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Bio-Conjugated Magnetic-Fluorescence Nanoarchitectures for the Capture and Identification of Lung-Tumor-Derived Programmed Cell Death Lighand 1-Positive Exosomes
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  • Avijit Pramanik
    Avijit Pramanik
    Department of Chemistry and Biochemistry, Jackson State University, Jackson, Mississippi 39217, United States
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    Orcidhttps://orcid.org/0000-0002-4623-2099
  • Shamily Patibandla
    Shamily Patibandla
    Department of Chemistry and Biochemistry, Jackson State University, Jackson, Mississippi 39217, United States
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  • Ye Gao
    Ye Gao
    Department of Chemistry and Biochemistry, Jackson State University, Jackson, Mississippi 39217, United States
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  • Lauren R. Corby
    Lauren R. Corby
    Department of Chemistry and Biochemistry, Jackson State University, Jackson, Mississippi 39217, United States
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  • Md Mhahabubur Rhaman
    Md Mhahabubur Rhaman
    Department of Chemistry and Biochemistry, Jackson State University, Jackson, Mississippi 39217, United States
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  • Sudarson Sekhar Sinha
    Sudarson Sekhar Sinha
    Department of Chemistry and Biochemistry, Jackson State University, Jackson, Mississippi 39217, United States
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    Orcidhttps://orcid.org/0000-0002-0831-2338
  • Paresh Chandra Ray*
    Paresh Chandra Ray
    Department of Chemistry and Biochemistry, Jackson State University, Jackson, Mississippi 39217, United States
    *Email: [email protected]. Fax: +16019793674.
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    Orcidhttps://orcid.org/0000-0001-5398-9930
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ACS Omega

Cite this: ACS Omega 2022, 7, 18, 16035–16042
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https://doi.org/10.1021/acsomega.2c01210
Published April 25, 2022

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Abstract

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As per the American Cancer Society, lung cancer is the leading cause of cancer-related death worldwide. Since the accumulation of exosomal programmed cell death ligand 1 (PD-L1) is associated with therapeutic resistance in programmed cell death 1 (PD-1) and PD-L1 immunotherapy, tracking PD-L1-positive (PD-L1 (+)) exosomes is very important for predicting anti-PD-1 and anti-PD-L1 therapy for lung cancer. Herein, we report the design of an anti-PD-L1 monoclonal antibody-conjugated magnetic-nanoparticle-attached yellow fluorescent carbon dot (YFCD) based magnetic-fluorescence nanoarchitecture for the selective separation and accurate identification of PD-L1-expressing exosomes. In this work, photostable YFCDs with a good photoluminescence quantum yield (23%) were synthesized by hydrothermal treatment. In addition, nanoarchitectures with superparamagnetic (28.6 emu/g), biocompatible, and selective bioimaging capabilities were developed by chemically conjugating the anti-PD-L1 antibody and YFCDs with iron oxide nanoparticles. Importantly, using human non-small-cell lung cancer H460 cells lines, which express a high amount of PD-L1 (+) exosomes, A549 lung cancer cells lines, which express a low amount of PD-L1 (+) exosomes, and the normal skin HaCaT cell line, which does not express any PD-L1 (+) exosomes, we demonstrate that nanoarchitectures are capable of effectively separating and tracking PD-L1-positive exosomes simultaneously. Furthermore, as a proof-of-concept of clinical setting applications, a whole blood sample infected with PD-L1 (+) exosomes was analyzed, and our finding shows that this nanoarchitecture holds great promise for clinical applications.

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1. Introduction

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As per the World Health Organization (WHO) and the American Cancer Society, even in 2021, lung cancer remains the leading cause of cancer-related death. (1,2) Among lung cancer patients, non-small-cell lung cancer (NSCLC) causes most of the deaths. (3−7) The reported lower survival rate for NSCLC is mainly due to its diagnosis at the advanced stages. (3−7) Recent advancement shows that immunotherapies using antibodies that target the programmed cell death 1 (PD-1) and programmed cell death ligand 1 (PD-L1) pathways (PD-1/PD-L1) have enhanced antitumor effects for NSCLC patients, which help to increase the survival rate. (8−13) In the last five years, clinical data have shown that anti-PD1/PDL1 therapy produced a limited response for many lung cancer patients. (10−16)
Recent clinical studies show that the excessive accumulation of exosomal PDL1 in the lymph node is associated with therapeutic resistance in PD-1/PD-L1 immunotherapy. (8−16) Due to the above fact, evaluating the presence of exosomal PD-L1 is very important to determine the immune escape and tumor progression. (12−17)
Herein, we report the design of an anti-PDL1 monoclonal antibody-conjugated magnetic-nanoparticle-attached yellow fluorescence carbon dot (YFCDs) based magnetic-fluorescence nanoarchitecture, as shown in Figure 1, which is capable of the targeted separation and accurate identification of PD-L1-expressing exosomes.

Figure 1

Figure 1. Scheme showing the design of the anti-PD-L1 monoclonal antibody-conjugated magnetic-fluorescence nanoarchitecture. (A) Hydrothermal synthesis of YFCDs from o-phenylenediamine and 4-aminobutyric acid. (B) Synthesis of acid-functionalized magnetic nanoparticles. (C) Synthesis of YFCD-attached magnetic nanoparticles. D) Synthesis of the anti-PD-L1 monoclonal antibody-attached nanoarchitecture.

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Exosomes are smaller sized (>200 nm) membrane vesicles that contain biologically active m-RNA, proteins, lipids, DNA, and other nucleic acids. (12−22) It is now well-documented that exosomes play a major role in the regulation of metastasis via cell-to-cell communication. (12−22) Several clinical studies indicate that exosome-carrying PD-L1 can be associated with a suppression of the antitumor immune response for NSCLC. (10−17) As a result, analyzing the PD-L1 expression exosomes in the tumor microenvironment is very important for the clinical success of lung cancer treatment. (12−17) Since biological fluids containing exosomes also have cell debris, proteins, different types of other vesicles, and several biologically important molecules, as we and others have reported before, isolation and enrichment steps are the initial steps to separate an exosome before it can be analyzed. (12−22) For this purpose, we have designed an immunomagnetic nanoarchitecture that can be used to isolate the PD-L1-positive (PD-L1 (+)) exosome from the cell culture and a whole-blood sample. In our design, an anti-PD-L1 antibody is used to bind the PD-L1 (+) exosome, and the exosome-attached magnetic nanoparticles are separated using a simple bar magnet. In addition, we have used YFCDs for the accurate identification of the PD-L1 (+) exosome after magnetic separation. Due to their simple large-scale synthesis, low toxicity, high fluorescence quantum yield, and excellent chemical stability, (23−37) YFCDs were used for the bioimaging of the PD-L1 (+) exosome. We used yellow fluorescence for exosome imaging because it has better tissue penetration and to avoid blue auto-fluorescence from the cell matrix. (30−34)

2. Results and Discussion

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2.1. Synthesis, Microscopy Characterization, and Optical Properties of Yellow Fluorescence Carbon Dots

The yellow fluorescent carbon dots (YFCDs) were synthesized by a hydrothermal treatment using o-phenylenediamine and γ-aminobutyric acid. (30) The experimental details are reported in the Supporting Information. For this purpose, o-phenylenediamine and γ-aminobutyric acid were added to distilled water, and the mixture was sonicated for 30 min. After that, the solution was heated for 8 h at 160 °C using a Teflon-lined stainless-steel autoclave. Next, we cooled the mixture to room temperature and then filtered it through membrane filter paper with a pore size of 0.45 μm. After that, we dialyzed the mixture with 3.5 KD MWCO Snakeskin dialysis tubing for three days. Finally, the pure solid product was obtained after lyophilization for 3–5 days by a freeze-drying process.
To characterize the YFCDs, we used high-resolution tunneling electron microscopy (HR-TEM), X-ray photoelectron spectroscopy (XPS), absorption spectroscopy, and fluorescence spectroscopy in addition to photoluminescence quantum yield (PLQY), fluorescence lifetime analysis, and dynamic light scattering (DLS) measurements (20,31,32,34) as reported in Figure 2 and Table S1 in the Supporting Information. The TEM image reported in Figure 2A shows the morphology of the YFCDs and indicates that the size of the YFCDs is ∼5 ± 2 nm. The size measurement by TEM matches very well with the DLS data, as reported in Table S1 in the Supporting Information. The inserted high-resolution TEM image indicates graphite type lattice fringes, where the interplanar spacing is ∼0.35 nm. From the energy-dispersive X-ray spectroscopy (EDX) analysis, we determined amount of C, N, O, and H to be ∼60%, ∼18%, ∼12%, and ∼10%, respectively. Figure 2F shows the XPS data for the YFCDs, which clearly indicate the presence of a C 1s peak at 284.8 eV, an O 1s peak at 532.5 eV, and a N 1s peak at 398.1 eV. (30−33) On the basis of the XPS and EDX data, we can conclude that YFCDs contains both carboxy and amine groups in the surface, as shown in Figure 1A.

Figure 2

Figure 2. (A) TEM image showing the morphology of yellow luminescent carbon dots derived from o-phenylenediamine and 4-aminobutyric acid. The inserted HR-TEM image shows graphite-type lattice fringes with an interplanar spacing of 0.35 nm for carbon dots derived from o-phenylenediamine and 4-aminobutyric acid. (B) TEM image showing the morphology of the acid-functionalized magnetic nanoparticles. The inserted EDX elemental map shows the presence of Fe. (C) TEM image showing the morphology of the yellow luminescent carbon dot-attached magnetic nanoparticle. The inserted EDX elemental map shows the presence of Fe and C. (D) FTIR spectrum from the yellow luminescent carbon dot-attached magnetic nanoparticle showing the presence of amide A, amide-I, amide-II, amide-III, and other bands. (E) The X-ray diffraction pattern from the yellow luminescent carbon dot-attached magnetic nanoparticle confirms the presence of (002) indices for graphitic carbon and (220), (311), (222), (511), and (440) indices for the magnetic nanoparticles. (F) The XPS spectrum from the yellow luminescent carbon dot-attached magnetic nanoparticle confirms peaks at 284.8, 398.1, 532.5, and 711.2 eV due to Fe, O, N and C, respectively.

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Figure 3A shows the absorption spectra of the YFCDAs, which clearly show two absorption peaks. The first higher-energy absorption peak, which is mainly due to the π–π* transition of C–C bonds within the cores of the YFCDs, was observed at 260 nm. (30−32) On the other hand, the second lower-energy absorption peak, which is mainly due to the n → π* transitions in C–O bonds originating from the surface functional groups attached to the carbon backbone of YFCDs, was observed at 436 nm. (30−33) Panels B and C in Figure 3 show photographs of the YFCDs in the presence and absence of 380 nm UV light, respectively. The photograph shown in Figure 3C clearly shows the emission of strong yellow fluorescence from the YFCDs in the presence of 380 nm UV light. Panels D and E of Figure 3 show the emission spectra of the YFCDs at excitation wavelengths of 300 and 480 nm, respectively. We observed two emission peaks when the YFCDs were excited at 300 nm, as shown in Figure 3D. The first sharp peak is visible around λmax = 390 nm of the emission, which is mainly due to the core emission from YFCDs. The sharp emission arises due to quantum confinement effects and the presence of π-domains within the cores of the YFCDs. The second broad peak is visible around λmax = 570 nm of the emission, which is mainly due to the surface −OH, −NH, ─C═O functional groups and other groups bonded to the cores of the YFCDs. (30−33) We observed only one emission peak when the YFCDs were excited at 480 nm, as shown in Figure 3E. The observed broad peak is around 570 nm, showing that the broad luminescence spectrum remains unchanged for YFCDs even when the the excitation wavelength is varied from 300 to 480 nm. To measure the photoluminescence quantum yield (PLQY), we used quinine sulfate as a standard (QY = 54%). (20,31−33) By measuring the fluorescence intensity from a standard and the YFCDs, we determined the PLQY for YFCDS is 0.31 at an excitation wavelength of 480 nm. Figure 3F shows the time-dependent photoluminescence decay profiles for YFCDs at an excitation wavelength of 480 nm. The observed that the time-resolved decays can be fit very well by a double -exponential function with τ1 = 1.8 ns and τ3 = 11.4 ns.

Figure 3

Figure 3. (A) Absorption spectrum of the YFCDs, which indicates two absorption peaks. The π–π* transition is visible at 260 nm, and the other transition due the functional groups conjugated on CDs is visible at 436 nm. (B) Photograph of YFCDs in the absence of UV light. (C) Photograph of YFCDs in the presence of UV light showing the strong yellow emission. (D) Emission spectrum of YFCDs in the presence of 300 nm excitation light. (E) Emission spectra of YFCDs and the anti-PD-L1 monoclonal antibody-conjugated magnetic-nanoparticle-attached YFCD-based nanoarchitecture in the presence of 480 nm excitation light. (F) Plot showing the time-resolved photo luminescence decay of YFCDs and the anti-PD-L1 monoclonal antibody-conjugated magnetic-nanoparticle-attached YFCD-based nanoarchitecture in the presence of 480 nm excitation light. (G) Luminescence intensity of the anti-PD-L1 monoclonal antibody-conjugated magnetic-nanoparticle-attached YFCDs as a function of time in the presence of 480 nm excitation light. The experiment was performed five times, and error bars were calculated from the standard deviation.

