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A Dual Targeting Dendrimer-Mediated siRNA Delivery System for Effective Gene Silencing in Cancer TherapyClick to copy article linkArticle link copied!
- Yiwen DongYiwen DongState Key Laboratory of Natural Medicines and Jiangsu Key Laboratory of Drug Discovery for Metabolic Diseases, Center of Drug Discovery, Center of Advanced Pharmaceutics and Biomaterials, China Pharmaceutical University, 24 Tong Jia Xiang, 210009 Nanjing, People’s Republic of ChinaMore by Yiwen Dong
- Tianzhu YuTianzhu YuAix-Marseille Université, CNRS, Centre Interdisciplinaire de Nanoscience de Marseille, UMR 7325, “Equipe Labellisée Ligue Contre le Cancer”, 13288 Marseille, FranceMore by Tianzhu Yu
- Ling DingLing DingAix-Marseille Université, CNRS, Centre Interdisciplinaire de Nanoscience de Marseille, UMR 7325, “Equipe Labellisée Ligue Contre le Cancer”, 13288 Marseille, FranceMore by Ling Ding
- Erik LauriniErik LauriniMolecular Biology and Nanotechnology Laboratory (MolBNL@UniTS), DEA, University of Trieste, 34127 Trieste, ItalyMore by Erik Laurini
- Yuanyu HuangYuanyu HuangAdvanced Research Institute of Multidisciplinary Science and School of Life Science, Beijing Institute of Technology, Beijing 100081, People’s Republic of ChinaSchool of Pharmacy, Hunan University of Chinese Medicine, Changsha 410208, People’s Republic of ChinaMore by Yuanyu Huang
- Mengjie ZhangMengjie ZhangAdvanced Research Institute of Multidisciplinary Science and School of Life Science, Beijing Institute of Technology, Beijing 100081, People’s Republic of ChinaMore by Mengjie Zhang
- Yuhua WengYuhua WengAdvanced Research Institute of Multidisciplinary Science and School of Life Science, Beijing Institute of Technology, Beijing 100081, People’s Republic of ChinaMore by Yuhua Weng
- Shuting LinShuting LinState Key Laboratory of Natural Medicines and Jiangsu Key Laboratory of Drug Discovery for Metabolic Diseases, Center of Drug Discovery, Center of Advanced Pharmaceutics and Biomaterials, China Pharmaceutical University, 24 Tong Jia Xiang, 210009 Nanjing, People’s Republic of ChinaMore by Shuting Lin
- Peng ChenPeng ChenState Key Laboratory of Natural Medicines and Jiangsu Key Laboratory of Drug Discovery for Metabolic Diseases, Center of Drug Discovery, Center of Advanced Pharmaceutics and Biomaterials, China Pharmaceutical University, 24 Tong Jia Xiang, 210009 Nanjing, People’s Republic of ChinaMore by Peng Chen
- Domenico MarsonDomenico MarsonMolecular Biology and Nanotechnology Laboratory (MolBNL@UniTS), DEA, University of Trieste, 34127 Trieste, ItalyMore by Domenico Marson
- Yifan JiangYifan JiangAix-Marseille Université, CNRS, Centre Interdisciplinaire de Nanoscience de Marseille, UMR 7325, “Equipe Labellisée Ligue Contre le Cancer”, 13288 Marseille, FranceMore by Yifan Jiang
- Suzanne GiorgioSuzanne GiorgioAix-Marseille Université, CNRS, Centre Interdisciplinaire de Nanoscience de Marseille, UMR 7325, “Equipe Labellisée Ligue Contre le Cancer”, 13288 Marseille, FranceMore by Suzanne Giorgio
- Sabrina PriclSabrina PriclMolecular Biology and Nanotechnology Laboratory (MolBNL@UniTS), DEA, University of Trieste, 34127 Trieste, ItalyMore by Sabrina Pricl
- Xiaoxuan Liu*Xiaoxuan Liu*[email protected]State Key Laboratory of Natural Medicines and Jiangsu Key Laboratory of Drug Discovery for Metabolic Diseases, Center of Drug Discovery, Center of Advanced Pharmaceutics and Biomaterials, China Pharmaceutical University, 24 Tong Jia Xiang, 210009 Nanjing, People’s Republic of ChinaAix-Marseille Université, CNRS, Centre Interdisciplinaire de Nanoscience de Marseille, UMR 7325, “Equipe Labellisée Ligue Contre le Cancer”, 13288 Marseille, FranceMore by Xiaoxuan Liu
- Palma RocchiPalma RocchiInserm, Aix-Marseille Université, Institut Paoli-Calmettes, CNRS, CRCM, 13009 Marseille, FranceMore by Palma Rocchi
- Ling Peng*Ling Peng*[email protected]Aix-Marseille Université, CNRS, Centre Interdisciplinaire de Nanoscience de Marseille, UMR 7325, “Equipe Labellisée Ligue Contre le Cancer”, 13288 Marseille, FranceMore by Ling Peng
Abstract
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Small interfering RNA (siRNA) is emerging as a novel therapeutic for treating various diseases, provided a safe and efficient delivery is available. In particular, specific delivery to target cells is critical for achieving high therapeutic efficacy while reducing toxicity. Amphiphilic dendrimers are emerging as novel promising carriers for siRNA delivery by virtue of the combined multivalent cooperativity of dendrimers with the self-assembling property of lipid vectors. Here, we report a ballistic approach for targeted siRNA delivery to cancer cells using an amphiphilic dendrimer equipped with a dual targeting peptide bearing an RGDK warhead. According to the molecular design, the amphiphilic dendrimer was expected to deliver siRNA effectively, while the aim of the targeting peptide was to home in on tumors via interaction of its warhead with integrin and the neuropilin-1 receptor on cancer cells. Coating the positively charged siRNA/dendrimer delivery complex with the negatively charged segment of the targeting peptide via electrostatic interactions led to small and stable nanoparticles which were able to protect siRNA from degradation while maintaining the accessibility of RGDK for targeting cancer cells and preserving the ability of the siRNA to escape from endosomes. The targeted system had enhanced siRNA delivery, stronger gene silencing, and more potent anticancer activity compared to nontargeted or covalent dendrimer-based systems. In addition, neither acute toxicity nor induced inflammation was observed. Consequently, this delivery system constitutes a promising nonviral vector for targeted delivery and can be further developed to provide RNAi-based personalized medicine against cancer. Our study also gives new perspectives on the use of nanotechnology based on self-assembling dendrimers in various biomedical applications.
