN:1932-6203. (Public Library of Science)
      Background: Elucidating the complex cell dynamics (divisions, movement, morphol. changes, etc.) underlying embryonic development and adult tissue regeneration requires an efficient means to track cells with high fidelity in space and time. To satisfy this criterion, we developed a transgenic zebrafish line, called PhOTO, that allows photoconvertible optical tracking of nuclear and membrane dynamics in vivo. Methodol.: PhOTO zebrafish ubiquitously express targeted blue fluorescent protein (FP) Cerulean and photoconvertible FP Dendra2 fusions, allowing for instantaneous, precise targeting and tracking of any no. of cells using Dendra2 photoconversion while simultaneously monitoring global cell behavior and morphol. Expression persists through adulthood, making the PhOTO zebrafish an excellent tool for studying tissue regeneration: after tail fin amputation and photoconversion of a ∼100μm stripe along the cut area, marked differences seen in how cells contribute to the new tissue give detailed insight into the dynamic process of regeneration. Photoconverted cells that contributed to the regenerate were sepd. into three distinct populations corresponding to the extent of cell division 7 days after amputation, and a subset of cells that divided the least were organized into an evenly spaced, linear orientation along the length of the newly regenerating fin. Conclusions/Significance: PhOTO zebrafish have wide applicability for lineage tracing at the systems-level in the early embryo as well as in the adult, making them ideal candidate tools for future research in development, traumatic injury and regeneration, cancer progression, and stem cell behavior.
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