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2.2. Synthesis, Microscopy Characterization, Magnetic and Optical Properties of the Anti-PD-L1 Monoclonal Antibody-Conjugated Nanoarchitecture

We have designed an anti-PD-L1 monoclonal antibody-conjugated magnetic-nanoparticle-attached YFCD-based multifunctional magnetic-fluorescence nanoarchitecture using a four-step procedure, as reported in Figure 1. In the first step, the yellow fluorescent carbon dots were synthesized as discussed in the previous section. In second step, carboxylic acid-functionalized magnetic nanoparticles were synthesized. As shown in Figure 1B, we used a coprecipitation method with ferric chloride and 1,6-hexanedioic acid for this purpose. (31−33) The experimental details are reported in the Supporting Information. After the reaction between ferric chloride and 1,6-hexanedioic acid was complete, the black precipitate was separated using a neodymium magnet. (31,32) The TEM image shown in Figure 2B shows the morphology of the acid-functionalized magnetic nanoparticle and indicates that the nanoparticle’s size is ∼20 ± 5 nm. The size measurement by TEM matches very well with the DLS data, as reported in Table S1 in the Supporting Information. Inserted energy-dispersive X-ray spectroscopy (EDX) mapping data from the magnetic nanoparticles, as reported in Figure 2B, indicates the presence of Fe. We measured the superparamagnetic properties using as SQUID magnetometer, as we have reported before, (31−33) and obtained a specific saturation magnetization of ∼34.6 emu/g.
As shown in the Figure 1C, in the third step we developed the multifunctional magnetic fluorescence nanoplatform by conjugating the acid-functionalized magnetic nanoparticle with the amine group of the YFCDS. The experimental details are reported in the Supporting Information. For this purpose, we used 1-ethyl-3-(3-(dimethylamino)propyl)-carbodiimide (EDC)-N-hydroxy succinimide (NHS) mediated esterification process, as reported previously by us and others. (31−33) Once the reaction was finished, we separated the YFCD-conjugated magnetic nanoparticles using a magnet. The TEM image shown in Figure 2C shows the morphology of the YFCD-conjugated magnetic nanoparticle and indicates that the nanoparticle’s size is ∼30 ± 6 nm. The size measurement by TEM matches very well with the DLS data, as reported in Table S1 in the Supporting Information. Energy-dispersive X-ray spectroscopy (EDX) mapping data from the nanoarchitecture, as reported in Figure S1A, and elemental mapping EDX data, as reported in Figure S1B, show the presence of Fe, C, O, and N, indicating that the YFCDs are conjugated with the magnetic nanoparticle. Figure 2D shows the FTIR spectrum of the YFCD-conjugated magnetic nanoparticle, where we can clearly see the presence of amide A, amide-I, amide-II, amide-III, and other bands. The presence of these bands indicates the coupling of the YFCDs with the magnetic nanoparticles via the esterification process. (31,32)Figure 2F shows the XPS data for the YFCD-conjugated magnetic nanoparticles, which clearly indicate the presence of a C 1s peak at 284.8 eV, an O 1s peak at 532.5 eV, a N 1s peak at 398.1 eV, and an Fe 2p peak at 712.4 eV. (31,32) We measured the superparamagnetic properties of the YFCD-attached magnetic nanoparticle using as SQUID magnetometer, and we obtained a specific saturation magnetization of ∼29.4 emu/g.
As shown in Figure 1D, in the fourth step we the conjugated anti-PD-L1 monoclonal antibody with the magnetic-nanoparticle-attached YFCDs. For this purpose, we used the EDC-NHS-mediated esterification process with the amine group of the antibody and the functionalized acid group of nanoarchitectures, as reported previously by us and others. (31,32,34) Once the reaction was finished, we separated the anti-PD-L1 monoclonal antibody-conjugated magnetic-nanoparticle-attached YFCDs using a magnet. To understand the amount of anti-PD-L1 monoclonal antibodies attached to the YFCDS-attached magnetic nanoparticles, we performed thermogravimetric analysis, as reported in Figure S1C in the Supporting Information. This analysis indicated that the weight percentage of the antibodies was around 4.1%. Figure 3E shows the emission spectrum from the nanoarchitecture at an excitation wavelength of 480 nm. By measuring the fluorescence intensity from the quinine sulfate standard and the anti-PD-L1 monoclonal antibody-conjugated magnetic-nanoparticle-attached YFCDs, we determined the PLQY of the nanoarchitecture to be 0.26 at an excitation wavelength of 480 nm. Figure 3F shows the time-dependent photo luminescence decay profiles of the anti-PD-L1 monoclonal antibody-conjugated magnetic-nanoparticle-attached YFCDs at an excitation wavelength of 480 nm. The observed time-resolved decays can be fit very well by a double-exponential function with τ1 = 1.9 ns and τ3 = 12.6 ns.

2.3. Finding the Photostability and Cytotoxicity of Antibody-Conjugated Magnetic-Nanoparticle-Attached YFCD Nanoarchitectures

Since photostability is one of the most important parameters for the optical imaging of biomolecules, (30−37) we determined the photostability of the anti-PD-L1 monoclonal antibody-conjugated magnetic-nanoparticle-attached YFCD-based nanoarchitectures. For this purpose, we performed time-dependent luminescence experiments for 2 h using an excitation wavelength of 480 nm. As reported in Figure 3G, the luminescence intensity from anti-PD-L1 monoclonal antibody-conjugated magnetic-nanoparticle-attached YFCD-based nanoarchitectures changed less than 5%, even after 2 h of exposure to 480 nm light. The data clearly show that the anti-PD-L1 monoclonal antibody-conjugated magnetic-nanoparticle-attached YFCD-based nanoarchitecture is photostable for bioimaging purposes. Since cytotoxicity is an important parameter for bioimaging applications, (30−37) we next determined the possible toxicity of the anti-PD-L1 monoclonal antibody-conjugated magnetic-nanoparticle-attached YFCD-based nanoarchitectures. For this purpose, we used breast cancer SK-BR-3 cells, normal skin HaCaT cells, prostate cancer LnCaP cells, and lung cancer H1264 and A549 cells. (20,31,32,34)
Initially, all cells were treated with the nanoarchitecture for 48 h. After that, we used an MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) assay to determine the cell viability. (20,31,32,34) The experimental details for the cell viability assays are reported in the Supporting Information. As reported in Figure 4A, our experimental data show that the cell viability hardly changed after treatment with the magnetic-nanoparticle-attached YFCDs based nanoarchitectures, indicating that the nanoarchitectures are highly biocompatible.

Figure 4

Figure 4. (A) Viability of LaCaT normal skin cells, SK-BR-3 breast cancer cells, LnCaP prostate cancer cells, and H1264 and A549 lung cancer cells after 24 h of treatment with the nanoarchitecture. The experiment was performed five times, and error bars were calculated from the standard deviation. (B) The percent of PD-L1-positive exosomes separated from different cell lines. We used the human PD-L1 ELISA kit for the quantitation of the PD-L1 (+) exosomes. (C) Photograph showing the separation of the PD-L1 (+) exosome-attached nanoarchitectures using bar magnet. The experiment was performed five times, and error bars were calculated from the standard deviation. (D) SEM image of PD-L1 (+) exosomes after magnetic separation from the H460 cell line. The inserted TEM image and SEM image show the nanostructures attached the PD-L1 (+) exosomes. (E) Bright-field image of the PD-L1 (+) exosome-attached nanoarchitectures after magnetic separation from the H460 cell line. (F) Fluorescence image showing the high number of PD-L1 (+) exosome-attached nanoarchitectures after magnetic separation from the H460 cell line. (G) Fluorescence image showing the low number of PD-L1 (+) exosomes after magnetic separation from the A549 cell line using the nanoarchitecture. (H) Fluorescence image showing the absence of PD-L1 (+) exosomes after magnetic separation from the HaCaT cell line using the nanoarchitecture. (I) Fluorescence image showing PD-L1 (+) exosome-attached nanoarchitectures after magnetic separation from the whole-blood sample.

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2.4. Demonstrating That Antibody-Conjugated Nanoarchitectures Can Be Used for the Selective Separation and the Accurate Identification of PD-L1-Expressing Exosomes

Due to the good photoluminescence quantum yield, photostability, superparamagnetic property, and high biocompatibility of the anti-PD-L1 monoclonal antibody-conjugated magnetic-nanoparticle-attached YFCD-based nanoarchitectures, we explored the possibility of using the nanostructures to track PD-L1 (+) exosomes. For this purpose, we used human NSCLC H460 cells lines, which express a high amount of the PD-L1 (+) exosomes, A549 lung cancer cells lines, which express a low amount of the PD-L1 (+) exosomes, and the normal skin HaCaT cell line, which does not express PD-L1 (+) exosomes. All cells were cultured using an ATCC (American Type Culture Collection) culture medium until they reached 60–70% confluency. (19,20) The experimental details for the cell culture are reported in the Supporting Information. After that, we replaced the culture medium with the exosome-depleted medium. (19,20) Next, non-small-cell lung cancer H460 cells, A549 lung cancer cells, and normal skin HaCaT cells were cultured for another three days. At the end, PD-L1 (+) exosomes and other types of exosomes were separated by differential centrifugation by removing cell debris and other different types of vesicles, as reported previously by us and others. (19−24) After that, we used DLS and SEM techniques to find the size distribution of the exosomes separated from different cell lines, as reported in Figures S2 and S3 and Table S2 in the Supporting Information. Using the DLS data reported in Table S2 and SEM data for exosomes separated from H460 and HaCaT cell lines, we found that the size of exosomes varies between 100 and 160 nm. We have also used the human PD-L1 enzyme-linked immunoassay kit for the quantitation of the PD-L1 (+) exosomes. (13−17) The ELISA data, shown in Figure 4B, indicate that the percentage of PD-L1 (+) exosomes is much higher for non-small-cell lung cancer H460 cells lines than for A549 lung cancer cells lines. We did not observe detectable PD-L1 (+) exosomes in case of the normal skin HaCaT cell line.
Next, to understand whether anti-PD-L1 monoclonal antibody-conjugated magnetic-nanoparticle-attached YFCD-based nanoarchitectures can be used for the accurate capture and selective identification of PD-L1 (+) exosomes, we mixed the nanoarchitectures (500 μg/mL) with cell culture supernatants. After being mixed continuously for 30 min, the nanoarchitecture-attached exosomes were separated using a bar magnet, as shown in Figure 4C. After that, we also used the human PD-L1 enzyme-linked immunoassay kit for the quantitation of the PD-L1 (+) exosomes. (13−17) The eperimental ELISA results are very similar to those we obtained by differential centrifugation. After magnetic separation, using the ELISA data, we found that the percentage of PD-L1 (+) exosomes is around five-times higher for non-small-cell lung cancer H460 cells lines than for A549 lung cancer cells lines. Additionally, we did not observe detectable PD-L1 (+) exosomes for normal skin HaCaT cell line. To compare the magnetic separation and exosome imaging efficiency of the nanoarchitecture with those of the separate magnetic nanoparticles and YFCDs , we separately performed the PD-L1 (+) exosome separation experiment with lung cancer H460 cell culture supernatants using the anti-PDL1 monoclonal antibody-conjugated carbon dots (500 μg/mL) and the anti-PDL1 monoclonal antibody-conjugated iron oxide nanoparticles (500 μg/mL). We used the PD-L1 enzyme-linked immunoassay kit for the quantitation of the PD-L1 (+) exosomes. As reported in Table S3 in the Supporting Information, the observed separation of PD-L1 (+) exosomes is 0% for YFCDs and 98 ± 2% for both the anti-PDL1 monoclonal antibody-conjugated iron oxide nanoparticles and the anti-PDL1 monoclonal antibody-conjugated nanoarchitectures. Similarly, as reported in Figure S4A and B in the Supporting Information, we did not observe any fluorescence image from the separated PD-L1 (+) exosomes when they were separated by anti-PDL1 monoclonal antibody-conjugated iron oxide nanoparticles in the absence of YFCDs. Similarly the fluorescence image shown in Figure S4C in the Supporting Information, shows the absence of PD-L1 (+) exosomes after separation when we tried to separate them using antibody-attached YFCDs. All the above data clearly show that the conjugation of YFCDs with magnetic nanoparticles is necessary for the separation and imaging of PD-L1 (+) exosomes from the cell culture supernatant.
The TEM image shown in Figure 4D clearly indicates that the anti-PD-L1 monoclonal antibody-conjugated nanoarchitectures are attached on the surfaces of the PD-L1 (+) exosomes. Similarly, the yellow fluorescence image of the PD-L1 (+) exosomes shown in Figure 4F shows that the anti-PD-L1 monoclonal antibody-conjugated magnetic-nanoparticle-attached YFCD-based nanoarchitectures can identify PD-L1 (+) exosomes after magnetic separation. Our experimental data clearly indicate that the anti-PD-L1 monoclonal antibody-conjugated magnetic-nanoparticle-attached YFCD-based nanoarchitectures are capable of the accurate separation and identification of PD-L1 (+) exosomes via fluorescence imaging.
Next, to find out whether the anti-PD-L1 monoclonal antibody-conjugated magnetic-nanoparticle-attached YFCD-based nanoarchitectures have the capability for the selective tracking of PD-L1 (+) exosomes, we also performed the same experiment with A549 lung cancer cells lines, which express a low amount of PD-L1 (+) exosomes, and the normal skin HaCaT cell line, which expresses the PD-L1 (−) exosome. As shown in Figure 4G, the yellow fluorescence image of the PD-L1 (+) exosomes shows that the anti-PD-L1 monoclonal antibody-conjugated nanoarchitectures can identify very few PD-L1 (+) exosomes after magnetic separation, which clearly shows that the number of PD-L1 (+) exosomes expressed by A549 lung cancer cells lines is much lower compared to that expressed by the lung cancer H460 cells lines. Similarly, as shown in Figure 4H, no PD-L1 (+) exosomes were separated by the anti-PD-L1 monoclonal antibody-conjugated nanoarchitectures from the normal skin HaCaT cell line. The above data clearly show that anti-PD-L1 monoclonal antibody-conjugated nanoarchitecture-based separation and identification of PD-L1 (+) exosomes is highly selective. Our experimental results also indicate that the normal skin HaCaT cell line does not express detectable PD-L1 (+) exosomes.
To understand whether anti-PD-L1 monoclonal antibody-conjugated nanoarchitectures can be used for the selective capture and identification of PD-L1 (+) exosomes from blood samples, we have used exosome-infected citrated whole rabbit blood as a proof-of-concept of clinical setting applications. For this purpose, 12 000 exosomes/mL PD-L1 (+) exosomes were injected into 5 mL of whole blood. After that, we added one million peripheral blood mononuclear cells per milliliter into the blood sample. In next step, the mixture was shaken gently for 2 h. We then combined the mixture with the nanoarchitectures (500 μg/mL). After the mixture was mixed for half an hour, nanoarchitecture-attached exosomes were separated using a bar magnet. Using the human PD-L1 enzyme-linked immunoassay kit, we found a PD-L1 (+) exosomes recovery of about 100%, as reported in Figure S5 in the Supporting Information. Figure 4I shows the yellow fluorescence image of the PD-L1 (+) exosomes after magnetic separation from whole blood. All the above data clearly indicate that the anti-PD-L1 monoclonal antibody-conjugated magnetic-nanoparticle-attached YFCD-based nanoarchitectures are capable of the accurate separation and identification of PD-L1 (+) exosomes via fluorescence imaging from an infected blood sample.

3. Conclusions

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In summary, we have designed and synthesized bioconjugated magnetic-nanoparticle-attached YFCD-based nanoarchitectures for the magnetic separation and identification of PD-L1 (+) exosomes. More importantly, using different microscopic and spectroscopic characterization techniques, we have demonstrated that the bioconjugated magnetic-nanoparticle-attached YFCD-based nanoarchitectures exhibit a good photoluminescence quantum yield (23%) and superparamagnetic (28.6 emu/g) behavior. Additionally, they are photostable and highly biocompatible. In this work, our finding reveals that anti-PD-L1 monoclonal antibody-conjugated magnetic-nanoparticle-attached YFCD-based nanoarchitectures are capable of accurately separating and tracking PD-L1 (+) exosomes from cancer cell lines as well as from a blood sample. In addition, using two different human lung cancer cells lines that expressed high and low amounts of PD-L1 (+) exosomes, we showed that the nanoarchitectures are capable of the effective separation and accurate identification of PD-L1 (+) exosomes via yellow luminescence imaging. On the other hand, using a cell line that expressed the PD-L1 (−) exosome, we further demonstrated that the nanoarchitecture-based separation and tracking of PD-L1 (+) exosomes is highly selective. As a proof-of-concept of clinical setting applications, we used a PD-L1 (+) exosome-infected whole-blood sample to demonstrate that nanoarchitectures are capable of separating and imaging PD-L1 (+) exosomes from infected blood sample. Taken together, reported data show the design of an innovative nanoplatform that has the potential to be a powerful tool for improving lung cancer detection and therapy.

Supporting Information

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The Supporting Information is available free of charge at https://pubs.acs.org/doi/10.1021/acsomega.2c01210.