Copyright © 2018 American Chemical Society
Introduction
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Gene therapy based on RNA interference (RNAi), a post-transcriptional gene silencing phenomenon triggered by small interfering RNA (siRNA), (1,2) is emerging as a promising therapeutic option for treating various diseases. (3−5) Particularly exciting is the first ever RNAi-based gene-silencing siRNA drug “patisiran”, which was approved by the FDA this year. (6) As siRNA targets and breaks down the corresponding mRNA via Watson–Crick base-pairing, in principle it can be harnessed to target any gene with known sequence, in particular, disease-associated genes for therapeutic purposes. (3−5) However, naked siRNA is not a stable therapeutic agent per se, as it can be rapidly degraded by enzymes such as nucleases or esterases, which pervade body fluids. In addition, siRNA molecules are hydrophilic and highly negatively charged and, hence, cannot readily cross cell membranes to reach the RNAi machinery in the cytosol for gene silencing. Moreover, if administered at high concentration, naked siRNA will often generate off-target effects, which can induce severe adverse effects. Consequently, there is a high demand for safe and effective siRNA delivery systems that are able to protect the nucleic acid from degradation, deliver it to the target cells, and ultimately promote functional gene silencing. (7−10)
Both viral and nonviral delivery vectors have been explored for siRNA delivery. Although viral delivery is more effective, increasing concerns over the immunogenicity and toxicity of viral vectors urge the development and improvement of synthetic carrier systems. (7−10) Lipids and polymers are the most commonly applied nonviral vectors for siRNA delivery. (11−15) Dendrimers, a special family of polymers, have emerged as promising siRNA carriers by virtue of their well-defined structural architecture, cooperative multivalence, and intriguing ability to carry a high cargo payload within a nanosized volume. (16−20) We have recently developed a series of cationic amphiphilic dendrimers (21−24) that couple the multivalent cooperativity of dendrimer vectors with the self-assembling property of lipid vectors, hence capitalizing on the advantageous characteristics of both lipid and dendrimer vectors for effective delivery. (25,26) One of these multivalent self-assembling dendrimers, AD (Scheme 1A), exhibits particularly high performance for siRNA delivery to a wide range of cell types, including highly challenging human primary cells and stem cells. (22) Importantly, AD is also able to deliver siRNA to tumors in xenograft mice for successful in vivo gene silencing and potent anticancer activity. (22)
Scheme 1
Scheme 1. Strategy for Active Delivery of siRNA Using an Amphiphilic Dendrimer AD Vector with the Dual Targeting Peptide: (A) Chemical Structure of the Amphiphilic Dendrimer AD; (B) The Targeting Peptide E16G6RGDK Composed of Three Distinct Functional Segments: RGDK as the Targeting Warhead, Oligo(glutamic acid) E16 as the Negatively Charged Sequence to Interact with Positively Charged siRNA/AD Complexes, and the Neutral Oligo(glycine) G6 as the Linker to Bridge the Targeting Unit and the siRNA Loading Complex; (C) Cartoon Illustration of the Formation of the siRNA/AD/E16G6RGDK Complexes for Targeted siRNA Delivery
With the aim of further improving the AD-mediated siRNA delivery, we wanted to endow AD with an active targeting ability for specific delivery to cancer cells within tumor lesions. In principle, active targeting can be realized by introducing a targeting moiety on the delivery system, which can interact with and bind to ligands or receptors present on the cell surface. (27,28) In this way, the therapeutic cargo can be delivered specifically to the target cells, thereby achieving higher therapeutic efficacy while sparing other cells to reduce toxicity. Different targeting agents such as antibodies, peptides, and small molecular ligands have been applied to construct active targeting systems. (27−31) Among them, the RGDK peptide is particularly appealing for cancer targeting because it has dual targeting capacity within a short peptide segment. (32) On one hand, RGD can target tumor endothelium by interacting with ανβ3 integrin, which is overexpressed in tumor vasculature; (33,34) on the other hand, RGDK is able to bind to the neuropilin-1 (Nrp-1) receptor, which is present on tumor cells, hence promoting cancer cell penetration and uptake. (32,35) In a previous study, we were able to demonstrate the validity of this dual targeting strategy for siRNA delivery and enhanced performance in gene silencing using a poly(amidoamine) PAMAM dendrimer of generation 5 (G5) that was decorated with the same targeting peptide. (36) However, producing a large quantity of pure, high-generation PAMAM dendrimers requires considerable cost, time, and effort. (37,38) Accordingly, in this paper we report the introduction of the dual targeting warhead RGDK to the small amphiphilic dendrimer AD-based delivery system (Scheme 1), which effectively led to targeted siRNA delivery and enhanced gene silencing compared to the nontargeting system. In contrast to our former study, (36) in the present effort we exploit the quintessence of nanotechnology, i.e., the controlled self-assembly of small, synthetically amenable building blocks to generate a nanosystem for siRNA delivery. We further demonstrate that decoration of the resulting siRNA/AD system with this dual targeting peptide not only is feasible but, most importantly, leads to in vitro and in vivo results substantially superior to those achieved with the covalent high-generation dendrimer decorated with the same peptide. This is the first report to explore a targeting strategy for self-assembling dendrimer-mediated siRNA delivery.
In our strategy to append the RGDK targeting moiety on the AD-based delivery system, we used the peptide E16G6RGDK, which is composed of three distinct functional segments: (1) the targeting unit RGDK, (2) the negatively charged oligo(glutamic acid) E16, and (3) the neutral oligo(glycine) G6 (Scheme 1B). The RGDK segment will mediate the dual active targeting function by homing to the tumor vasculature via RGD/integrin binding and, at the same time, targeting cancer cells via binding of RGDK to Nrp-1 receptors on the cell surface. The negatively charged oligo(glutamic acid) segment E16 will serve to promote the attachment of the targeting peptide to the positively charged siRNA/AD complex via electrostatic interaction. (36,39) The neutral oligo(glycine) segment G6 will act as the linker to connect the targeting warhead RGDK to the siRNA/AD delivery complexes (Scheme 1C). To prove the concept of this targeting delivery, we used PC-3 prostate cancer cells as the cancer model, because PC-3 cells have highly overexpressed integrin and Nrp-1 receptors on the surface. (30,40)
Prostate cancer (PCa) has the highest incidence rate and is the major cause of cancer-related deaths in males in Western countries. (41) Although androgen deprivation therapy is beneficial as the standard first-line treatment in early stage hormone-naive PCa, castration-resistant prostate cancer (CRPC) unfortunately often develops within one or two years. (42,43) CRPC is associated with poor prognosis, high apoptosis resistance, and high mortality, (44) and no efficacious treatment for managing CRPC is clinically available to date. (43) Recently, we demonstrated that using AD-mediated siRNA delivery to target the cancer cell survival gene Hsp27, which encodes heat shock protein 27, (45−47) is an effective approach for treating CRPC. (22) In this study, we provide further proof that the AD-based delivery system equipped with the RGDK targeting peptide is much more effective than the nontargeted one and superior to the covalent G5 PAMAM dendrimer decorated with the same peptide for siRNA delivery and gene silencing of Hsp27, (36) ultimately leading to more potent anticancer activity in CRPC models in vitro and in vivo. The superior delivery efficiency can be ascribed to the active dual targeting mechanism via RGD/integrin and RGDK/Nrp-1 receptor interactions in addition to the excellent delivery performance of the amphiphilic dendrimer AD. Therefore, this study demonstrates that the strategy to coat the amphiphilic dendrimer-based siRNA delivery system with the dual targeting RGDK warhead constitutes a powerful approach to achieve effective and specific tumor targeting for more efficient siRNA delivery and potent gene silencing. This approach can be further developed for RNAi-based personalized medicine in fighting cancer.
Results and Discussion
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Formation of Small and Stable Peptide-Decorated siRNA/AD/E16G6RGDK Complexes
For effective siRNA delivery, it is important that the delivery system is small and stable. This is because small nanoparticulate complexes can penetrate deep into tumor tissue and be taken up efficiently by cancer cells, and stable delivery complexes effectively protect the siRNA against enzyme degradation. In our system, by simply adding the targeting peptide E16G6RGDK to the siRNA/AD complex in solution, small and spherical nanoparticles were formed, as illustrated by the results obtained using transmission electron microscopy (TEM) (Figure 1A) and dynamic light scattering (DLS) analysis (Figure 1B). The dimensions of the peptide-decorated siRNA/AD/E16G6RGDK complexes are around 30–45 nm, which are in the size range required for effective cellular uptake. In addition, the zeta potential of the siRNA/AD/E16G6RGDK nanoparticles is +15 mV, which is lower than the noncoated siRNA/AD complexes (+32 mV). This finding indicates that the negatively charged E16G6RGDK peptide indeed bound to the positively charged siRNA/AD complexes as expected, hence decreasing the positive surface charge.
Figure 1
Figure 1. Small and stable siRNA/AD/E16G6RGDK complexes formed by adding the peptide E16G6RGDK to the siRNA/AD complexes. (A) TEM imaging and (B) DLS analysis of the siRNA/AD/E16G6RGDK complexes (siRNA/AD at an N/P ratio of 10, AD/peptide at a molar ratio of 5.0). (C) Representative integrated ITC profiles for titration of the siRNA/AD complexes with the E16G6RGDK peptide in ultrapure water (T = 25 °C). The solid red lines are data fitted with a sigmoidal function. The inset shows the corresponding ITC raw data. All experiments were run in triplicate. (D) Agarose gel shift analysis of the siRNA/AD/E16G6RGDK complexes versus the siRNA/AD complexes (siRNA/AD at an N/P ratio of 10, AD/peptide ratio varying from 2.0 to 20). (E) The siRNA/AD/E16G6RGDK complexes are able to protect siRNA from RNase A digestion. (siRNA/AD at an N/P ratio of 10; AD/peptide ratio of 5.0).
We further assessed the binding thermodynamics of the E16G6RGDK peptides to the siRNA/AD complexes by carrying out isothermal titration calorimetry (ITC) measurements. The binding process is mainly characterized by a favorable enthalpic contribution (ΔΗ = −5.0 ± 0.2 kcal/mol), as testified by the exothermic peaks of the corresponding thermogram (Figure 1C). A small favorable entropy change is also estimated (−TΔS = −1.9 kcal/mol), and, accordingly, the overall complex formation is thermodynamically favored, with a free energy of binding (ΔG) value of −6.8 kcal/mol. The substantial enthalpic nature of the binding supports the fact that the electrostatic forces play the leading role, while the positive entropic term can be reasonably ascribed to stabilizing peptide/complex hydrophobic interactions and water/ion release into the bulk solvent.
We next studied the stability of the siRNA/AD/E16G6RGDK complexes using gel mobility shift assays in the presence of RNase. As shown in Figure 1D, adding the peptide E16G6RGDK to the siRNA/AD complexes at different peptide/AD ratios did not cause any siRNA release, highlighting the formation of stable siRNA/AD/E16G6RGDK complexes and complete encapsulation of siRNA. Further experiments with RNase treatment demonstrate that the siRNA/AD/E16G6RGDK complexes effectively protected siRNA from enzymatic digestion, whereas free siRNA was not stable and was degraded rapidly within 5.0 min (Figure 1E). Collectively, our results show that the peptide-coated siRNA/AD/E16G6RGDK complexes are small and stable and are able to protect siRNA from degradation. All these are important and beneficial features for effective siRNA delivery.
Accessible RGDK Targeting Moieties in the Stable Peptide-Coated Complexes
To get further insight into the peptide-coated siRNA/AD/E16G6RGDK complexes at the molecular level, we performed atomistic molecular dynamics (MD) simulations as we did in our previous work. (21,48) As can be seen in Figure 2A, a stable (1.0 μs) Janus-like nanoparticle was formed, in which four E16G6RGDK peptides are adsorbed onto the siRNA/AD assembly, with the nucleic acids on the opposite side. From the same figure, it is evident that, as initially surmised, the negative tails of the peptides (E16) are in close contact with the positive charges of the PAMAM dendron heads of AD and, most importantly, the RGDK warhead groups protrude well into the solvent (Figure 2A). This qualitative observation is quantitatively supported by the results in Figure 2B, which shows the radial distribution function (RDF) for the positively charged terminals of the AD molecules and the RGDK terminals of the four E16G6RGDK peptides. These curves clearly indicate that the RDGK moieties are located away from the nanoparticle periphery, thus being available for interaction with the cellular receptors. Finally, the targeting peptides are compared in Figure 2C. In agreement with the experimentally determined zeta-potentials, binding of the negatively charged peptides on the surface of the siRNA/AD complex results in a lower positive electrostatic surface compared to the undecorated siRNA/AD binary assembly.
Figure 2
Figure 2. (A) (Left) Cartoon showing the arrangement of the siRNA molecule (gray) and the four E16G6RGDK moieties (colored as in the right panel) on the AD nanomicelle (blue), as derived from the detailed atomistic molecular simulations. (Center) Equilibrated molecular dynamics (MD) snapshot of an siRNA/AD micelle in complex with four E16G6RGDK peptides numbered as E16G6RGDK1 to E16G6RGDK4 and colored as follows: E16G6RGDK1, tail (E16G6) sandy brown, head (RGDK) firebrick; E16G6RGDK2, tail light green, head olive drab; E16G6RGDK3, tail khaki, head golden rod; E16G6RGDK4, tail plum, head magenta. The siRNA molecule is portrayed with its van der Waals surface in gray. The AD micelle is shown in dark slate blue sticks and balls, while the four peptides are depicted as colored spheres, as above precised. Ions and counterions are shown as green and purple hollow spheres; water is shown as a light cyan surface. (Right) Zoomed-in view of the system in panel A showing the RGDK warhead group of E16G6RGDK4 protruding into the solvent as an example. (B) Radial distribution function as a function of the distance from the AD micelle center of mass for the AD positively charged terminal groups (dark slate blue) and for each of the four RGDK warhead groups. Colors as in panel A. (C) Electrostatic surface potential of the siRNA/AD micelle (left) and of the siRNA/AD/(E16G6RGDK)4 complex (right) as extracted from the equilibrated portion of the corresponding MD simulations. Dark blue represents a highly positively charged surface, while red represents a highly negatively charged surface. (D) Free energy of binding (ΔGb) of each E16G6RGDK peptide on the siRNA/AD micelle. Colors as in panel A. The empty color bars (left bar of each pair) represent the value of ΔGb for the entire peptide molecule, while the filled color bars (right bar of each pair) give the contribution to ΔGb from the negatively charged E16G6 tails only.
To estimate the intensity of the interaction between each peptide and the siRNA/AD complex, the MD data were further processed using the MM/PBSA approach. (49−51) The free energy of binding (ΔGb) between each of the four E16G6RGDK peptides and the siRNA/AD complex is shown in Figure 2D. All peptides are characterized by a favorable (i.e., negative) ΔGb value (in the range −7.0 ± 0.2 to −6.1 ± 0.2 kcal/mol, empty bars in Figure 2D). The major contribution to binding is the strong electrostatic interaction between the negatively charged peptide tails (E16) and the protonated amines at the AD terminals (filled bars in Figure 2D). Altogether, our molecular simulation results further support our initial molecular concept and hypothesis that the E16G6RGDK peptides form stable complexes with siRNA/AD, ultimately yielding nanoparticles with a lower positive surface charge while leaving the RGDK warheads available for cellular receptor interactions. All the simulation data are in line with our experimental results.