  • Design and characterization of the anti-PD-L1 monoclonal antibody=conjugated magnetic-nanoparticle-attached YFCD-based nanoarchitectures and other experiments, including cell cultures, separation of the PD-L1 (+) exosomes, and luminescence imaging (PDF)

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Author Information

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  • Authors
    • Avijit Pramanik - Department of Chemistry and Biochemistry, Jackson State University, Jackson, Mississippi 39217, United States;  Orcidhttps://orcid.org/0000-0002-4623-2099
    • Shamily Patibandla - Department of Chemistry and Biochemistry, Jackson State University, Jackson, Mississippi 39217, United States
    • Ye Gao - Department of Chemistry and Biochemistry, Jackson State University, Jackson, Mississippi 39217, United States
    • Lauren R. Corby - Department of Chemistry and Biochemistry, Jackson State University, Jackson, Mississippi 39217, United States
    • Md Mhahabubur Rhaman - Department of Chemistry and Biochemistry, Jackson State University, Jackson, Mississippi 39217, United States
    • Sudarson Sekhar Sinha - Department of Chemistry and Biochemistry, Jackson State University, Jackson, Mississippi 39217, United States;  Orcidhttps://orcid.org/0000-0002-0831-2338
  • Notes
    The authors declare no competing financial interest.

Acknowledgments

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Dr. Ray thanks NSF-PREM (Grant DMR-1826886) for their generous funding, which was used for the design of the nanoarchitectures. We are also thankful for NIH-NIMHD Grant U54MD015929-01 for lung cancer research and the bioimaging core facility.

References

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This article references 37 other publications.