Enhanced Cell Uptake via Dual Receptor-Mediated Interactions Followed by Effective Endosomal Escape
Our aim in decorating the siRNA/AD delivery complex with the dual targeting peptide E16G6RGDK was to improve the delivery efficiency and specificity by actively targeting cancer cells via both RGD/integrin binding and RGDK/Nrp-1 interaction while also ensuring effective endosomal escape. We therefore first investigated the uptake of the peptide-decorated complexes by PC-3 prostate cancer cells, which are characterized by high expression of both integrin and Nrp-1 receptors. (30,40) Using siRNA labeled with the fluorescent dye Cy5, we found that the internalization of the peptide-coated Cy5-siRNA/AD/E16G6RGDK complexes was significantly (3.0-fold) higher than the noncoated Cy5-siRNA/AD complexes in PC-3 cells (Figure 3A). In addition, the uptake of the peptide-decorated Cy5-siRNA/AD/E16G6RGDK complexes was considerably reduced in the presence of cyclic RGD (cRGD) (Figure 3B), indicating that cRGD competed with the peptide-coated nanoparticles for integrin binding. This confirms that the peptide-decorated delivery complexes indeed bound to integrin via the RGD motif. Also, as shown by confocal microscopic imaging in Figure 3C, cells pretreated with anti-Nrp-1-receptor monoclonal antibody had dramatically reduced internalization of the Cy5-siRNA/AD/E16G6RGDK complexes compared to untreated cells. This highlights that the peptide-decorated complexes are effectively taken up by cells via RGDK/Nrp-1 receptor interaction. Collectively, these results provide evidence that the cellular uptake of the peptide-coated siRNA/dendrimer complexes was indeed mediated by RGD/integrin and RGDK/Nrp-1 receptor interactions, and the uptake of the decorated complexes by PC-3 cells was more efficient than the nondecorated ones.
Figure 3
Figure 3. SiRNA/AD/E16G6RGDK complexes are effectively taken up by PC-3 prostate cancer cells via RGD/integrin and RGDK/neuropilin-1 (Nrp-1) receptor interactions and are then released from endosomes. (A) Flow cytometry analysis of the cellular uptake of siRNA/AD/E16G6RGDK complexes compared to siRNA/AD complexes using Cy5-labeled siRNA. (B) Flow cytometry analysis of the cellular uptake of siRNA/AD/E16G6RGDK complexes in the absence and presence of cyclic RGD (cRGD). (C) Confocal microscopic imaging of the cellular uptake of siRNA/AD/E16G6RGDK complexes in the absence and presence of Nrp-1-receptor antibody. (D) Confocal microscopic imaging of the endosomal escape of the siRNA/AD/E16G6RGDK complexes after incubation times of 0 (control), 0.5, 1.0, and 2.0 h. Red channel image shows the Cy5-labeled siRNA/AD/E16G6RGDK complexes, green channel image shows the endosomes marked by LysoTracker red, and blue channel image shows the nuclei of PC-3 cells stained by DAPI (C) or Hoechst33342 (D). The siRNA/AD/E16G6RGDK complexes were formed using 50 nM siRNA, an N/P ratio of 10, and AD/peptide molar ratio of 5.0. Data are presented as mean ± SD. **, p ≤ 0.01 as calculated by Student’s t test.
After cellular uptake, it is important that the peptide-decorated delivery complexes are able to escape from the endosomes and release siRNA for subsequent gene silencing. We therefore further examined the endosomal escape of the fluorescent Cy5-siRNA/AD/E16G6RGDK complexes in the presence of LysoTracker, which fluorescently labels acidic compartments. As we can see in the confocal microscopic images (Figure 3D), after 0.5 h of incubation the fluorescent signals from the LysoTracker and the Cy5 dye colocalized in sharp and clear-cut spots, implying that the Cy5-siRNA/AD/E16G6RGDK complexes were entrapped in the endosomes. Notably, after 1.0 h of incubation, dispersed and smeared Cy5 fluorescent signals were observed, suggesting that the some of the Cy5-siRNA/AD/E16G6RGDK complexes had escaped from the endosomes into the cytoplasm. After 2.0 h, more of the Cy5 fluorescent signals were diffuse in the cytoplasm and there was less colocalization with the LysoTracker, indicating the successful escape of the Cy5-siRNA from the endosomes. Consequently, the peptide-decorated siRNA delivery complexes are able to circumvent endosome trapping and effectively release siRNA in the cytoplasm for subsequent gene silencing.
Targeted Delivery Increases Gene Silencing and Anticancer Activity in Vitro
We next compared the ability of the targeting peptide-decorated siRNA delivery complexes and the nondecorated ones to down-regulate Hsp27 in PC-3 prostate cancer cells. Using a low concentration (20 nM) of siRNA targeting Hsp27, a small chaperone protein involved in cancer cell proliferation and drug resistance, the peptide-coated siRNA/AD/E16G6RGDK complexes were significantly more effective than the noncoated siRNA/AD complexes at knocking down Hsp27 at the mRNA level (Figure 4A), leading to more than 90% inhibition of Hsp27 protein expression (Figure 4B). Of note, a significantly higher siRNA concentration (50 nM) was necessary to produce comparable effects using the generation 5 PAMAM dendrimer decorated with the same peptide. (36) This highlights that the peptide-coated delivery system effectively improved gene silencing. The enhanced down-regulation of Hsp27 by the targeting complexes was reduced in the presence of either cRGD or anti-Nrp-1-receptor antibody (Figure 4C), indicating that cRGD and anti-Nrp-1-receptor antibody competed with the peptide-coated nanoparticles for binding with integrin and Nrp-1 receptors, respectively. This again supports the view that the peptide-decorated delivery complexes indeed act via integrin- and Nrp-1 receptor-mediated targeting. Further assessment of in vitro anticancer activity using the MTT assay revealed that the peptide-decorated siRNA/AD/E16G6RGDK complexes drastically reduced the proliferation of PC-3 cells with respect to the noncoated siRNA/AD complexes (Figure 4D). Collectively, our results demonstrate that actively targeted delivery via the peptide-coated nanosystem is indeed more effective for siRNA-mediated gene silencing of Hsp27 and leads to a more pronounced reduction in proliferation than the nontargeted delivery system.
Figure 4
Figure 4. Targeted siRNA/AD/E16G6RGDK system is much more effective than the nontargeted siRNA/AD system for Hsp27 silencing and antiproliferation in PC-3 prostate cancer cells. Hsp27 silencing at (A) mRNA and (B) protein levels, determined using qRT-PCR and Western blotting, respectively. (C) The improved down-regulation of Hsp27 at the mRNA level by the targeting complexes is reduced in the presence of either cRGD or anti-Nrp-1-receptor antibody. (D) MTT assay of the antiproliferation effect of the complexes on PC-3 cells. Conditions used: 20 nM siRNA, N/P ratio of 10, AD/peptide molar ratio of 5.0. Data are presented as mean ± SD. **, p ≤ 0.01; ***, p ≤ 0.001 as calculated by Student’s t test.
Targeted Delivery Enhances Gene Silencing and Antitumor Activity in Vivo
To investigate the power of the targeting system for siRNA delivery in vivo, we used the PC-3 xenograft nude mouse model. We first assessed the tumor targeting capability of these formulations using fluorescent Cy5-labeled siRNA. Ex vivo imaging of isolated tumors showed that the targeting system siRNA/AD/E16G6RGDK had significantly higher mean florescence intensity (MFI) in tumors than the nontargeting system siRNA/AD (Figure 5A and B). This result demonstrates that decoration with the targeting peptide indeed enhanced the tumor targeting capability of the amphiphilic dendrimer in vivo.
Figure 5
Figure 5. Targeted siRNA/AD/E16G6RGDK delivery system (A, B) accumulates more efficiently in tumor tissues and (C, D) is much more potent than the nontargeted siRNA/AD system for gene silencing and anticancer activity in tumor xenograft mice. Cy5-siRNA/AD complexes and Cy5-siRNA/AD/E16G6RGDK complexes were administered to PC-3 xenograft mice via i.v. injection in PBS buffer (1.0 mg/kg siRNA, N/P ratio 5.0, AD/peptide molar ratio 5). (A) Fluorescence images of siRNAs accumulated in isolated tumors. (B) Fluorescence quantification analysis of tumors in (A) using imaging software. Data were normalized to the tumors from PBS-treated animals. PC-3 xenograft nude mice were administered twice per week with PBS buffer, siRNA/AD complexes, or siRNA/AD/E16G6RGDK complexes (0.25 mg/kg siRNA, N/P ratio 5.0, AD/peptide molar ratio 5). (C) Tumor growth assessed by measuring tumor size. (D) Cancer cell proliferation in tumor tissue revealed by immunohistochemistry using Ki67 staining. (E) Expression of Hsp27 protein in tumors quantified using Western blotting. (F) Mouse body weight monitoring during the treatment. Data are presented as mean ± SD. *, p ≤ 0.05; **, p ≤ 0.01, ***, p ≤ 0.001 as calculated by Student’s t test.
We further examined gene silencing and tumor growth inhibition with both targeting and nontargeting systems. The siRNA delivery complexes were administered twice per week for 4.0 weeks. It is worth mentioning that we applied a very low siRNA concentration of 0.25 mg/kg at an N/P ratio of 5, which is more than 10 times lower than that used when performing the same experiments using the covalent G5 PAMAM dendrimer, (36) i.e., the conventional siRNA concentration used for in vivo siRNA delivery in mice (3.0 mg/kg). Remarkably, the targeted siRNA/AD/E16G6RGDK delivery system reduced the tumor growth much more effectively than the nontargeted siRNA/AD system (Figure 5C). Also, immunohistochemistry (IHC) analysis revealed that cancer cell proliferation was inhibited more efficiently in tumors from mice treated with the targeted siRNA/AD/E16G6RGDK complexes than in tumors from mice treated with nontargeted ones (Figure 5D). Further Western blotting analysis of the protein level of Hsp27 in tumor tissue (Figure 5E) confirmed that the silencing of Hsp27 was indeed more effective in mice treated with the targeted siRNA/AD/E16G6RGDK delivery system than the nontargeted one. All these data demonstrate that the targeted delivery approach is more potent in gene silencing than nontargeted delivery, and hence more effective in inhibiting cancer cell proliferation and retarding tumor growth in PC-3 xenografts. In addition, there was no alteration of the body weights of the mice (Figure 5F), which highlights the promising safety profile of this delivery system. Altogether, these results provide strong evidence for enhanced siRNA delivery specifically to cancer cells using the amphiphilic dendrimer AD-based delivery system equipped with the dual targeting peptide.
The Targeted Delivery System Is Safe and Devoid of Toxicity
The superior delivery capacity of the targeted delivery system motivated us to further evaluate its toxicity profile for eventual therapeutic applications. We performed the MTT assay, which measures cell metabolic activity and provides an indication of metabolic toxicity, and the LDH assay, which determines the membrane integrity by quantifying the lactate dehydrogenase released from cells into the extracellular medium. Results from both MTT and LDH assays using a nontargeting scramble siRNA control revealed that neither metabolic toxicity nor membrane damage was induced in cancer cells (PC-3 cells) (Figure 6A and B) and noncancer cells (HEK cells) (Figure 6C and D) after treatment with the targeted siRNA/AD/E16G6RGDK delivery system and the nontargeted one. Neither the targeted siRNA/AD/E16G6RGDK nanoparticles nor the nontargeted siRNA/AD nanoparticles caused any notable hemolytic toxicity at low concentrations. It is noteworthy that the targeted system caused significantly less hemolysis at high concentrations than the nontargeted system (Figure 6E). This finding indicates that coating the positively charged siRNA/AD complexes with the negatively charged E16G6RGDK peptide reduced the hemolytic toxicity. This may be ascribed to the decreased positive surface charge of the peptide-coated delivery system, as revealed by zeta potential measurement and molecular simulations described above.
Figure 6
Figure 6. In vitro toxicity assessment of the targeted siRNA/AD/E16G6RGDK delivery system versus the nontargeted siRNA/AD system. Toxicity assessment using the MTT assay and LDH assay for (A, B) PC-3 prostate cancer cells and (C, D) human embryonic kidney (HEK 293) cells (20 nM siRNA, N/P ratio of 10, AD/peptide molar ratio of 5.0). (E) Left panel: Hemolysis assay of the siRNA/AD complexes and the siRNA/AD/E16G6RGDK complexes in comparison with AD alone at different concentrations of AD (0.50, 1.0, 2.5, 5.0, and 10 μM), which correspond to siRNA concentrations of 10, 20, 50, 100, and 200 nM. Right panel: Quantitative analysis of hemolysis determined by UV absorption at 540 nm. Data are presented as mean ± SD. ***, p ≤ 0.001 as calculated by Student’s t test.
Furthermore, in healthy mice treated with phosphate-buffered saline (PBS), the targeted delivery system siRNA/AD/E16G6RGDK and the nontargeted system siRNA/AD did not cause any signs of discomfort, unusual behavior, or body weight change when delivering the scrambled control siRNA. In addition, mice treated with either the targeted or the nontargeted siRNA/AD systems showed no evidence of induced inflammation, whereas mice treated with the positive control lipopolysaccharide (LPS) exhibited significantly elevated levels of inflammatory factors such as IL-6, INF-γ, TNF-α, GM-CSF, MCP-1, KC, and IL-1β (Figure 7A). Moreover, several major serum biochemistry parameters, including alanine transaminase (ALT), aspartate transaminase (AST), total bilirubin (TBIL), urea, total protein (TP), alkaline phosphatase (ALP), triacylglycerol (TG), and total cholesterol (TCHO), remained at normal levels at 24 h postadministration, indicating that the main organs, including the liver and kidneys, function well after treatment with these formulations (Figure 7B). Histological analysis of the main organs collected at 24 h post-treatment revealed that both siRNA/AD and siRNA/AD/E16G6RGDK were devoid of acute toxicity since no significant pathological change was observed in any of the tissue sections (Figure 7C). All these data highlight that the targeted delivery system composed of AD and E16G6RGDK is safe, as judged by the lack of cytotoxic effects, acute toxicity, or inflammatory responses.
Figure 7
Figure 7. In vivo toxicity assessment of the targeted siRNA/AD/E16G6RGDK delivery system versus the nontargeted siRNA/AD system. (A) Cytokine response in mice determined by quantifying the serum levels of IL-6, INF-γ, TNF-α, GM-CSF, MCP-1, KC, and IL-1β at 3 h postinjection using Luminex-detection technology according to the manufacturer’s protocol. Lipopolysaccharide (LPS) was used as the positive control. Data are presented as mean ± SEM. *, p < 0.05, ***, p < 0.001, versus PBS group, as calculated by Student’s t test. (B) Major serum biochemistry parameters measured in mouse serum collected at 24 h postinjection. Alanine transaminase (ALT), aspartate transaminase (AST), and alkaline phosphatase (ALP) are measured as U/L; total bilirubin (TBIL), urea, triacylglycerol (TG), and total cholesterol (TCHO) are measured as mmol/L; total protein (TP) is measured as g/L. Data are shown as mean ± SEM. (C) Histopathological analysis of major organs from mice treated with siRNA/AD and siRNA/AD/E16G6RGDK. Tissue samples were collected at 24 h postadministration. No significant histopathological changes were observed in any of the tissue sections. Images were enlarged 200 times with the microscope.