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    Kwizera, Elyahb Allie; O'Connor, Ryan; Vinduska, Vojtech; Williams, Melody; Butch, Elizabeth R.; Snyder, Scott E.; Chen, Xiang; Huang, Xiaohua
    Theranostics (2018), 8 (10), 2722-2738CODEN: THERDS; ISSN:1838-7640. (Ivyspring International Publisher)
    Exosomes are a potential source of cancer biomarkers. Probing tumor-derived exosomes can offer a potential non-invasive way to diagnose cancer, assess cancer progression, and monitor treatment responses. Novel mol. methods would facilitate exosome anal. and accelerate basic and clin. exosome research. Methods: A std. gold-coated glass microscopy slide was used to develop a miniaturized affinity-based device to capture exosomes in a target-specific manner with the assistance of low-cost 3-D printing technol. Gold nanorods coated with QSY21 Raman reporters were used as the label agent to quant. detect the target proteins based on surface enhanced Raman scattering spectroscopy. The expressions of several surface protein markers on exosomes from conditioned culture media of breast cancer cells and from HER2-pos. breast cancer patients were quant. measured. The data was statistically analyzed and compared with healthy controls. Results: A miniaturized 17 × 5 Au array device with 2-mm well size was fabricated to capture exosomes in a target-specific manner and detect the target proteins on exosomes with surface enhanced Raman scattering gold nanorods. This assay can specifically detect exosomes with a limit of detection of 2 × 106 exosomes/mL and analyze over 80 purified samples on a single device within 2 h. Using the assay, we have showed that exosomes derived from MDA-MB-231, MDA-MB-468, and SKBR3 breast cancer cells give distinct protein profiles compared to exosomes derived from MCF12A normal breast cells. We have also showed that exosomes in the plasma from HER2-pos. breast cancer patients exhibit significantly (P ≤ 0.01) higher level of HER2 and EpCAM than those from healthy donors. Conclusion: We have developed a simple, inexpensive, highly efficient, and portable Raman exosome assay for detection and protein profiling of exosomes. Using the assay and model exosomes from breast cancer cells, we have showed that exosomes exhibit diagnostic surface protein markers, reflecting the protein profile of their donor cells. Through proof-of-concept studies, we have identified HER2 and EpCAM biomarkers on exosomes in plasma from HER2-pos. breast cancer patients, suggesting the diagnostic potential of these markers for breast cancer diagnostics. This assay would accelerate exosome research and pave a way to the development of novel cancer liq. biopsy for cancer detection and monitoring.
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  19. 19
    Pramanik, A.; Mayer, J.; Patibandla, S.; Gates, K.; Gao, Ye; Davis, D.; Seshadri, R.; Ray, P. C. Mixed-Dimensional Heterostructure Material-Based SERS for Trace Level Identification of Breast Cancer-Derived Exosomes. ACS-Omega 2020, 5 (27), 16602– 16611,  DOI: 10.1021/acsomega.0c01441
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    19
    Mixed-Dimensional Heterostructure Material-Based SERS for Trace Level Identification of Breast Cancer-Derived Exosomes
    Pramanik, Avijit; Mayer, Justin; Patibandla, Shamily; Gates, Kaelin; Gao, Ye; Davis, Dalephine; Seshadri, Ram; Ray, Paresh Chandra
    ACS Omega (2020), 5 (27), 16602-16611CODEN: ACSODF; ISSN:2470-1343. (American Chemical Society)
    Raman spectroscopy has capability for fingerprint mol. identification with high sensitivity if weak Raman scattering signal can be enhanced by several orders of magnitudes. Herein, the authors report a heterostructure-based surface-enhanced Raman spectroscopy (SERS) platform using 2D graphene oxide (GO) and 0D plasmonic gold nanostar (GNS), with capability of Raman enhancement factor (EF) in the range of ~ 1010 via light-matter and matter-matter interactions. The current manuscript reveals huge Raman enhancement for heterostructure materials occurring via both electromagnetic enhancement mechanism though plasmonic GNS nanoparticle (EF ~ 107) and chem. enhancement mechanism through 2D-GO material (EF ~ 102). Finite-difference time-domain (FDTD) simulation data and GNS allows light to be concd. into nanoscale "hotspots" formed on the heterostructure surface, which significantly enhanced Raman efficiency via a plasmon-exciton light coupling process. Notably, mixed-dimensional heterostructure-based SERS can be used for tracking of cancer-derived exosomes from triple-neg. breast cancer and HER2(+) breast cancer with a limit of detection (LOD) of 3.8 × 102 exosomes/mL for TNBC-derived exosomes and 4.4 × 102 exosomes/mL for HER2(+) breast cancer-derived exosomes.
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  20. 20
    Pramanik, A.; Gates, K.; Patibandla, S.; Davis, D.; Begum, S.; Iftekhar, R.; Alamgir, S.; Paige, S.; Porter, M. M.; Ray, P. C. Water-Soluble and Bright Luminescent Cesium-Lead-Bromide Perovskite Quantum Dot-Polymer Composites for Tumor-Derived Exosome Imaging. ACS Appl. Bio Mater. 2019, 2, 5872– 5879,  DOI: 10.1021/acsabm.9b00837
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    20
    Water-Soluble and Bright Luminescent Cesium-Lead-Bromide Perovskite Quantum Dot-Polymer Composites for Tumor-Derived Exosome Imaging
    Pramanik, Avijit; Gates, Kaelin; Patibandla, Shamily; Davis, Dalephine; Begum, Salma; Iftekhar, Riwad; Alamgir, Saadman; Paige, Shekyra; Porter, Maurice M.; Ray, Paresh Chandra
    ACS Applied Bio Materials (2019), 2 (12), 5872-5879CODEN: AABMCB; ISSN:2576-6422. (American Chemical Society)
    Cesium-lead-halide perovskite quantum dots (PQDs) are a highly promising class of the next-generation optical material for bioimaging applications. Herein, we present a nanocomposite strategy for the design of water-sol., highly luminescence CsPbBr3 PQD nanocomposites without modifying the crystal symmetry and photoluminescence (PL) property. Water-sol. PQDs are reproducibly synthesized via encapsulating CsPbBr3 PQDs with polystyrene-block-poly(ethylene-ran-butylene)-block-polystyrene (PS-PEB-PS) and poly(ethylene glycol)-block-poly(propylene glycol)-block-poly(ethylene glycol (PEG-PPG-PEG). In the reported design, the polystyrene triblock polymers strongly interact with the hydrophobic parts of PQDs, and the water-sol. PEG moiety acts as a protection layer to effectively prevent degrdn. of PQDs in water. The outer shell PEG layer also helps to develop biocompatible PQDs. Reported data indicate that encapsulating CsPbBr3 PQDs with a polymer helps to improve the photoluminescence quantum yield (PLQY) from 83% to 88%, which may be due to a decrease in the surface defects after the effective polymer coating. Exptl. data show that the PL intensity from CsPbBr3 PQD nanocomposites remains unchanged even after 30 days of exposure in air. Similarly, reported data indicate that nanocomposites retain their luminescence properties in water for the first 8 days and then decrease slowly to 60% of its initial PL intensity after one month. On the other hand, the PL emission for the PQD without polymer encapsulation is completely quenched within a few hours. Exosomes are a highly promising avenue for accessing tumor type and stage and monitoring cancer treatment response. Reported data reveal that anti-CD63 antibody-attached PQD nanocomposites are capable of tracking triple-neg. MDA-MB-231 breast tumor-derived exosomes via binding using anti-CD63 antibody and selective green luminescence imaging using PQD nanocomposites.
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  21. 21
    Yan, H.; Li, Y.; Cheng, S.; Zeng, Y. Advances in Analytical Technologies for Extracellular Vesicles. Anal. Chem. 2021, 93, 4739– 4774,  DOI: 10.1021/acs.analchem.1c00693
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    21
    Advances in Analytical Technologies for Extracellular Vesicles
    Yan, He; Li, Yutao; Cheng, Shibo; Zeng, Yong
    Analytical Chemistry (Washington, DC, United States) (2021), 93 (11), 4739-4774CODEN: ANCHAM; ISSN:0003-2700. (American Chemical Society)
    A review. Liq. biopsy is extremely appealing in early diagnosis, prognosis, and precision treatment of cancer, as tissue biopsy is highly invasive, costly, and often infeasible to repeat. Extracellular vesicles (EVs), membrane nanovesicles actively released by cells, are emerging as a new paradigm of liq. biopsy for cancer diagnosis and monitoring response to therapy. EVs, including exosomes, are increasingly recognized as important mediators of cell-cell communication which transport important biomarkers for disease diagnoses and prognosis. Despite their biomedical value, it remains challenging to isolate and measure these molecularly diverse nanosized vesicles in biol. samples, which calls for the development of new anal. technologies and approaches for EV anal. Here we present a comprehensive and crit. review to survey the std. methods and emerging technologies for EV isolation, sample prepn., phys. and mol. characterization, detection, and data processing. In addn., the crit. preanal. variables and paths toward standardization of the anal. method in EV research will be also discussed.
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  22. 22
    Kalluri, R.; LeBleu, V. S. The Biology, Function, and Biomedical Applications of Exosomes. Science 2020, 367, eaau6977  DOI: 10.1126/science.aau6977
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    There is no corresponding record for this reference.
  23. 23
    Qin, Y.; Bai, Y.; Huang, P.; Wu, F. Y. Dual-Emission Carbon Dots for Ratiometric Fluorescent Water Sensing, Relative Humidity Sensing, and Anticounterfeiting Applications. ACS Applied Nano Materials 2021, 4 (10), 10674– 10681,  DOI: 10.1021/acsanm.1c02148
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    23
    Dual-Emission Carbon Dots for Ratiometric Fluorescent Water Sensing, Relative Humidity Sensing, and Anticounterfeiting Applications
    Qin, Yujuan; Bai, Yongju; Huang, Pengcheng; Wu, Fang-Ying
    ACS Applied Nano Materials (2021), 4 (10), 10674-10681CODEN: AANMF6; ISSN:2574-0970. (American Chemical Society)
    We synthesized blue fluorescent carbon quantum dots (CDs) by the solvothermal strategy using 2,5-dihydroxyterephthalic acid as the precursor. The as-prepd. CD surfaces contain abundant carboxyl and hydroxyl groups and show excitation-independent emission and excellent chem. stability. Interestingly, with the increment of water contents in org. solvents, the CDs underwent a visual fluorescence color transition from blue to green, which could be attributed to the excited-state intramol. proton transfer effect via the intermol. hydrogen bonding between CDs and water. Based on this, we designed an effective ratiometric fluorescence water sensor in org. solvents, which featured self-calibration, visualization, rapid response (<20 s), and high sensitivity (limit of detection = 0.052%, vol./vol., in ethanol). The smartphone-based quant. assay was also realized using CD-loaded paper strips through a color processing application and successfully applied to monitor the water content in spirit samples. Humidity sensing was further evaluated through the as-prepd. CDs/polymer films. Remarkably, the CD-based sensors were well recyclable both with paper strips and polymer films. The as-prepd. CDs also hold great potential for anticounterfeiting.
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  24. 24
    Anwar, S.; Ding, H.; Xu, M.; Hu, X.; Li, Z.; Wang, J.; Liu, L.; Jiang, L.; Wang, D.; Dong, C.; Yan, M.; Wang, Q.; Bi, H. Recent Advances in Synthesis, Optical Properties, and Biomedical Applications of Carbon Dots. ACS Appl. Energy Mater. 2019, 2, 2317– 2338,  DOI: 10.1021/acsabm.9b00112
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    There is no corresponding record for this reference.
  25. 25
    Wareing, T. C.; Gentile, P.; Phan, A. N. Biomass-based carbon dots: current development and future perspectives. ACS Nano 2021, 15, 15471– 15501,  DOI: 10.1021/acsnano.1c03886
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    25
    Biomass-based carbon dots: current development and future perspectives
    Wareing, Thomas C.; Gentile, Piergiorgio; Phan, Anh N.
    ACS Nano (2021), 15 (10), 15471-15501CODEN: ANCAC3; ISSN:1936-0851. (American Chemical Society)
    A review. Carbon dots have been considered as a soln. to the challenges that semiconductor quantum dots have encountered because they are more biocompatible and can be synthesized from abundant and nontoxic materials such as biomass. This review will highlight the advantages of these biomass-based carbon dots in terms of synthesis, properties, and applications in the biomedical field. Furthermore, future applications esp. in the biomedical field of biomass-based carbon dots as well as the challenges of semiconductor quantum dots such as biocompatibility, photobleaching, environmental challenges, toxicity, and poor soly. will be discussed in detail. Biomass-derived quantum dots, a subsection of carbon dots that are the most desirable for future research, will be focused upon including from synthesis to applications. Finally, the future development of biomass derived quantum dots in the biomedical field will be discussed and evaluated to unlock the potential for their applications.
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  26. 26
    Yang, Y.; Kannisto, E.; Patnaik, S. K.; Reid, M. E.; Li, L.; Wu, Y. Ultrafast Detection of Exosomal RNAs via Cationic Lipoplex Nanoparticles in a Micromixer Biochip for Cancer Diagnosis. ACS Appl. Nano Mater. 2021, 4, 2806– 2819,  DOI: 10.1021/acsanm.0c03426
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    26
    Ultrafast Detection of Exosomal RNAs via Cationic Lipoplex Nanoparticles in a Micromixer Biochip for Cancer Diagnosis
    Yang, Yunchen; Kannisto, Eric; Patnaik, Santosh K.; Reid, Mary E.; Li, Lei; Wu, Yun
    ACS Applied Nano Materials (2021), 4 (3), 2806-2819CODEN: AANMF6; ISSN:2574-0970. (American Chemical Society)
    Exosomes are cell-derived, nanosized extracellular vesicles for intercellular communication. Exosomal RNAs have been shown as one type of promising cancer liq. biopsy biomarkers. Conventional methods to characterize exosomal RNAs such as quant. reverse transcription polymerase chain reaction (qRT-PCR) are limited by low sensitivity, large sample consumption, time-consuming process, and high cost. Many technologies have been developed to overcome these challenges; however, many hours are still required to complete the assays, esp. when exosome lysis and RNA extn. are required. We have developed a microfluidic cationic lipoplex nanoparticles (mCLN) assay that utilizes a micromixer biochip to allow for the effective capture of exosomes by cationic lipoplex nanoparticles and thus enables ultrafast and sensitive exosomal RNA detection for cancer diagnosis. The sensing performance and diagnostic performance of the mCLN assay were investigated using non-small cell lung cancer (NSCLC) as the disease model and exosomal microRNA-21 and TTF-1 mRNA as the biomarkers. The limits of detection of the mCLN assay were 2.06 x 109 and 3.71 x 109 exosomes/mL for microRNA-21 and TTF-1 mRNA, resp., indicating that the mCLN assay may require as low as 1 μL of serum for exosomal RNA detection. The mCLN assay successfully distinguished NSCLC from normal controls by detecting significantly higher microRNA-21 and TTF-1 mRNA levels in exosomes from both NSCLC patient serum samples and A549 NSCLC cells than those from normal controls and BEAS-2B normal bronchial epithelial cells. Compared with conventional qRT-PCR assay, the mCLN assay showed a higher diagnostic accuracy in lung cancer, required less sample vol. (30 vs 100 μL), and consumed much less time (10 min vs 4 h).
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  27. 27
    Wareing, T. C.; Gentile, P.; Phan, A. N. Biomass-based carbon dots: current development and future perspectives. ACS Nano 2021, 15, 15471– 15501,  DOI: 10.1021/acsnano.1c03886
    Google Scholar
    27
    Biomass-based carbon dots: current development and future perspectives
    Wareing, Thomas C.; Gentile, Piergiorgio; Phan, Anh N.
    ACS Nano (2021), 15 (10), 15471-15501CODEN: ANCAC3; ISSN:1936-0851. (American Chemical Society)
    A review. Carbon dots have been considered as a soln. to the challenges that semiconductor quantum dots have encountered because they are more biocompatible and can be synthesized from abundant and nontoxic materials such as biomass. This review will highlight the advantages of these biomass-based carbon dots in terms of synthesis, properties, and applications in the biomedical field. Furthermore, future applications esp. in the biomedical field of biomass-based carbon dots as well as the challenges of semiconductor quantum dots such as biocompatibility, photobleaching, environmental challenges, toxicity, and poor soly. will be discussed in detail. Biomass-derived quantum dots, a subsection of carbon dots that are the most desirable for future research, will be focused upon including from synthesis to applications. Finally, the future development of biomass derived quantum dots in the biomedical field will be discussed and evaluated to unlock the potential for their applications.
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  28. 28
    Xu, D.; Lin, Q.; Chang, H.-T. Recent Advances and Sensing Applications of Carbon Dots. Small Methods 2020, 4, 1900387,  DOI: 10.1002/smtd.201900387
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    28
    Recent Advances and Sensing Applications of Carbon Dots
    Xu, Dong; Lin, Qinlu; Chang, Huan-Tsung
    Small Methods (2020), 4 (4), 1900387CODEN: SMMECI; ISSN:2366-9608. (Wiley-VCH Verlag GmbH & Co. KGaA)
    A review. Carbon dots (C dots) with biocompatibility, brightness, stability against photoirradn. and salt, and ease in prepn. have become important materials for sensing and imaging. They can be prepd. from natural materials and small org. mols. through hydrothermal, microwave-assistant, and electrochem. methods, with advantages of simplicity and low cost. To enhance the quantum yields of C dots in the red and near-IR regions, doping of C dots with heteroatoms such as nitrogen and sulfur has been suggested. C dots both with and without being functionalized recognition elements such as antibodies and aptamers are selective and sensitive for sensing of analytes, including metal ions (e.g., Fe3+, Hg2+, Cu2+), small mols. (e.g., H2O2, cysteine, glutathione), and biopolymers like proteins, as well as for in vitro and in vivo imaging. Depending on the size, charge, and surface ligands of C dots used to label cells, fluorescence images of different organelles are shown. Multicolor images of bacteria, mammalian cells, and plant tissues incubated with C dots are realized when excited at different wavelengths. In this review, many excellent sensing and imaging examples of C dots are presented to highlight their features and to show their challenges for anal. applications.
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  29. 29
    Zhu, Z.; Liu, C.; Song, X.-M.; Mao, Q.; Ma, T. Carbon Dots as an Indicator of Acid–Base Titration and a Fluorescent Probe for Endoplasm Reticulum Imaging. ACS Appl. Bio Mater. 2021, 4, 3623– 3629,  DOI: 10.1021/acsabm.1c00121
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    29
    Carbon Dots as an Indicator of Acid-Base Titration and a Fluorescent Probe for Endoplasm Reticulum Imaging
    Zhu, Zhan; Liu, Chenlu; Song, Xi-Ming; Mao, Quanxing; Ma, Tianyi
    ACS Applied Bio Materials (2021), 4 (4), 3623-3629CODEN: AABMCB; ISSN:2576-6422. (American Chemical Society)
    In this study, carbon dots (CDs) with red color are successfully prepd. via hydrothermal treatment of o-phenylenediamine and urea. The as-prepd. red CDs exhibit an acidichromism feature, making them turn purple at pH 4.4 and become blue at pH 3.3. Further investigations reveal that the surface chem. bond species of CDs are responsible for the acidichromism feature. Taking advantage of the acidichromism feature, the CDs are employed as a titrn. indicator for anal. of alkali samples, which gives rise to satisfactory results without significant difference between the titrn. methods using CDs and methyl orange or a mixt. of methyl red and bromocresol green as indicators. The CDs show excitation-independent fluorescence with dual-emission at 600 and 650 nm, along with a respectable quantum yield of 20.1%, which provides the CDs with deep tissue penetration and min. autofluorescence background that is desirable in bioimaging. In addn., the CDs are found to light up endoplasm reticulum particularly, indicating their endoplasm reticulum targeting capability, which is proven by a colocalization study with other classical subcellular dyes. Endocytosis inhibiting investigations confirm that the endoplasm reticulum targeting ability is mainly attributed to the caveolin/lipid-raft-mediated endocytosis pathways of CDs. This study not only presents a facile approach for red CDs but also explores the possibility of CDs in titrn. anal. and in endoplasm reticulum targeting imaging.
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  30. 30
    Lu, W.; Jiao, Y.; Gao, Y.; Qiao, J.; Mozneb, M.; Shuang, S.; Dong, C.; Li, C.-Z. Bright Yellow Fluorescent Carbon Dots as a Multifunctional Sensing Platform for the Label-Free Detection of Fluoroquinolones and Histidine. ACS Appl. Mater. Interfaces 2018, 10, 42915– 42924,  DOI: 10.1021/acsami.8b16710
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    30
    Bright Yellow Fluorescent Carbon Dots as a Multifunctional Sensing Platform for the Label-Free Detection of Fluoroquinolones and Histidine
    Lu, Wenjing; Jiao, Yuan; Gao, Yifang; Qiao, Jie; Mozneb, Maedeh; Shuang, Shaomin; Dong, Chuan; Li, Chen-zhong
    ACS Applied Materials & Interfaces (2018), 10 (49), 42915-42924CODEN: AAMICK; ISSN:1944-8244. (American Chemical Society)
    Owing to their diverse properties, fluorescent carbon dots (CDs) have attracted more attention and present enormous potential in development of sensors, bioimaging, drug delivery, microfluidics, photodynamic therapy, light emitting diode, and so forth. Herein, a multifunctional sensing platform based on bright yellow fluorescent CDs (Y-CDs) was designed for the label-free detection of fluoroquinolones (FQs) and histidine (His). The Y-CDs with superior optical and biol. merits including high chem. stability, good biocompatibility, and low cytotoxicity were simply synthesized via one-step hydrothermal treatment of o-phenylenediamine (o-PD) and 4-aminobutyric acid (GABA). The Y-CDs can be utilized to directly monitor the amt. of FQs based on fluorescence static quenching owing to the specific interaction between FQs and Y-CDs. Then, the fluorescence of this system can be effectively recovered upon addn. of His. The multifunctional sensing platform exhibited high sensitivity and selectivity toward three kinds of FQs and His with low detection limits of 17-67 and 35 nM, resp. Benefiting from these outstanding characters, the Y-CDs were successfully employed for trace detection of FQs in real samples such as antibiotic tablets and milk products. Furthermore, the probe was also extended to cellular imaging. All of the above prove that this multifunctional sensing platform presents great prospect in multiple applications such as biosensing, biomedicine, disease diagnosis, and environmental monitoring.
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  31. 31
    Pramanik, A.; Jones, S.; Pedraza, F.; Vangara, A.; Sweet, C.; Williams, M. S.; Ruppa-Kasani, V.; Risher, S. E.; Sardar, D.; Ray, P. C. Fluorescent, Magnetic Multifunctional Carbon Dots for Selective Separation, Identification, and Eradication of Drug-Resistant Superbugs. ACS Omega 2017, 2, 554– 562,  DOI: 10.1021/acsomega.6b00518
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    Fluorescent, Magnetic Multifunctional Carbon Dots for Selective Separation, Identification, and Eradication of Drug-Resistant Superbugs
    Pramanik, Avijit; Jones, Stacy; Pedraza, Francisco; Vangara, Aruna; Sweet, Carrie; Williams, Mariah S.; Ruppa-Kasani, Vikram; Risher, Sean Edward; Sardar, Dhiraj; Ray, Paresh Chandra
    ACS Omega (2017), 2 (2), 554-562CODEN: ACSODF; ISSN:2470-1343. (American Chemical Society)
    The emergence of drug resistance superbugs remains a major burden to society. Since the mortality rate caused by sepsis due to superbugs is >40%, accurate identification of blood infections during the early stage will have huge significance in the clin. setting. Here the authors report the synthesis of red/blue fluorescent carbon dots (CDs)-attached magnetic nanoparticles-based multicolor multifunctional CDs-based nanosystems, which can be used for selective sepn. and identification of superbugs from infected blood samples. The reported data show that multifunctional fluorescent magneto-carbon dots nanoparticles are capable of isolating MRSA and Salmonella DT104 superbug from whole blood samples, followed by accurate identification via multicolor fluorescence imaging. Since multiple drug resistance superbugs are resistant to antibiotics available in the market, this article also reports the design of antimicrobial peptide conjugated multicolor fluorescent magneto-carbon dots for effective sepn., accurate identification and complete disinfection of MDR superbugs from infected blood. The reported data demonstrates that by combining pardaxin antimicrobial peptides, magnetic nanoparticle and multicolor fluorescent carbon dots into a single system, multifunctional carbon dots represent a novel material for efficient sepn., differentiation, and eradication of superbugs. This material shows great promise for use in clin. settings.
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  32. 32
    Pramanik, A.; Vangara, A.; Nellore, B. P. V.; Sinha, S. S.; Chavva, S. R.; Jones, S.; Ray, P. C. Development of Multifunctional Fluorescent-Magnetic Nanoprobes for Selective Capturing and Multicolor Imaging of Heterogeneous Circulating Tumor Cells. ACS Appl. Mater. Interfaces 2016, 8, 15076– 15085,  DOI: 10.1021/acsami.6b03262
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    32
    Development of Multifunctional Fluorescent-Magnetic Nanoprobes for Selective Capturing and Multicolor Imaging of Heterogeneous Circulating Tumor Cells
    Pramanik, Avijit; Vangara, Aruna; Viraka Nellore, Bhanu Priya; Sinha, Sudarson Sekhar; Chavva, Suhash Reddy; Jones, Stacy; Ray, Paresh Chandra
    ACS Applied Materials & Interfaces (2016), 8 (24), 15076-15085CODEN: AAMICK; ISSN:1944-8244. (American Chemical Society)
    Circulating tumor cells (CTC) are highly heterogeneous in nature due to epithelial-mesenchymal transition (EMT), which is the major obstacle for CTC anal. via "liq. biopsy". This article reports the development of a new class of multifunctional fluorescent-magnetic multicolor nanoprobes for targeted capturing and accurate identification of heterogeneous CTC. A facile design approach for the synthesis and characterization of bioconjugated multifunctonal nanoprobes that exhibit excellent magnetic properties and emit very bright and photostable multicolor fluorescence at red, green, and blue under 380 nm excitation is reported. Exptl. data presented show that the multifunctional multicolor nanoprobes can be used for targeted capture and multicolor fluorescence mapping of heterogeneous CTC and can distinguish targeted CTC from nontargeted cells.
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  33. 33
    Pramanik, A.; Begum, S.; Rightsell, C.; Gates, K.; Zhang, Q.; Jones, S.; Gao, Y.; Ruppa-Kasani, V.; Banerjee, R.; Shukla, J.; Ignatius, A.; Sardar, D.; Han, F. X.; Ray, P. C. Designing Highly Crystalline Multifunctional Multicolor Luminescence Nanosystem for Tracking Breast Cancer Heterogeneity. Nanoscale Adv. 2019, 1, 1021– 1034,  DOI: 10.1039/C8NA00089A
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    33
    Designing highly crystalline multifunctional multicolor-luminescence nanosystem for tracking breast cancer heterogeneity
    Pramanik, Avijit; Begum, Salma; Rightsell, Chris; Gates, Kaelin; Zhang, Qinku; Jones, Stacy; Gao, Ye; Ruppa-Kasani, Vikram; Banerjee, Rimika; Shukla, Jayanti; Ignatius, Ashley; Sardar, Dhiraj; Han, Fengxiang. X.; Chandra Ray, Paresh
    Nanoscale Advances (2019), 1 (3), 1021-1034CODEN: NAADAI; ISSN:2516-0230. (Royal Society of Chemistry)
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  1. Avijit Pramanik, Sanchita Kundu, Kaelin Gates, Animesh Kumar, Olorunsola Praise Kolawole, Arohan Talukdar, Ridwan Iftekhar, Lauren R. Corby, Paresh Chandra Ray. Multi-Color-Emissive Magneto-Luminescent Nanoarchitectures for Targeted Identification of Heterogeneous Exosomes Associated with Lung Cancer Metastasis. ACS Applied Bio Materials 2023, 6 (6) , 2446-2458. https://doi.org/10.1021/acsabm.3c00255
  2. Avijit Pramanik, Justin Mayer, Sudarson Sekhar Sinha, Poonam C. Sharma, Shamily Patibandla, Ye Gao, Lauren R. Corby, John T. Bates, Michael A. Bierdeman, Ritesh Tandon, Ram Seshadri, Paresh Chandra Ray. Human ACE2 Peptide-Attached Plasmonic-Magnetic Heterostructure for Magnetic Separation, Surface Enhanced Raman Spectroscopy Identification, and Inhibition of Different Variants of SARS-CoV-2 Infections. ACS Applied Bio Materials 2022, 5 (9) , 4454-4464. https://doi.org/10.1021/acsabm.2c00573
  3. Xin Zhang, Xuemei Wang, Lijian Hou, Zheng Xu, Yu’e Liu, Xueju Wang. Nanoparticles overcome adaptive immune resistance and enhance immunotherapy via targeting tumor microenvironment in lung cancer. Frontiers in Pharmacology 2023, 14 https://doi.org/10.3389/fphar.2023.1130937
  4. Nanhang Zhu, Xuekang Wang, Yujia Zhang, Yanchao Mao, Yue Yu, Qiangying Yi, Yao Wu. Self-calibrated magnetic aptamer sensor with dual Lanthanide-assisted Time-resolved luminescence for high-sensitive detection of melanoma exosomal PD-L1. Materials & Design 2023, 227 , 111714. https://doi.org/10.1016/j.matdes.2023.111714
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  • Abstract

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    Figure 1

    Figure 1. Scheme showing the design of the anti-PD-L1 monoclonal antibody-conjugated magnetic-fluorescence nanoarchitecture. (A) Hydrothermal synthesis of YFCDs from o-phenylenediamine and 4-aminobutyric acid. (B) Synthesis of acid-functionalized magnetic nanoparticles. (C) Synthesis of YFCD-attached magnetic nanoparticles. D) Synthesis of the anti-PD-L1 monoclonal antibody-attached nanoarchitecture.