Conclusions
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In this study, we established a novel system for targeted siRNA delivery based on the amphiphilic dendrimer AD equipped with the targeting peptide E16G6RGDK, which bears the dual-targeting warhead RGDK, the negatively charged oligo(glutamic acid) E16, and the neutral spacer oligo(glycine) G6. This peptide stably coated the positively charged siRNA/AD delivery complexes via electrostatic interaction with its negatively charged E16 segment. The so-formed nanoparticles were small, stable, and able to protect siRNA from degradation. Furthermore, the targeting segment RGDK was accessible for binding to and interacting with the integrin and the neuropilin-1 receptor molecules on the surface of PC-3 prostate cancer cells. This consequently led to specific and enhanced cellular uptake of siRNA followed by effective endosomal escape of the siRNA, which further promoted much stronger gene silencing and resulted in more potent anticancer activity than the nontargeted system in castration-resistant prostate cancer models in vitro and in vivo. In addition, in vitro cytotoxicity, acute in vivo toxicity, and induced in vivo inflammation were not observed for the targeted delivery system. These results indicate the potential of this targeting system for safe and functional siRNA delivery and consequent gene silencing and anticancer activity. This targeting system hence holds great promise for treating prostate cancer, in particular castration-resistant prostate cancer, for which there is no efficacious treatment yet.
It is worth mentioning that our amphiphilic dendrimer AD has been previously demonstrated to deliver siRNA to tumors in xenograft mice for successful gene silencing and anticancer activity. (22) Those results can mainly be attributed to passive tumor targeting via the enhanced permeation and retention effect in addition to the excellent delivery ability of AD. In this study, we equipped this siRNA delivery system with the dual targeting peptide, further imparting the capacity to specifically target cancer cells for improved gene silencing and hence much more potent anticancer activity at a significantly lower dosage of siRNA. This is the first report to explore a targeting strategy for self-assembling dendrimer-mediated siRNA delivery. Compared with our previous studies using conventional covalent dendrimers, (36,52) this amphiphilic dendrimer system has similar siRNA loading capacity but more than 10-fold greater potency for in vivo siRNA delivery and consequent antitumor activity. We expect that this approach using a dual targeting peptide to decorate the amphiphilic dendrimer-based delivery system (26,27) can be applied for siRNA delivery to develop RNAi-based personalized medicine against various cancers in general. We are actively working in this direction.
Supporting Information
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The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/jacs.8b10021.
Materials and methods as well as all experimental protocols for TEM, DLS, computational details, ITC, cell uptake and endosome release, siRNA delivery, gene silencing, anticancer activity and toxicity, etc. (PDF)
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Author Information
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- Ling Peng - Aix-Marseille Université, CNRS, Centre Interdisciplinaire de Nanoscience de Marseille, UMR 7325, “Equipe Labellisée Ligue Contre le Cancer”, 13288 Marseille, France;
http://orcid.org/0000-0003-3990-5248;
- Erik Laurini - Molecular Biology and Nanotechnology Laboratory (MolBNL@UniTS), DEA, University of Trieste, 34127 Trieste, Italy;http://orcid.org/0000-0001-6092-6532
- Yuanyu Huang - Advanced Research Institute of Multidisciplinary Science and School of Life Science, Beijing Institute of Technology, Beijing 100081, People’s Republic of China; School of Pharmacy, Hunan University of Chinese Medicine, Changsha 410208, People’s Republic of China;http://orcid.org/0000-0003-3935-7245
Acknowledgments
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Financial support from ARTP (L.P., X.L.), La Ligue Nationale Contre le Cancer (EL2016.LNCC/LPP) (L.P.), and the French National Research Agency under the frame of EuroNanoMed II (ANR-15-ENM2-0006-02, ANR-16-ENM2-0004-02) (L.P.), National Natural Science Foundation of China (No. 51773227, 81701815) (X.L.), Natural Science Foundation of Jiangsu Province (BK20170735) (X.L.), Recruitment Program for Youth Talents (X.L.), the Program for Jiangsu Province Innovative Research Talents (X.L.), the Program for Jiangsu Province Innovative Research Team (X.L.), the Jiangsu Specially-Appointed Professors Program (X.L.), the Six Talent Peaks Project of Jiangsu Province of China (X.L.), the State Key Laboratory of Natural Medicines at China Pharmaceutical University (SKLNMKF201703, SKLNMZZRC201804) (L.P., X.L.), the Italian Association for Cancer Research (AIRC, IG 17413 to S.P.), Beijing Institute of Technology Research Fund Program for Young Scholars (Y.H.), the Fundamental Research Funds for the Central Universities (Y.H.), the Hunan Provincial Natural Science Foundation of China (2018JJ1019) (Y.H.), and Huxiang Young Talent Program (Y.H.) is gratefully acknowledged. L.D. is supported by the China Scholarship Council and Y.J. by the Fondation de Recherche Médicale (SPF20160936294).
References
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This article references 52 other publications.
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- 15Wittrup, A.; Ai, A.; Liu, X.; Hamar, P.; Trifonova, R.; Charisse, K.; Manoharan, M.; Kirchhausen, T.; Lieberman, J. Visualizing lipid-formulated siRNA release from endosomes and target gene knockdown. Nat. Biotechnol. 2015, 33, 870– 876, DOI: 10.1038/nbt.3298Google Scholar15https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2MXhtF2murjF&md5=1e896c5372fff738d373ef1deb2ac412Visualizing lipid-formulated siRNA release from endosomes and target gene knockdownWittrup, Anders; Ai, Angela; Liu, Xing; Hamar, Peter; Trifonova, Radiana; Charisse, Klaus; Manoharan, Muthiah; Kirchhausen, Tomas; Lieberman, JudyNature Biotechnology (2015), 33 (8), 870-876CODEN: NABIF9; ISSN:1087-0156. (Nature Publishing Group)A central hurdle in developing small interfering RNAs (siRNAs) as therapeutics is the inefficiency of their delivery across the plasma and endosomal membranes to the cytosol, where they interact with the RNA interference machinery. With the aim of improving endosomal release, a poorly understood and inefficient process, we studied the uptake and cytosolic release of siRNAs, formulated in lipoplexes or lipid nanoparticles, by live-cell imaging and correlated it with knockdown of a target GFP reporter. siRNA release occurred invariably from maturing endosomes within ∼5-15 min of endocytosis. Cytosolic galectins immediately recognized the damaged endosome and targeted it for autophagy. However, inhibiting autophagy did not enhance cytosolic siRNA release. Gene knockdown occurred within a few hours of release and required <2,000 copies of cytosolic siRNAs. The ability to detect cytosolic release of siRNAs and understand how it is regulated will facilitate the development of rational strategies for improving the cytosolic delivery of candidate drugs.