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    Figure 2

    Figure 2. (A) TEM image showing the morphology of yellow luminescent carbon dots derived from o-phenylenediamine and 4-aminobutyric acid. The inserted HR-TEM image shows graphite-type lattice fringes with an interplanar spacing of 0.35 nm for carbon dots derived from o-phenylenediamine and 4-aminobutyric acid. (B) TEM image showing the morphology of the acid-functionalized magnetic nanoparticles. The inserted EDX elemental map shows the presence of Fe. (C) TEM image showing the morphology of the yellow luminescent carbon dot-attached magnetic nanoparticle. The inserted EDX elemental map shows the presence of Fe and C. (D) FTIR spectrum from the yellow luminescent carbon dot-attached magnetic nanoparticle showing the presence of amide A, amide-I, amide-II, amide-III, and other bands. (E) The X-ray diffraction pattern from the yellow luminescent carbon dot-attached magnetic nanoparticle confirms the presence of (002) indices for graphitic carbon and (220), (311), (222), (511), and (440) indices for the magnetic nanoparticles. (F) The XPS spectrum from the yellow luminescent carbon dot-attached magnetic nanoparticle confirms peaks at 284.8, 398.1, 532.5, and 711.2 eV due to Fe, O, N and C, respectively.

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    Figure 3

    Figure 3. (A) Absorption spectrum of the YFCDs, which indicates two absorption peaks. The π–π* transition is visible at 260 nm, and the other transition due the functional groups conjugated on CDs is visible at 436 nm. (B) Photograph of YFCDs in the absence of UV light. (C) Photograph of YFCDs in the presence of UV light showing the strong yellow emission. (D) Emission spectrum of YFCDs in the presence of 300 nm excitation light. (E) Emission spectra of YFCDs and the anti-PD-L1 monoclonal antibody-conjugated magnetic-nanoparticle-attached YFCD-based nanoarchitecture in the presence of 480 nm excitation light. (F) Plot showing the time-resolved photo luminescence decay of YFCDs and the anti-PD-L1 monoclonal antibody-conjugated magnetic-nanoparticle-attached YFCD-based nanoarchitecture in the presence of 480 nm excitation light. (G) Luminescence intensity of the anti-PD-L1 monoclonal antibody-conjugated magnetic-nanoparticle-attached YFCDs as a function of time in the presence of 480 nm excitation light. The experiment was performed five times, and error bars were calculated from the standard deviation.

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    Figure 4

    Figure 4. (A) Viability of LaCaT normal skin cells, SK-BR-3 breast cancer cells, LnCaP prostate cancer cells, and H1264 and A549 lung cancer cells after 24 h of treatment with the nanoarchitecture. The experiment was performed five times, and error bars were calculated from the standard deviation. (B) The percent of PD-L1-positive exosomes separated from different cell lines. We used the human PD-L1 ELISA kit for the quantitation of the PD-L1 (+) exosomes. (C) Photograph showing the separation of the PD-L1 (+) exosome-attached nanoarchitectures using bar magnet. The experiment was performed five times, and error bars were calculated from the standard deviation. (D) SEM image of PD-L1 (+) exosomes after magnetic separation from the H460 cell line. The inserted TEM image and SEM image show the nanostructures attached the PD-L1 (+) exosomes. (E) Bright-field image of the PD-L1 (+) exosome-attached nanoarchitectures after magnetic separation from the H460 cell line. (F) Fluorescence image showing the high number of PD-L1 (+) exosome-attached nanoarchitectures after magnetic separation from the H460 cell line. (G) Fluorescence image showing the low number of PD-L1 (+) exosomes after magnetic separation from the A549 cell line using the nanoarchitecture. (H) Fluorescence image showing the absence of PD-L1 (+) exosomes after magnetic separation from the HaCaT cell line using the nanoarchitecture. (I) Fluorescence image showing PD-L1 (+) exosome-attached nanoarchitectures after magnetic separation from the whole-blood sample.

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      10
      Exosomal PD-L1 contributes to immunosuppression and is associated with anti-PD-1 response
      Chen, Gang; Huang, Alexander C.; Zhang, Wei; Zhang, Gao; Wu, Min; Xu, Wei; Yu, Zili; Yang, Jiegang; Wang, Beike; Sun, Honghong; Xia, Houfu; Man, Qiwen; Zhong, Wenqun; Antelo, Leonardo F.; Wu, Bin; Xiong, Xuepeng; Liu, Xiaoming; Guan, Lei; Li, Ting; Liu, Shujing; Yang, Ruifeng; Lu, Youtao; Dong, Liyun; McGettigan, Suzanne; Somasundaram, Rajasekharan; Radhakrishnan, Ravi; Mills, Gordon; Lu, Yiling; Kim, Junhyong; Chen, Youhai H.; Dong, Haidong; Zhao, Yifang; Karakousis, Giorgos C.; Mitchell, Tara C.; Schuchter, Lynn M.; Herlyn, Meenhard; Wherry, E. John; Xu, Xiaowei; Guo, Wei
      Nature (London, United Kingdom) (2018), 560 (7718), 382-386CODEN: NATUAS; ISSN:0028-0836. (Nature Research)
      Tumor cells evade immune surveillance by upregulating the surface expression of programmed death-ligand 1 (PD-L1), which interacts with programmed death-1 (PD-1) receptor on T cells to elicit the immune checkpoint response. Anti-PD-1 antibodies have shown remarkable promise in treating tumors, including metastatic melanoma. However, the patient response rate is low. A better understanding of PD-L1-mediated immune evasion is needed to predict patient response and improve treatment efficacy. Here we report that metastatic melanomas release extracellular vesicles, mostly in the form of exosomes, that carry PD-L1 on their surface. Stimulation with interferon-γ (IFN-γ) increases the amt. of PD-L1 on these vesicles, which suppresses the function of CD8 T cells and facilitates tumor growth. In patients with metastatic melanoma, the level of circulating exosomal PD-L1 pos. correlates with that of IFN-γ, and varies during the course of anti-PD-1 therapy. The magnitudes of the increase in circulating exosomal PD-L1 during early stages of treatment, as an indicator of the adaptive response of the tumor cells to T cell reinvigoration, stratifies clin. responders from non-responders. Our study unveils a mechanism by which tumor cells systemically suppress the immune system, and provides a rationale for the application of exosomal PD-L1 as a predictor for anti-PD-1 therapy.
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      https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1cXhsVynsrjK&md5=8ccaee77c054148091d35c07ce3479ce
    11. 11
      Poggio, M.; Hu, T.; Pai, C. C.; Chu, B.; Belair, C. D.; Chang, A.; Montabana, E.; Lang, U. E.; Fu, Q.; Fong, L.; Blelloch, R. Suppression of Exosomal PD-L1 Induces Systemic Anti-Tumor Immunity and Memory. Cell 2019, 177, 414– 427,  DOI: 10.1016/j.cell.2019.02.016
      11
      Suppression of Exosomal PD-L1 Induces Systemic Anti-tumor Immunity and Memory
      Poggio, Mauro; Hu, Tianyi; Pai, Chien-Chun; Chu, Brandon; Belair, Cassandra D.; Chang, Anthony; Montabana, Elizabeth; Lang, Ursula E.; Fu, Qi; Fong, Lawrence; Blelloch, Robert
      Cell (Cambridge, MA, United States) (2019), 177 (2), 414-427.e13CODEN: CELLB5; ISSN:0092-8674. (Cell Press)
      PD-L1 on the surface of tumor cells binds its receptor PD-1 on effector T cells, thereby suppressing their activity. Antibody blockade of PD-L1 can activate an anti-tumor immune response leading to durable remissions in a subset of cancer patients. Here, we describe an alternative mechanism of PD-L1 activity involving its secretion in tumor-derived exosomes. Removal of exosomal PD-L1 inhibits tumor growth, even in models resistant to anti-PD-L1 antibodies. Exosomal PD-L1 from the tumor suppresses T cell activation in the draining lymph node. Systemically introduced exosomal PD-L1 rescues growth of tumors unable to secrete their own. Exposure to exosomal PD-L1-deficient tumor cells suppresses growth of wild-type tumor cells injected at a distant site, simultaneously or months later. Anti-PD-L1 antibodies work additively, not redundantly, with exosomal PD-L1 blockade to suppress tumor growth. Together, these findings show that exosomal PD-L1 represents an unexplored therapeutic target, which could overcome resistance to current antibody approaches.
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      https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1MXmvFSmt70%253D&md5=b9d1fd0563ce8076c157ba03effd11f2
    12. 12
      Huang, M.; Yang, J.; Wang, T.; Song, J.; Xia, J.; Wu, L.; Wang, W.; Wu, Q.; Zhu, Z.; Song, Y.; Yang, C. Homogeneous, Low-volume, Efficient, and Sensitive Quantitation of Circulating Exosomal PD-L1 for Cancer Diagnosis and Immunotherapy Response Prediction. Angew. Chem. 2020, 132, 4830– 4835,  DOI: 10.1002/ange.201916039
      There is no corresponding record for this reference.
    13. 13
      Gordon, S. R.; Maute, R. L.; Dulken, B. W.; Hutter, G.; George, B. M.; McCracken, M. N.; Gupta, R.; Tsai, J. M.; Sinha, R.; Corey, D.; Ring, A. M.; Connolly, A. J.; Weissman, I. L. PD-1 Expression by Tumour-Associated Macrophages Inhibits Phagocytosis and Tumour Immunity. Nature 2017, 545, 495– 499,  DOI: 10.1038/nature22396
      13
      PD-1 expression by tumour-associated macrophages inhibits phagocytosis and tumour immunity
      Gordon, Sydney R.; Maute, Roy L.; Dulken, Ben W.; Hutter, Gregor; George, Benson M.; McCracken, Melissa N.; Gupta, Rohit; Tsai, Jonathan M.; Sinha, Rahul; Corey, Daniel; Ring, Aaron M.; Connolly, Andrew J.; Weissman, Irving L.
      Nature (London, United Kingdom) (2017), 545 (7655), 495-499CODEN: NATUAS; ISSN:0028-0836. (Nature Publishing Group)
      Programmed cell death protein 1 (PD-1) is an immune checkpoint receptor that is upregulated on activated T cells for the induction of immune tolerance. Tumor cells frequently overexpress the ligand for PD-1, programmed cell death ligand 1 (PD-L1), facilitating their escape from the immune system. Monoclonal antibodies that block the interaction between PD-1 and PD-L1, by binding to either the ligand or receptor, have shown notable clin. efficacy in patients with a variety of cancers, including melanoma, colorectal cancer, non-small-cell lung cancer and Hodgkin's lymphoma. Although it is well established that PD-1-PD-L1 blockade activates T cells, little is known about the role that this pathway may have in tumor-assocd. macrophages (TAMs). Here we show that both mouse and human TAMs express PD-1. TAM PD-1 expression increases over time in mouse models of cancer and with increasing disease stage in primary human cancers. TAM PD-1 expression correlates neg. with phagocytic potency against tumor cells, and blockade of PD-1-PD-L1 in vivo increases macrophage phagocytosis, reduces tumor growth and lengthens the survival of mice in mouse models of cancer in a macrophage-dependent fashion. This suggests that PD-1-PD-L1 therapies may also function through a direct effect on macrophages, with substantial implications for the treatment of cancer with these agents.
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      https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2sXnvVCrs70%253D&md5=f428abc6d34ac6e3a18bfcf9371ea312
    14. 14
      Wang, X.; Shang, H.; Ma, C.; Chen, L. A Fluorescence Assay for Exosome Detection Based on Bivalent Cholesterol Anchor Triggered Target Conversion and Enzyme-Free Signal Amplification. Anal. Chem. 2021, 93, 8493– 8500,  DOI: 10.1021/acs.analchem.1c00796
      14
      A Fluorescence Assay for Exosome Detection Based on Bivalent Cholesterol Anchor Triggered Target Conversion and Enzyme-Free Signal Amplification
      Wang, Xiaokun; Shang, Hezhen; Ma, Cuiping; Chen, Lingxin
      Analytical Chemistry (Washington, DC, United States) (2021), 93 (24), 8493-8500CODEN: ANCHAM; ISSN:0003-2700. (American Chemical Society)
      Exosomes are emerging as one of the most promising biomarkers for early disease diagnosis and prognosis. The significant challenges facing the available methods include improving the detection specificity and sensitivity in complex biol. samples. Herein, a fluorescence assay was established based on a combination of immunomagnetic sepn. and a two-step signal amplification strategy for direct isolation and subsequent detection of exosomes. First, immunomagnetic beads capture and enrich the exosomes via antibody-antigen reactions. Second, bivalent cholesterol (BC) anchors spontaneously insert into the lipid bilayer of bead-captured exosomes, forming a "one to many" amplification effect. The simultaneous recognition of the surface protein and the lipid bilayer structure of the exosome significantly eliminates the interference risk from free proteins. The detection of exosomes converts to the detection of BC-anchors. Finally, the sticky end of the BC-anchor acts as the initiator to trigger the enzyme-free DNA circuits for secondary signal amplification. Under the optimal conditions, highly sensitive and selective detection of exosomes was achieved ranging from 5.5 x 103 to 1.1 x 107 particles/μL with a limit of detection of 1.29 x 103 particles/μL. Moreover, this method allows the isolation and quant. anal. of exosomes in several biol. fluids with satisfactory recovery rates (92.25-106.8%). Thus, this approach provides a sensitive, anti-interference platform for isolating and detecting exosomes.
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      https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BB3MXht1OiurrO&md5=008b1c947886c2f8c94200ce1cd3fe7c
    15. 15
      Li, B.; Pan, W.; Liu, C.; Guo, J.; Shen, J.; Feng, J.; Luo, T.; Situ, B.; Zhang, Y.; An, T.; Xu, C.; Zheng, W.; Zheng, L. Homogenous Magneto-Fluorescent Nanosensor for Tumor-Derived Exosome Isolation and Analysis. ACS Sens. 2020, 5, 2052– 2060,  DOI: 10.1021/acssensors.0c00513
      15
      Homogenous Magneto-Fluorescent Nanosensor for Tumor-Derived Exosome Isolation and Analysis
      Li, Bo; Pan, Weilun; Liu, Chunchen; Guo, Jingyun; Shen, Jianlei; Feng, Junjie; Luo, Tingting; Situ, Bo; Zhang, Ye; An, Taixue; Xu, Chunzuan; Zheng, Wancheng; Zheng, Lei
      ACS Sensors (2020), 5 (7), 2052-2060CODEN: ASCEFJ; ISSN:2379-3694. (American Chemical Society)
      Tumor-derived exosomes carrying unique surface proteins have shown great promise as novel biomarkers for liq. biopsies. However, point-of-care anal. for tumor-derived exosomes in the blood with low-cost and easy processing is still challenging. Herein, we develop an integrated approach, homogeneous magneto-fluorescent exosome (hMFEX) nanosensor, for rapid and on-site tumor-derived exosomes anal. Tumor-derived exosomes are captured immunomagnetically, which further initiates the aptamer-triggered assembly of DNA three-way junctions in homogeneous soln. contg. aggregation-induced emission luminogens and graphene oxide, resulting in an amplified fluorescence signal. By integrating magnetic isolation and enhanced fluorescence measurement, the hMFEX nanosensor detects tumor-derived exosomes in the dynamic range spanning 5 orders of magnitude with high specificity, and the limit of detection is 6.56 x 104 particles/μL. Analyzing tumor-derived exosomes in limited vol. plasma from breast cancer patients demonstrates the excellent clin. diagnostic efficacy of the hMFEX nanosensor. This study provides new insights into the point-of-care testing of tumor-derived exosomes for cancer diagnostics.
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      https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BB3cXht1Ohu7vP&md5=0f30b75c0751d403bd7f030ef2533ec1
    16. 16
      Vinduska, V.; Gallops, C. E.; O’Connor, R.; Wang, Y.; Huang, X. Exosomal Surface Protein Detection with Quantum Dots and Immunomagnetic Capture for Cancer Detection. Nanomaterials 2021, 11, 1853,  DOI: 10.3390/nano11071853
      16
      Exosomal Surface Protein Detection with Quantum Dots and Immunomagnetic Capture for Cancer Detection
      Vinduska, Vojtech; Gallops, Caleb Edward; O'Connor, Ryan; Wang, Yongmei; Huang, Xiaohua
      Nanomaterials (2021), 11 (7), 1853CODEN: NANOKO; ISSN:2079-4991. (MDPI AG)
      Exosomes carry mol. contents reflective of parental cells and thereby hold great potential as a source of biomarkers for non-invasive cancer detection and monitoring. However, simple and rapid exosomal mol. detection remains challenging. Here, we report a facile method for exosome surface protein detection using quantum dot coupled with immunomagnetic capture and enrichment. In this method, exosomes were captured by magnetic beads based on CD81 protein expression. Surface protein markers of interest were recognized by primary antibody and then detected by secondary antibody-conjugated quantum dot with fluorescent spectroscopy. Validated by ELISA, our method can specifically detect different surface markers on exosomes from different cancer cell lines and differentiate cancer exosomes from normal exosomes. The clin. potential was demonstrated with pilot plasma samples using HER2-pos. breast cancer as the disease model. The results show that exosomes from HER2-pos. breast cancer patients exhibited a five times higher level of HER2 expression than healthy controls. Exosomal HER2 showed strong diagnostic power for HER2-pos. patients, with the area under the curve of 0.969. This quantum dot-based exosome method is rapid (less than 5 h) and only requires microliters of dild. plasma without pre-purifn., practical for routine use for basic vesicle research, and clin. applications.
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      https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BB3MXitl2gs7bP&md5=1cd34df1daca361cfd509b3e203cb6e1
    17. 17
      Wang, C.; Huang, C. H.; Gao, Z.; Shen, J.; He, J.; MacLachlan, A.; Ma, C.; Chang, Y.; Yang, W.; Cai, Y.; Lou, Y.; Dai, S.; Chen, W.; Li, F.; Chen, P. Nanoplasmonic Sandwich Immunoassay for Tumor-Derived Exosome Detection and Exosomal PD-L1 Profiling. ACS Sensors 2021, 6 (9), 3308– 3319,  DOI: 10.1021/acssensors.1c01101
      17
      Nanoplasmonic Sandwich Immunoassay for Tumor-Derived Exosome Detection and Exosomal PD-L1 Profiling
      Wang, Chuanyu; Huang, Chung-Hui; Gao, Zhuangqiang; Shen, Jialiang; He, Jiacheng; MacLachlan, Alana; Ma, Chao; Chang, Ya; Yang, Wen; Cai, Yuxin; Lou, Yang; Dai, Siyuan; Chen, Weiqiang; Li, Feng; Chen, Pengyu
      ACS Sensors (2021), 6 (9), 3308-3319CODEN: ASCEFJ; ISSN:2379-3694. (American Chemical Society)
      Tumor-derived exosomes play a vital role in the process of cancer development. Quant. anal. of exosomes and exosome-shuttled proteins would be of immense value in understanding cancer progression and generating reliable predictive biomarkers for cancer diagnosis and treatment. Recent studies have indicated the crit. role of exosomal programmed death ligand 1 (PD-L1) in immune checkpoint therapy and its application as a patient stratification biomarker in cancer immunotherapy. Here, we present a nanoplasmonic exosome immunoassay utilizing gold-silver (Au@Ag) core-shell nanobipyramids and gold nanorods, which form sandwich immune complexes with target exosomes. The immunoassay generates a distinct plasmonic signal pattern unique to exosomes with specific exosomal PD-L1 expression, allowing rapid, highly sensitive exosome detection and accurate identification of PD-L1 exosome subtypes in a single assay. The developed nanoplasmonic sandwich immunoassay provides a novel and viable approach for tumor cell-derived exosome detection and anal. with quant. mol. details of key exosomal proteins, manifesting its great potential as a transformative diagnostic tool for early cancer detection, prognosis, and post-treatment monitoring.
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      https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BB3MXhvFGhtLbK&md5=ba6bc6ea6f6328e17e7fec8f3667443a
    18. 18
      Kwizera, E. A.; O’Connor, R.; Vinduska, V.; Williams, M.; Butch, E. R.; Snyder, S. E.; Chen, X.; Huang, X. Molecular Detection and Analysis of Exosomes Using Surface-Enhanced Raman Scattering Gold Nanorods and a Miniaturized Device. Theranostics 2018, 8, 2722– 2738,  DOI: 10.7150/thno.21358
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      Molecular detection and analysis of exosomes using surface-enhanced raman scattering gold nanorods and a miniaturized device
      Kwizera, Elyahb Allie; O'Connor, Ryan; Vinduska, Vojtech; Williams, Melody; Butch, Elizabeth R.; Snyder, Scott E.; Chen, Xiang; Huang, Xiaohua
      Theranostics (2018), 8 (10), 2722-2738CODEN: THERDS; ISSN:1838-7640. (Ivyspring International Publisher)
      Exosomes are a potential source of cancer biomarkers. Probing tumor-derived exosomes can offer a potential non-invasive way to diagnose cancer, assess cancer progression, and monitor treatment responses. Novel mol. methods would facilitate exosome anal. and accelerate basic and clin. exosome research. Methods: A std. gold-coated glass microscopy slide was used to develop a miniaturized affinity-based device to capture exosomes in a target-specific manner with the assistance of low-cost 3-D printing technol. Gold nanorods coated with QSY21 Raman reporters were used as the label agent to quant. detect the target proteins based on surface enhanced Raman scattering spectroscopy. The expressions of several surface protein markers on exosomes from conditioned culture media of breast cancer cells and from HER2-pos. breast cancer patients were quant. measured. The data was statistically analyzed and compared with healthy controls. Results: A miniaturized 17 × 5 Au array device with 2-mm well size was fabricated to capture exosomes in a target-specific manner and detect the target proteins on exosomes with surface enhanced Raman scattering gold nanorods. This assay can specifically detect exosomes with a limit of detection of 2 × 106 exosomes/mL and analyze over 80 purified samples on a single device within 2 h. Using the assay, we have showed that exosomes derived from MDA-MB-231, MDA-MB-468, and SKBR3 breast cancer cells give distinct protein profiles compared to exosomes derived from MCF12A normal breast cells. We have also showed that exosomes in the plasma from HER2-pos. breast cancer patients exhibit significantly (P ≤ 0.01) higher level of HER2 and EpCAM than those from healthy donors. Conclusion: We have developed a simple, inexpensive, highly efficient, and portable Raman exosome assay for detection and protein profiling of exosomes. Using the assay and model exosomes from breast cancer cells, we have showed that exosomes exhibit diagnostic surface protein markers, reflecting the protein profile of their donor cells. Through proof-of-concept studies, we have identified HER2 and EpCAM biomarkers on exosomes in plasma from HER2-pos. breast cancer patients, suggesting the diagnostic potential of these markers for breast cancer diagnostics. This assay would accelerate exosome research and pave a way to the development of novel cancer liq. biopsy for cancer detection and monitoring.