- 16Lee, C.; MacKay, J.; Frechet, J.; Szoka, F. Designing dendrimers for biological applications. Nat. Biotechnol. 2005, 23, 1517– 1526, DOI: 10.1038/nbt1171Google Scholar16https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2MXht1yisrnE&md5=d1306ae17979250c01f2fb51fa76a080Designing dendrimers for biological applicationsLee, Cameron C.; MacKay, John A.; Frechet, Jean M. J.; Szoka, Francis C.Nature Biotechnology (2005), 23 (12), 1517-1526CODEN: NABIF9; ISSN:1087-0156. (Nature Publishing Group)A review. Dendrimers are branched, synthetic polymers with layered architectures that show promise in several biomedical applications. By regulating dendrimer synthesis, it is possible to precisely manipulate both their mol. wt. and chem. compn., thereby allowing predictable tuning of their biocompatibility and pharmacokinetics. Advances in our understanding of the role of mol. wt. and architecture on the in vivo behavior of dendrimers, together with recent progress in the design of biodegradable chemistries, has enabled the application of these branched polymers as anti-viral drugs, tissue repair scaffolds, targeted carriers of chemotherapeutics and optical oxygen sensors. Before such products can reach the market, however, the field must not only address the cost of manuf. and quality control of pharmaceutical-grade materials, but also assess the long-term human and environmental health consequences of dendrimer exposure in vivo.
- 17Khandare, J.; Calderon, M.; Dagia, N.; Haag, R. Multifunctional dendritic polymers in nanomedicine: opportunities and challenges. Chem. Soc. Rev. 2012, 41, 2824– 2848, DOI: 10.1039/C1CS15242DGoogle Scholar17https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC38Xjs1CksLg%253D&md5=2096b686d6657325955ec41bbbc006f2Multifunctional dendritic polymers in nanomedicine: opportunities and challengesKhandare, Jayant; Calderon, Marcelo; Dagia, Nilesh M.; Haag, RainerChemical Society Reviews (2012), 41 (7), 2824-2848CODEN: CSRVBR; ISSN:0306-0012. (Royal Society of Chemistry)A review. Nanotechnol. has resulted in materials that have greatly improved the effectiveness of drug delivery because of their ability to control matter on the nanoscale. Advanced forms of nanomedicine have been synthesized for better pharmacokinetics to obtain higher efficacy, less systemic toxicity, and better targeting. These criteria have long been the goal in nanomedicine, in particular, for systemic applications in oncol. disorders. Now, the "holy grail" in nanomedicine is to design and synthesize new advanced macromol. nanocarriers and to translate them from lab to clinic. This review describes the current and future perspectives of nanomedicine with particular emphasis on the clin. targets in cancer and inflammation. The advanced forms of liposomes and polyethylene glycol (PEG) based nanocarriers, as well as dendritic polymer conjugates will be discussed with particular attention paid to designs, synthetic strategies, and chem. pathways. In this crit. review, we also report on the current status and perspective of dendritic polymer nanoconjugate platforms (e.g. polyamidoamine dendrimers and dendritic polyglycerols) for cellular localization and targeting of specific tissues (192 refs.).
- 18Liu, X.; Rocchi, P.; Peng, L. Dendrimers as non-viral vectors for siRNA delivery. New J. Chem. 2012, 36, 256– 263, DOI: 10.1039/C1NJ20408DGoogle ScholarThere is no corresponding record for this reference.
- 19Liu, X.; Liu, C.; Catapano, C.; Peng, L.; Zhou, J.; Rocchi, P. Structurally flexible triethanolamine-core poly(amidoamine) dendrimers as effective nanovectors to deliver RNAi-based therapeutics. Biotechnol. Adv. 2014, 32, 844– 852, DOI: 10.1016/j.biotechadv.2013.08.001Google ScholarThere is no corresponding record for this reference.
- 20Reebye, V.; Sætrom, P.; Mintz, P.; Huang, K.; Swiderski, P.; Peng, L.; Liu, C.; Liu, X.; Lindkaer-Jensen, S.; Zacharoulis, D. Novel RNA oligonucleotide improves liver function and inhibits liver carcinogenesis in vivo. Hepatology 2014, 59, 216– 227, DOI: 10.1002/hep.26669Google ScholarThere is no corresponding record for this reference.
- 21Yu, T.; Liu, X.; Bolcato-Bellemin, A.; Wang, Y.; Liu, C.; Erbacher, P.; Qu, F.; Rocchi, P.; Behr, J.; Peng, L. An amphiphilic dendrimer for effective delivery of small interfering RNA and gene silencing in vitro and in vivo. Angew. Chem., Int. Ed. 2012, 51, 8478– 8484, DOI: 10.1002/anie.201203920Google Scholar21https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC38XhtVyjs7rO&md5=176386f529e80f5778008b8aba3c2714An Amphiphilic Dendrimer for Effective Delivery of Small Interfering RNA and Gene Silencing In Vitro and In VivoYu, Tianzhu; Liu, Xiaoxuan; Bolcato-Bellemin, Anne-Laure; Wang, Yang; Liu, Cheng; Erbacher, Patrick; Qu, Fanqi; Rocchi, Palma; Behr, Jean-Paul; Peng, LingAngewandte Chemie, International Edition (2012), 51 (34), 8478-8484, S8478/1-S8478/33CODEN: ACIEF5; ISSN:1433-7851. (Wiley-VCH Verlag GmbH & Co. KGaA)An amphiphilic dendrimer bearing a hydrophobic alkyl chain and hydrophilic poly(amidoamine) dendrons is able to combine the advantageous features of lipid and dendrimers vectors to deliver a heat shock protein 27 siRNA and produce potent gene silencing and anticancer activity in vitro and in vivo in a prostate cancer model. This dendrimer can be used alternatively for treating various diseases.
- 22Liu, X.; Zhou, J.; Yu, T.; Chen, C.; Cheng, Q.; Sengupta, K.; Huang, Y.; Li, H.; Liu, C.; Wang, Y.; Posocco, P.; Wang, M.; Cui, Q.; Giorgio, S.; Fermeglia, M.; Qu, F.; Pricl, S.; Shi, Y.; Liang, Z.; Rocchi, P.; Rossi, J.; Peng, L. Adaptive amphiphilic dendrimer-based nanoassemblies as robust and versatile siRNA delivery systems. Angew. Chem., Int. Ed. 2014, 53, 11822– 11827, DOI: 10.1002/anie.201406764Google Scholar22https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2cXhsFCisrvF&md5=5cb14bd9e508eb76c4b008b6752ed806Adaptive Amphiphilic Dendrimer-Based Nanoassemblies as Robust and Versatile siRNA Delivery SystemsLiu, Xiaoxuan; Zhou, Jiehua; Yu, Tianzhu; Chen, Chao; Cheng, Qiang; Sengupta, Kheya; Huang, Yuanyu; Li, Haitang; Liu, Cheng; Wang, Yang; Posocco, Paola; Wang, Menghua; Cui, Qi; Giorgio, Suzanne; Fermeglia, Maurizio; Qu, Fanqi; Pricl, Sabrina; Shi, Yanhong; Liang, Zicai; Rocchi, Palma; Rossi, John J.; Peng, LingAngewandte Chemie, International Edition (2014), 53 (44), 11822-11827CODEN: ACIEF5; ISSN:1433-7851. (Wiley-VCH Verlag GmbH & Co. KGaA)SiRNA delivery remains a major challenge in RNAi-based therapy. Here, we report for the first time that an amphiphilic dendrimer is able to self-assemble into adaptive supramol. assemblies upon interaction with siRNA, and effectively delivers siRNAs to various cell lines, including human primary and stem cells, thereby outperforming the currently available nonviral vectors. In addn., this amphiphilic dendrimer is able to harness the advantageous features of both polymer and lipid vectors and hence promotes effective siRNA delivery. Our study demonstrates for the first time that dendrimer-based adaptive supramol. assemblies represent novel and versatile means for functional siRNA delivery, heralding a new age of dendrimer-based self-assembled drug delivery in biomedical applications.