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    19. 19
      Pramanik, A.; Mayer, J.; Patibandla, S.; Gates, K.; Gao, Ye; Davis, D.; Seshadri, R.; Ray, P. C. Mixed-Dimensional Heterostructure Material-Based SERS for Trace Level Identification of Breast Cancer-Derived Exosomes. ACS-Omega 2020, 5 (27), 16602– 16611,  DOI: 10.1021/acsomega.0c01441
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      Mixed-Dimensional Heterostructure Material-Based SERS for Trace Level Identification of Breast Cancer-Derived Exosomes
      Pramanik, Avijit; Mayer, Justin; Patibandla, Shamily; Gates, Kaelin; Gao, Ye; Davis, Dalephine; Seshadri, Ram; Ray, Paresh Chandra
      ACS Omega (2020), 5 (27), 16602-16611CODEN: ACSODF; ISSN:2470-1343. (American Chemical Society)
      Raman spectroscopy has capability for fingerprint mol. identification with high sensitivity if weak Raman scattering signal can be enhanced by several orders of magnitudes. Herein, the authors report a heterostructure-based surface-enhanced Raman spectroscopy (SERS) platform using 2D graphene oxide (GO) and 0D plasmonic gold nanostar (GNS), with capability of Raman enhancement factor (EF) in the range of ~ 1010 via light-matter and matter-matter interactions. The current manuscript reveals huge Raman enhancement for heterostructure materials occurring via both electromagnetic enhancement mechanism though plasmonic GNS nanoparticle (EF ~ 107) and chem. enhancement mechanism through 2D-GO material (EF ~ 102). Finite-difference time-domain (FDTD) simulation data and GNS allows light to be concd. into nanoscale "hotspots" formed on the heterostructure surface, which significantly enhanced Raman efficiency via a plasmon-exciton light coupling process. Notably, mixed-dimensional heterostructure-based SERS can be used for tracking of cancer-derived exosomes from triple-neg. breast cancer and HER2(+) breast cancer with a limit of detection (LOD) of 3.8 × 102 exosomes/mL for TNBC-derived exosomes and 4.4 × 102 exosomes/mL for HER2(+) breast cancer-derived exosomes.
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    20. 20
      Pramanik, A.; Gates, K.; Patibandla, S.; Davis, D.; Begum, S.; Iftekhar, R.; Alamgir, S.; Paige, S.; Porter, M. M.; Ray, P. C. Water-Soluble and Bright Luminescent Cesium-Lead-Bromide Perovskite Quantum Dot-Polymer Composites for Tumor-Derived Exosome Imaging. ACS Appl. Bio Mater. 2019, 2, 5872– 5879,  DOI: 10.1021/acsabm.9b00837
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      Water-Soluble and Bright Luminescent Cesium-Lead-Bromide Perovskite Quantum Dot-Polymer Composites for Tumor-Derived Exosome Imaging
      Pramanik, Avijit; Gates, Kaelin; Patibandla, Shamily; Davis, Dalephine; Begum, Salma; Iftekhar, Riwad; Alamgir, Saadman; Paige, Shekyra; Porter, Maurice M.; Ray, Paresh Chandra
      ACS Applied Bio Materials (2019), 2 (12), 5872-5879CODEN: AABMCB; ISSN:2576-6422. (American Chemical Society)
      Cesium-lead-halide perovskite quantum dots (PQDs) are a highly promising class of the next-generation optical material for bioimaging applications. Herein, we present a nanocomposite strategy for the design of water-sol., highly luminescence CsPbBr3 PQD nanocomposites without modifying the crystal symmetry and photoluminescence (PL) property. Water-sol. PQDs are reproducibly synthesized via encapsulating CsPbBr3 PQDs with polystyrene-block-poly(ethylene-ran-butylene)-block-polystyrene (PS-PEB-PS) and poly(ethylene glycol)-block-poly(propylene glycol)-block-poly(ethylene glycol (PEG-PPG-PEG). In the reported design, the polystyrene triblock polymers strongly interact with the hydrophobic parts of PQDs, and the water-sol. PEG moiety acts as a protection layer to effectively prevent degrdn. of PQDs in water. The outer shell PEG layer also helps to develop biocompatible PQDs. Reported data indicate that encapsulating CsPbBr3 PQDs with a polymer helps to improve the photoluminescence quantum yield (PLQY) from 83% to 88%, which may be due to a decrease in the surface defects after the effective polymer coating. Exptl. data show that the PL intensity from CsPbBr3 PQD nanocomposites remains unchanged even after 30 days of exposure in air. Similarly, reported data indicate that nanocomposites retain their luminescence properties in water for the first 8 days and then decrease slowly to 60% of its initial PL intensity after one month. On the other hand, the PL emission for the PQD without polymer encapsulation is completely quenched within a few hours. Exosomes are a highly promising avenue for accessing tumor type and stage and monitoring cancer treatment response. Reported data reveal that anti-CD63 antibody-attached PQD nanocomposites are capable of tracking triple-neg. MDA-MB-231 breast tumor-derived exosomes via binding using anti-CD63 antibody and selective green luminescence imaging using PQD nanocomposites.
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    21. 21
      Yan, H.; Li, Y.; Cheng, S.; Zeng, Y. Advances in Analytical Technologies for Extracellular Vesicles. Anal. Chem. 2021, 93, 4739– 4774,  DOI: 10.1021/acs.analchem.1c00693
      21
      Advances in Analytical Technologies for Extracellular Vesicles
      Yan, He; Li, Yutao; Cheng, Shibo; Zeng, Yong
      Analytical Chemistry (Washington, DC, United States) (2021), 93 (11), 4739-4774CODEN: ANCHAM; ISSN:0003-2700. (American Chemical Society)
      A review. Liq. biopsy is extremely appealing in early diagnosis, prognosis, and precision treatment of cancer, as tissue biopsy is highly invasive, costly, and often infeasible to repeat. Extracellular vesicles (EVs), membrane nanovesicles actively released by cells, are emerging as a new paradigm of liq. biopsy for cancer diagnosis and monitoring response to therapy. EVs, including exosomes, are increasingly recognized as important mediators of cell-cell communication which transport important biomarkers for disease diagnoses and prognosis. Despite their biomedical value, it remains challenging to isolate and measure these molecularly diverse nanosized vesicles in biol. samples, which calls for the development of new anal. technologies and approaches for EV anal. Here we present a comprehensive and crit. review to survey the std. methods and emerging technologies for EV isolation, sample prepn., phys. and mol. characterization, detection, and data processing. In addn., the crit. preanal. variables and paths toward standardization of the anal. method in EV research will be also discussed.
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    22. 22
      Kalluri, R.; LeBleu, V. S. The Biology, Function, and Biomedical Applications of Exosomes. Science 2020, 367, eaau6977  DOI: 10.1126/science.aau6977
      There is no corresponding record for this reference.
    23. 23
      Qin, Y.; Bai, Y.; Huang, P.; Wu, F. Y. Dual-Emission Carbon Dots for Ratiometric Fluorescent Water Sensing, Relative Humidity Sensing, and Anticounterfeiting Applications. ACS Applied Nano Materials 2021, 4 (10), 10674– 10681,  DOI: 10.1021/acsanm.1c02148
      23
      Dual-Emission Carbon Dots for Ratiometric Fluorescent Water Sensing, Relative Humidity Sensing, and Anticounterfeiting Applications
      Qin, Yujuan; Bai, Yongju; Huang, Pengcheng; Wu, Fang-Ying
      ACS Applied Nano Materials (2021), 4 (10), 10674-10681CODEN: AANMF6; ISSN:2574-0970. (American Chemical Society)
      We synthesized blue fluorescent carbon quantum dots (CDs) by the solvothermal strategy using 2,5-dihydroxyterephthalic acid as the precursor. The as-prepd. CD surfaces contain abundant carboxyl and hydroxyl groups and show excitation-independent emission and excellent chem. stability. Interestingly, with the increment of water contents in org. solvents, the CDs underwent a visual fluorescence color transition from blue to green, which could be attributed to the excited-state intramol. proton transfer effect via the intermol. hydrogen bonding between CDs and water. Based on this, we designed an effective ratiometric fluorescence water sensor in org. solvents, which featured self-calibration, visualization, rapid response (<20 s), and high sensitivity (limit of detection = 0.052%, vol./vol., in ethanol). The smartphone-based quant. assay was also realized using CD-loaded paper strips through a color processing application and successfully applied to monitor the water content in spirit samples. Humidity sensing was further evaluated through the as-prepd. CDs/polymer films. Remarkably, the CD-based sensors were well recyclable both with paper strips and polymer films. The as-prepd. CDs also hold great potential for anticounterfeiting.
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    24. 24
      Anwar, S.; Ding, H.; Xu, M.; Hu, X.; Li, Z.; Wang, J.; Liu, L.; Jiang, L.; Wang, D.; Dong, C.; Yan, M.; Wang, Q.; Bi, H. Recent Advances in Synthesis, Optical Properties, and Biomedical Applications of Carbon Dots. ACS Appl. Energy Mater. 2019, 2, 2317– 2338,  DOI: 10.1021/acsabm.9b00112
      There is no corresponding record for this reference.
    25. 25
      Wareing, T. C.; Gentile, P.; Phan, A. N. Biomass-based carbon dots: current development and future perspectives. ACS Nano 2021, 15, 15471– 15501,  DOI: 10.1021/acsnano.1c03886
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      Biomass-based carbon dots: current development and future perspectives
      Wareing, Thomas C.; Gentile, Piergiorgio; Phan, Anh N.
      ACS Nano (2021), 15 (10), 15471-15501CODEN: ANCAC3; ISSN:1936-0851. (American Chemical Society)
      A review. Carbon dots have been considered as a soln. to the challenges that semiconductor quantum dots have encountered because they are more biocompatible and can be synthesized from abundant and nontoxic materials such as biomass. This review will highlight the advantages of these biomass-based carbon dots in terms of synthesis, properties, and applications in the biomedical field. Furthermore, future applications esp. in the biomedical field of biomass-based carbon dots as well as the challenges of semiconductor quantum dots such as biocompatibility, photobleaching, environmental challenges, toxicity, and poor soly. will be discussed in detail. Biomass-derived quantum dots, a subsection of carbon dots that are the most desirable for future research, will be focused upon including from synthesis to applications. Finally, the future development of biomass derived quantum dots in the biomedical field will be discussed and evaluated to unlock the potential for their applications.
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    26. 26
      Yang, Y.; Kannisto, E.; Patnaik, S. K.; Reid, M. E.; Li, L.; Wu, Y. Ultrafast Detection of Exosomal RNAs via Cationic Lipoplex Nanoparticles in a Micromixer Biochip for Cancer Diagnosis. ACS Appl. Nano Mater. 2021, 4, 2806– 2819,  DOI: 10.1021/acsanm.0c03426
      26
      Ultrafast Detection of Exosomal RNAs via Cationic Lipoplex Nanoparticles in a Micromixer Biochip for Cancer Diagnosis
      Yang, Yunchen; Kannisto, Eric; Patnaik, Santosh K.; Reid, Mary E.; Li, Lei; Wu, Yun
      ACS Applied Nano Materials (2021), 4 (3), 2806-2819CODEN: AANMF6; ISSN:2574-0970. (American Chemical Society)
      Exosomes are cell-derived, nanosized extracellular vesicles for intercellular communication. Exosomal RNAs have been shown as one type of promising cancer liq. biopsy biomarkers. Conventional methods to characterize exosomal RNAs such as quant. reverse transcription polymerase chain reaction (qRT-PCR) are limited by low sensitivity, large sample consumption, time-consuming process, and high cost. Many technologies have been developed to overcome these challenges; however, many hours are still required to complete the assays, esp. when exosome lysis and RNA extn. are required. We have developed a microfluidic cationic lipoplex nanoparticles (mCLN) assay that utilizes a micromixer biochip to allow for the effective capture of exosomes by cationic lipoplex nanoparticles and thus enables ultrafast and sensitive exosomal RNA detection for cancer diagnosis. The sensing performance and diagnostic performance of the mCLN assay were investigated using non-small cell lung cancer (NSCLC) as the disease model and exosomal microRNA-21 and TTF-1 mRNA as the biomarkers. The limits of detection of the mCLN assay were 2.06 x 109 and 3.71 x 109 exosomes/mL for microRNA-21 and TTF-1 mRNA, resp., indicating that the mCLN assay may require as low as 1 μL of serum for exosomal RNA detection. The mCLN assay successfully distinguished NSCLC from normal controls by detecting significantly higher microRNA-21 and TTF-1 mRNA levels in exosomes from both NSCLC patient serum samples and A549 NSCLC cells than those from normal controls and BEAS-2B normal bronchial epithelial cells. Compared with conventional qRT-PCR assay, the mCLN assay showed a higher diagnostic accuracy in lung cancer, required less sample vol. (30 vs 100 μL), and consumed much less time (10 min vs 4 h).
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    27. 27
      Wareing, T. C.; Gentile, P.; Phan, A. N. Biomass-based carbon dots: current development and future perspectives. ACS Nano 2021, 15, 15471– 15501,  DOI: 10.1021/acsnano.1c03886
      27
      Biomass-based carbon dots: current development and future perspectives
      Wareing, Thomas C.; Gentile, Piergiorgio; Phan, Anh N.
      ACS Nano (2021), 15 (10), 15471-15501CODEN: ANCAC3; ISSN:1936-0851. (American Chemical Society)
      A review. Carbon dots have been considered as a soln. to the challenges that semiconductor quantum dots have encountered because they are more biocompatible and can be synthesized from abundant and nontoxic materials such as biomass. This review will highlight the advantages of these biomass-based carbon dots in terms of synthesis, properties, and applications in the biomedical field. Furthermore, future applications esp. in the biomedical field of biomass-based carbon dots as well as the challenges of semiconductor quantum dots such as biocompatibility, photobleaching, environmental challenges, toxicity, and poor soly. will be discussed in detail. Biomass-derived quantum dots, a subsection of carbon dots that are the most desirable for future research, will be focused upon including from synthesis to applications. Finally, the future development of biomass derived quantum dots in the biomedical field will be discussed and evaluated to unlock the potential for their applications.
      >> More from SciFinder ®
      https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BB3MXitFWjsrrN&md5=21d3f80890bc1033db85819b4c0c8777
    28. 28
      Xu, D.; Lin, Q.; Chang, H.-T. Recent Advances and Sensing Applications of Carbon Dots. Small Methods 2020, 4, 1900387,  DOI: 10.1002/smtd.201900387
      28
      Recent Advances and Sensing Applications of Carbon Dots
      Xu, Dong; Lin, Qinlu; Chang, Huan-Tsung
      Small Methods (2020), 4 (4), 1900387CODEN: SMMECI; ISSN:2366-9608. (Wiley-VCH Verlag GmbH & Co. KGaA)
      A review. Carbon dots (C dots) with biocompatibility, brightness, stability against photoirradn. and salt, and ease in prepn. have become important materials for sensing and imaging. They can be prepd. from natural materials and small org. mols. through hydrothermal, microwave-assistant, and electrochem. methods, with advantages of simplicity and low cost. To enhance the quantum yields of C dots in the red and near-IR regions, doping of C dots with heteroatoms such as nitrogen and sulfur has been suggested. C dots both with and without being functionalized recognition elements such as antibodies and aptamers are selective and sensitive for sensing of analytes, including metal ions (e.g., Fe3+, Hg2+, Cu2+), small mols. (e.g., H2O2, cysteine, glutathione), and biopolymers like proteins, as well as for in vitro and in vivo imaging. Depending on the size, charge, and surface ligands of C dots used to label cells, fluorescence images of different organelles are shown. Multicolor images of bacteria, mammalian cells, and plant tissues incubated with C dots are realized when excited at different wavelengths. In this review, many excellent sensing and imaging examples of C dots are presented to highlight their features and to show their challenges for anal. applications.
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    29. 29
      Zhu, Z.; Liu, C.; Song, X.-M.; Mao, Q.; Ma, T. Carbon Dots as an Indicator of Acid–Base Titration and a Fluorescent Probe for Endoplasm Reticulum Imaging. ACS Appl. Bio Mater. 2021, 4, 3623– 3629,  DOI: 10.1021/acsabm.1c00121
      29
      Carbon Dots as an Indicator of Acid-Base Titration and a Fluorescent Probe for Endoplasm Reticulum Imaging
      Zhu, Zhan; Liu, Chenlu; Song, Xi-Ming; Mao, Quanxing; Ma, Tianyi
      ACS Applied Bio Materials (2021), 4 (4), 3623-3629CODEN: AABMCB; ISSN:2576-6422. (American Chemical Society)
      In this study, carbon dots (CDs) with red color are successfully prepd. via hydrothermal treatment of o-phenylenediamine and urea. The as-prepd. red CDs exhibit an acidichromism feature, making them turn purple at pH 4.4 and become blue at pH 3.3. Further investigations reveal that the surface chem. bond species of CDs are responsible for the acidichromism feature. Taking advantage of the acidichromism feature, the CDs are employed as a titrn. indicator for anal. of alkali samples, which gives rise to satisfactory results without significant difference between the titrn. methods using CDs and methyl orange or a mixt. of methyl red and bromocresol green as indicators. The CDs show excitation-independent fluorescence with dual-emission at 600 and 650 nm, along with a respectable quantum yield of 20.1%, which provides the CDs with deep tissue penetration and min. autofluorescence background that is desirable in bioimaging. In addn., the CDs are found to light up endoplasm reticulum particularly, indicating their endoplasm reticulum targeting capability, which is proven by a colocalization study with other classical subcellular dyes. Endocytosis inhibiting investigations confirm that the endoplasm reticulum targeting ability is mainly attributed to the caveolin/lipid-raft-mediated endocytosis pathways of CDs. This study not only presents a facile approach for red CDs but also explores the possibility of CDs in titrn. anal. and in endoplasm reticulum targeting imaging.
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    30. 30
      Lu, W.; Jiao, Y.; Gao, Y.; Qiao, J.; Mozneb, M.; Shuang, S.; Dong, C.; Li, C.-Z. Bright Yellow Fluorescent Carbon Dots as a Multifunctional Sensing Platform for the Label-Free Detection of Fluoroquinolones and Histidine. ACS Appl. Mater. Interfaces 2018, 10, 42915– 42924,  DOI: 10.1021/acsami.8b16710
      30
      Bright Yellow Fluorescent Carbon Dots as a Multifunctional Sensing Platform for the Label-Free Detection of Fluoroquinolones and Histidine
      Lu, Wenjing; Jiao, Yuan; Gao, Yifang; Qiao, Jie; Mozneb, Maedeh; Shuang, Shaomin; Dong, Chuan; Li, Chen-zhong
      ACS Applied Materials & Interfaces (2018), 10 (49), 42915-42924CODEN: AAMICK; ISSN:1944-8244. (American Chemical Society)
      Owing to their diverse properties, fluorescent carbon dots (CDs) have attracted more attention and present enormous potential in development of sensors, bioimaging, drug delivery, microfluidics, photodynamic therapy, light emitting diode, and so forth. Herein, a multifunctional sensing platform based on bright yellow fluorescent CDs (Y-CDs) was designed for the label-free detection of fluoroquinolones (FQs) and histidine (His). The Y-CDs with superior optical and biol. merits including high chem. stability, good biocompatibility, and low cytotoxicity were simply synthesized via one-step hydrothermal treatment of o-phenylenediamine (o-PD) and 4-aminobutyric acid (GABA). The Y-CDs can be utilized to directly monitor the amt. of FQs based on fluorescence static quenching owing to the specific interaction between FQs and Y-CDs. Then, the fluorescence of this system can be effectively recovered upon addn. of His. The multifunctional sensing platform exhibited high sensitivity and selectivity toward three kinds of FQs and His with low detection limits of 17-67 and 35 nM, resp. Benefiting from these outstanding characters, the Y-CDs were successfully employed for trace detection of FQs in real samples such as antibiotic tablets and milk products. Furthermore, the probe was also extended to cellular imaging. All of the above prove that this multifunctional sensing platform presents great prospect in multiple applications such as biosensing, biomedicine, disease diagnosis, and environmental monitoring.
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    31. 31
      Pramanik, A.; Jones, S.; Pedraza, F.; Vangara, A.; Sweet, C.; Williams, M. S.; Ruppa-Kasani, V.; Risher, S. E.; Sardar, D.; Ray, P. C. Fluorescent, Magnetic Multifunctional Carbon Dots for Selective Separation, Identification, and Eradication of Drug-Resistant Superbugs. ACS Omega 2017, 2, 554– 562,  DOI: 10.1021/acsomega.6b00518
      31
      Fluorescent, Magnetic Multifunctional Carbon Dots for Selective Separation, Identification, and Eradication of Drug-Resistant Superbugs
      Pramanik, Avijit; Jones, Stacy; Pedraza, Francisco; Vangara, Aruna; Sweet, Carrie; Williams, Mariah S.; Ruppa-Kasani, Vikram; Risher, Sean Edward; Sardar, Dhiraj; Ray, Paresh Chandra
      ACS Omega (2017), 2 (2), 554-562CODEN: ACSODF; ISSN:2470-1343. (American Chemical Society)
      The emergence of drug resistance superbugs remains a major burden to society. Since the mortality rate caused by sepsis due to superbugs is >40%, accurate identification of blood infections during the early stage will have huge significance in the clin. setting. Here the authors report the synthesis of red/blue fluorescent carbon dots (CDs)-attached magnetic nanoparticles-based multicolor multifunctional CDs-based nanosystems, which can be used for selective sepn. and identification of superbugs from infected blood samples. The reported data show that multifunctional fluorescent magneto-carbon dots nanoparticles are capable of isolating MRSA and Salmonella DT104 superbug from whole blood samples, followed by accurate identification via multicolor fluorescence imaging. Since multiple drug resistance superbugs are resistant to antibiotics available in the market, this article also reports the design of antimicrobial peptide conjugated multicolor fluorescent magneto-carbon dots for effective sepn., accurate identification and complete disinfection of MDR superbugs from infected blood. The reported data demonstrates that by combining pardaxin antimicrobial peptides, magnetic nanoparticle and multicolor fluorescent carbon dots into a single system, multifunctional carbon dots represent a novel material for efficient sepn., differentiation, and eradication of superbugs. This material shows great promise for use in clin. settings.
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    32. 32
      Pramanik, A.; Vangara, A.; Nellore, B. P. V.; Sinha, S. S.; Chavva, S. R.; Jones, S.; Ray, P. C. Development of Multifunctional Fluorescent-Magnetic Nanoprobes for Selective Capturing and Multicolor Imaging of Heterogeneous Circulating Tumor Cells. ACS Appl. Mater. Interfaces 2016, 8, 15076– 15085,  DOI: 10.1021/acsami.6b03262
      32
      Development of Multifunctional Fluorescent-Magnetic Nanoprobes for Selective Capturing and Multicolor Imaging of Heterogeneous Circulating Tumor Cells
      Pramanik, Avijit; Vangara, Aruna; Viraka Nellore, Bhanu Priya; Sinha, Sudarson Sekhar; Chavva, Suhash Reddy; Jones, Stacy; Ray, Paresh Chandra
      ACS Applied Materials & Interfaces (2016), 8 (24), 15076-15085CODEN: AAMICK; ISSN:1944-8244. (American Chemical Society)
      Circulating tumor cells (CTC) are highly heterogeneous in nature due to epithelial-mesenchymal transition (EMT), which is the major obstacle for CTC anal. via "liq. biopsy". This article reports the development of a new class of multifunctional fluorescent-magnetic multicolor nanoprobes for targeted capturing and accurate identification of heterogeneous CTC. A facile design approach for the synthesis and characterization of bioconjugated multifunctonal nanoprobes that exhibit excellent magnetic properties and emit very bright and photostable multicolor fluorescence at red, green, and blue under 380 nm excitation is reported. Exptl. data presented show that the multifunctional multicolor nanoprobes can be used for targeted capture and multicolor fluorescence mapping of heterogeneous CTC and can distinguish targeted CTC from nontargeted cells.
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      https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC28XptVKku70%253D&md5=544ddd0bea55f0fb8d88be37d64eae35
    33. 33
      Pramanik, A.; Begum, S.; Rightsell, C.; Gates, K.; Zhang, Q.; Jones, S.; Gao, Y.; Ruppa-Kasani, V.; Banerjee, R.; Shukla, J.; Ignatius, A.; Sardar, D.; Han, F. X.; Ray, P. C. Designing Highly Crystalline Multifunctional Multicolor Luminescence Nanosystem for Tracking Breast Cancer Heterogeneity. Nanoscale Adv. 2019, 1, 1021– 1034,  DOI: 10.1039/C8NA00089A
      33
      Designing highly crystalline multifunctional multicolor-luminescence nanosystem for tracking breast cancer heterogeneity
      Pramanik, Avijit; Begum, Salma; Rightsell, Chris; Gates, Kaelin; Zhang, Qinku; Jones, Stacy; Gao, Ye; Ruppa-Kasani, Vikram; Banerjee, Rimika; Shukla, Jayanti; Ignatius, Ashley; Sardar, Dhiraj; Han, Fengxiang. X.; Chandra Ray, Paresh
      Nanoscale Advances (2019), 1 (3), 1021-1034CODEN: NAADAI; ISSN:2516-0230. (Royal Society of Chemistry)
      Breast tumor heterogeneity was responsible for the death of ∼40 000 women in 2017 in the USA. Triple-neg. breast cancers (TNBCs) are very aggressive, and this is the only subgroup of breast cancers that still lacks effective therapeutics. As a result, the early-stage detection of TNBCs is vital and will have huge significance in clin. practice. Driven by this need, we here report the design of highly cryst. antibody-conjugated multifunctional multicolor-luminescence nanosystems derived from the naturally available popular tropical fruits mangoes and prunes, which have the ability to detect breast cancer heterogeneity via the selective sepn. and accurate identification of TNBC and HER-2(+) or ER/PR(+) breast cancer cells selectively and simultaneously. The detailed synthesis and characterization of the multifunctional multicolor nanosystems derived from tropical fruits have been reported. Exptl. results show that by changing the fruits multicolor-luminescence carbon dots (LCDs) can be developed, which is mainly due to the formation of highly cryst. nanodots with different heavy metal dopants and is also due to the presence of different types of surface functional group. Exptl. data that are presented show that the multifunctional multicolor nanoprobe can be used for the highly selective and simultaneous capture of targeted TNBC and HER-2(+) or ER(+) breast cancer cells, and the capture efficiency can be as high as 98%. Reported data indicate that multicolor fluorescence imaging can be used for mapping heterogeneous breast cancer cells simultaneously and can distinguish targeted TNBC from non-targeted HER-2(+) or ER/PR(+) breast cancer. Our finding suggests the excellent potential of the design of multicolor nanosystems derived from natural fruits for detecting cancer heterogeneity in clin. practice.
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      https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1MXmslKqsrk%253D&md5=0b493079d36b581f1369f758cbc11015
    34. 34
      Pramanik, A.; Patibandla, S.; Gao, Y.; Gates, K.; Ray, P. C. Water Triggered Synthesis of Highly Stable and Biocompatible 1D Nanowire, 2D Nanoplatelet, and 3D Nanocube CsPbBr3 Perovskites for Multicolor Two-Photon Cell Imaging. J. Am. Chem. Soc. Au 2021, 1 (1), 53– 65,  DOI: 10.1021/jacsau.0c00038
      34
      Water Triggered Synthesis of Highly Stable and Biocompatible 1D Nanowires, 2D Nanoplatelets and 3D Nanocubes CsPbBr3 Perovskites for Multicolor Two-Photon Cell Imaging
      Pramanik, Avijit; Patibandla, Shamily; Gao, Ye; Gates, Kaelin; Ray, Paresh Chandra
      JACS Au (2021), 1 (1), 53-65CODEN: JAAUCR; ISSN:2691-3704. (American Chemical Society)
      Two-photon imaging in the near-IR window holds huge promise for real life biol. imaging due to the increased penetration depth. All-inorg. CsPbX3 nanocrystals with bright luminescence and broad spectral tunability are excellent smart probes for two-photon bioimaging. But the poor stability in water is a well-documented issue for limiting their practical use. Herein, we present the development of specific antibody attached water-resistant one-dimensional (1D) CsPbBr3 nanowires, two-dimensional (2D) CsPbBr3 nanoplatelets and three-dimensional (3D) CsPbBr3 nanocubes which can be used for selective and simultaneous two-photon imaging of heterogeneous breast cancer cells in near IR biol. window. Current manuscript reports the design of excellent photoluminescence quantum yield (PLQY), biocompatible and photostable 1D CsPbBr3 nanowires, 2D CsPbBr3 nanoplatelets and 3D CsPbBr3 nanocubes through an interfacial conversion from zero-dimensional (0D) Cs4PbBr6 nanocrystals via water triggered strategy. Reported data show that just by varying the amt. of water one can control the dimension of CsPbBr3 perovskite crystals. Time-dependent TEM and emission spectra have been reported to find the possible pathway for the formation of 1D, 2D and 3D CsPbBr3 nanocrystals from 0D Cs4PbBr6 nanocrystals. Biocompatible 1D, 2D and 3D CsPbBr3 nanocrystals were developed by coating with amine-poly(ethylene glycol) (PEG)-propionic acid. Exptl. data show the water-driven design of 1D, 2D and 3D CsPbBr3 nanocrystals exhibits strong single-photon (1P) PLQY ∼ 88-66% as well as excellent two-photon absorption (2PA) properties (2) ∼ 8.3 x 105 GM - 7.1 x 104 GM. Furthermore, reported data show more than 86% of PL intensity remain for 1D, 2D and 3D CsPbBr3 nanocrystals after 35 days under water and they exhibit excellent photostability of keeping 99% PL intensity after 3 h under UV light. Current report demonstrates for the first time that antibody attached 1D and 2D perovskite have capability for simultaneous two-photon imaging of triple neg. breast cancer (TNBC) cells and human epidermal growth factor receptor 2 (HER2) pos. breast cancer cells. Since CsPbBr3 nanocrystals exhibit very high TPA cross-section and good photostability in water, which are much superior to that of commonly used org. probes (σ2 = 11 GM for fluorescein) and therefore they have capability to be a better probe for bioimaging applications.
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    35. 35
      Wang, J.; Li, Q.; Zheng, J.; Yang, Y.; Liu, X.; Xu, B. N, B-codoping induces high-efficiency solid-state fluorescence and dual emission of yellow/orange carbon dots. ACS Sustainable Chem. Eng. 2021, 9, 2224– 2236,  DOI: 10.1021/acssuschemeng.0c07992
      35
      N, B-Codoping Induces High-Efficiency Solid-State Fluorescence and Dual Emission of Yellow/Orange Carbon Dots
      Wang, Junli; Li, Qiang; Zheng, Jingxia; Yang, Yongzhen; Liu, Xuguang; Xu, Bingshe
      ACS Sustainable Chemistry & Engineering (2021), 9 (5), 2224-2236CODEN: ASCECG; ISSN:2168-0485. (American Chemical Society)
      Carbon dots (CDs) have attracted a lot of attention because of their tunable emission wavelength, high photobleaching resistance, and environmental friendliness. However, they suffer from aggregation-induced quenching in the solid state, which limits their application in solid-state fields. In this work, yellow- and orange-emissive N, B-codoped CDs (y-NB-CDs and o-NB-CDs) with highly efficient solid-state fluorescence and dual emission were achieved by a facile one-step microwave method. The obtained y-NB-CDs in the powder state show bright yellow fluorescence with a high solid-state QY of 39.0% and typical dual emission peaks at 484 and 565 nm. The as-synthesized o-NB-CDs in the powder state exhibit bright orange fluorescence with a high solid-state QY of 31.1% and dual emission at 484 and 585 nm. After systematically studying the effect of N, B-codoping on the solid-state fluorescence of NB-CDs, we demonstrate that the hydrogen bond between B-OH on the surface of the NB-CDs can inhibit the direct contact of nanoparticles, and a high content of graphitic N in NB-CDs can increase the probability of the radiative process of the arom. domains, both of which trigger high-efficiency solid-state fluorescence of NB-CDs. This finding provides a general and efficient method for highly emissive solid-state CDs. In addn., N, B-codoping can also give NB-CDs dual emission in the short-wavelength and long-wavelength regions, ascribed to the carbon core and surface defect state, resp. Finally, y-NB-CDs were demonstrated as a phosphor to prep. a near white light-emitting diode with a color rendering index of 84 by combining them with an UV chip.
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    36. 36
      Meng, T.; Wang, Z.; Yuan, T.; Li, X.; Li, Y.; Zhang, Y.; Fan, L. Gram-scale synthesis of highly efficient rare-earth element-free red/green/blue solid-state bandgap fluorescent carbon quantum rings for white light-emitting diodes. Angew. Chem., Int. Ed. 2021, 60, 16343– 16348,  DOI: 10.1002/anie.202103361
      36
      Gram-Scale Synthesis of Highly Efficient Rare-Earth-Element-Free Red/Green/Blue Solid-State Bandgap Fluorescent Carbon Quantum Rings for White Light-Emitting Diodes
      Meng, Ting; Wang, Zifei; Yuan, Ting; Li, Xiaohong; Li, Yunchao; Zhang, Yang; Fan, Louzhen
      Angewandte Chemie, International Edition (2021), 60 (30), 16343-16348CODEN: ACIEF5; ISSN:1433-7851. (Wiley-VCH Verlag GmbH & Co. KGaA)
      The neg. impact of rare-earth elements (REEs) on the environment, limited supply and high cost prompt the need for REE-free phosphor-converted white light-emitting diodes (LEDs). Report the gram-scale synthesis of red/green/blue solid-state bandgap fluorescent C quantum rings (R/G/B-SBF-CQRs) with high quantum yields ≤30-46%. This was achieved using cyano-group-bearing p-phenyldiacetonitrile as precursor and forming C quantum rings of different diams. through the linkage of curved C quantum ribbons of different lengths. The results show the role of cyano groups in inducing the curvature of the C quantum ribbons for CQR formation and emission of stable solid-state bandgap fluorescence. R/G/B-SBF-CQRs-phosphor-based LEDs emitted warm white light with low CCT (3576 K), high CRI (96.6), and high luminous efficiency (48.7 lm W-1), comparable to REE-phosphor-based LEDs.
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    37. 37
      Liang, T.; Liu, E.; Li, M.; Ushakova, E. V.; Kershaw, S. V.; Rogach, A. L.; Tang, Z.; Qu, S. Morphology control of luminescent carbon nanomaterials: from dots to rolls and belts. ACS Nano 2021, 15, 1579– 1586,  DOI: 10.1021/acsnano.0c09053
      37
      Morphology Control of Luminescent Carbon Nanomaterials: From Dots to Rolls and Belts
      Liang, Tao; Liu, Enshan; Li, Minghui; Ushakova, Elena V.; Kershaw, Stephen V.; Rogach, Andrey L.; Tang, Zikang; Qu, Songnan
      ACS Nano (2021), 15 (1), 1579-1586CODEN: ANCAC3; ISSN:1936-0851. (American Chemical Society)
      In this work, we report a successful extension of the family of light-emitting colloidal carbon nanostructures to a no. of different shapes and morphologies, namely, carbon nanorolls (CNRs) and carbon nanobelts (CNBs). Near IR (NIR)-emissive CNRs were synthesized via a solvothermal fusion of carbon dots (CDs) triggered by a dehydration process of their surface functional groups. They appear in a form of short cylinders, with diams. ranging from 20 to 40 nm and cylinder lengths ranging from 7 to 20 nm. In ethanol soln., CNRs have a max. absorption peak at 665 nm and a NIR emission band extending from 650 to 800 nm, with a photoluminescence quantum yield of 9.2%. Intriguingly, the rolled structure of CNRs can be uncoiled under 655 nm laser irradn. (power d. 1 W·cm-2) of their soln. in ethanol, forming CNBs with a width of 7-20 nm and lengths reaching several hundreds of nanometers, which is accompanied by a considerably decreased absorption band at 665 nm and a decreased NIR emission. This unfolding is ascribed to the decrease of the strength of interlayer hydrogen bonding, owing to the photothermally induced dehydration and further carbonization of the CNRs. Alongside the decreased NIR emission, CNBs exhibit enhanced green and red emissions under UV and green light excitation, resp., which allows us to demonstrate multiple-level luminescence encryptions on a paper stamped with CNR- and CNB-inks.
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    • Design and characterization of the anti-PD-L1 monoclonal antibody=conjugated magnetic-nanoparticle-attached YFCD-based nanoarchitectures and other experiments, including cell cultures, separation of the PD-L1 (+) exosomes, and luminescence imaging (PDF)


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