- 23Chen, C.; Posocco, P.; Liu, X.; Cheng, Q.; Laurini, E.; Zhou, J.; Liu, C.; Wang, Y.; Tang, J.; Col, V.; Yu, T.; Giorgio, S.; Fermeglia, M.; Qu, F.; Liang, Z.; Rossi, J.; Liu, M.; Rocchi, P.; Pricl, S.; Peng, L. siRNA delivery: mastering dendrimer self-assembly for efficient siRNA delivery: from conceptual design to in vivo efficient gene silencing. Small 2016, 12, 3667– 3676, DOI: 10.1002/smll.201503866Google ScholarThere is no corresponding record for this reference.
- 24Liu, X.; Wang, Y.; Chen, C.; Tintaru, A.; Cao, Y.; Liu, J.; Ziarelli, F.; Tang, J.; Guo, H.; Rosas, R.; Giorgio, S.; Charle, L.; Rocchi, P.; Peng, L. A fluorinated bola-amphiphilic dendrimer for on-demand delivery of siRNA, via specific response to reactive oxygen species. Adv. Funct. Mater. 2016, 26, 8594– 8603, DOI: 10.1002/adfm.201604192Google Scholar24https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC28XhslGitLjE&md5=931ea4546e4a792fc32c41dd25b69a8aA Fluorinated Bola-Amphiphilic Dendrimer for On-Demand Delivery of siRNA, via Specific Response to Reactive Oxygen SpeciesLiu, Xiaoxuan; Wang, Yang; Chen, Chao; Tintaru, Aura; Cao, Yu; Liu, Juan; Ziarelli, Fabio; Tang, Jingjie; Guo, Hongbo; Rosas, Roseline; Giorgio, Suzanne; Charles, Laurence; Rocchi, Palma; Peng, LingAdvanced Functional Materials (2016), 26 (47), 8594-8603CODEN: AFMDC6; ISSN:1616-301X. (Wiley-VCH Verlag GmbH & Co. KGaA)Functional materials capable of responding to stimuli intrinsic to diseases are extremely important for specific drug delivery at the disease site. However, developing on-demand stimulus-responsive vectors for targeted delivery is highly challenging. Here, a stimulus-responsive fluorinated bola-amphiphilic dendrimer is reported for on-demand delivery of small interfering RNA (siRNA) in response to the characteristic high level of reactive oxygen species (ROS) in cancer cells. This dendrimer bears a ROS-sensitive thioacetal in the hydrophobic core and pos. charged poly(amidoamine) dendrons at the terminals, capable of interacting and compacting the neg. charged siRNA into nanoparticles to protect the siRNA and promote cellular uptake. The ROS-sensitive feature of this dendrimer boosts specific and efficient disassembly of the siRNA/vector complexes in ROS-rich cancer cells for effective siRNA delivery and gene silencing. Moreover, the fluorine tags in the vector enable 19F-NMR anal. of the ROS-responsive delivery process. In addn., this ingenious and distinct bola-amphiphilic dendrimer is also able to combine the advantageous delivery features of both lipid and dendrimer vectors. Therefore, it represents an innovative on-demand stimulus-responsive delivery platform.
- 25Percec, V.; Wilson, D.; Leowanawat, P.; Wilson, C.; Hughes, A.; Kaucher, M.; Hammer, D.; Levine, D.; Kim, A.; Bates, F. Self-assembly of Janus dendrimers into uniform dendrimersomes and other complex architectures. Science 2010, 328, 1009– 1014, DOI: 10.1126/science.1185547Google Scholar25https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3cXmtFCnsLo%253D&md5=f27fa5e6ae26f177e85c36ca5e46047eSelf-Assembly of Janus Dendrimers into Uniform Dendrimersomes and Other Complex ArchitecturesPercec, Virgil; Wilson, Daniela A.; Leowanawat, Pawaret; Wilson, Christopher J.; Hughes, Andrew D.; Kaucher, Mark S.; Hammer, Daniel A.; Levine, Dalia H.; Kim, Anthony J.; Bates, Frank S.; Davis, Kevin P.; Lodge, Timothy P.; Klein, Michael L.; De Vane, Russell H.; Aqad, Emad; Rosen, Brad M.; Argintaru, Andreea O.; Sienkowska, Monika J.; Rissanen, Kari; Nummelin, Sami; Ropponen, JarmoScience (Washington, DC, United States) (2010), 328 (5981), 1009-1014CODEN: SCIEAS; ISSN:0036-8075. (American Association for the Advancement of Science)Self-assembled nanostructures obtained from natural and synthetic amphiphiles serve as mimics of biol. membranes and enable the delivery of drugs, proteins, genes, and imaging agents. Yet the precise mol. arrangements demanded by these functions are difficult to achieve. Libraries of amphiphilic Janus dendrimers, prepd. by facile coupling of tailored hydrophilic and hydrophobic branched segments, have been screened by cryogenic transmission electron microscopy, revealing a rich palette of morphologies in water, including vesicles, denoted dendrimersomes, cubosomes, disks, tubular vesicles, and helical ribbons. Dendrimersomes marry the stability and mech. strength obtainable from polymersomes with the biol. function of stabilized phospholipid liposomes, plus superior uniformity of size, ease of formation, and chem. functionalization. This modular synthesis strategy provides access to systematic tuning of mol. structure and of self-assembled architecture.
- 26Sherman, S.; Xiao, Q.; Percec, V. Mimicking complex biological membranes and their programmable glycan ligands with dendrimersomes and glycodendrimersomes. Chem. Rev. 2017, 117, 6538– 6631, DOI: 10.1021/acs.chemrev.7b00097Google Scholar26https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2sXmtVyqur8%253D&md5=7448c0318ceb9b46a0b12963822a166bMimicking Complex Biological Membranes and Their Programmable Glycan Ligands with Dendrimersomes and GlycodendrimersomesSherman, Samuel E.; Xiao, Qi; Percec, VirgilChemical Reviews (Washington, DC, United States) (2017), 117 (9), 6538-6631CODEN: CHREAY; ISSN:0009-2665. (American Chemical Society)A review. Synthetic vesicles have been assembled and co-assembled from phospholipids, their modified versions, and other single amphiphiles into liposomes, and from block copolymers into polymersomes. Their time-consuming synthesis and prepn. as stable, monodisperse, and biocompatible liposomes and polymersomes called for the elaboration of new synthetic methodologies. Amphiphilic Janus dendrimers (JDs) and glycodendrimers (JGDs) represent the most recent self-assembling amphiphiles capable of forming monodisperse, stable, and multifunctional unilamellar and multilamellar onion-like vesicles denoted dendrimersomes (DSs) and glycodendrimersomes (GDSs), dendrimercubosomes (DCs), glycodendrimercubosomes (GDCs), and other complex architectures. Amphiphilic JDs consist of hydrophobic dendrons connected to hydrophilic dendrons and can be thought of as monodisperse oligomers of a single amphiphile. They can be functionalized with a variety of mols. such as dyes, and, in the case of JGDs, with carbohydrates. Their iterative modular synthesis provides efficient access to sequence control at the mol. level, resulting in topologies with specific epitope sequence and d. DSs, GDSs, and other architectures from JDs and JGDs serve as powerful tools for mimicking biol. membranes and for biomedical applications such as targeted drug and gene delivery and theranostics. This Review covers all aspects of the synthesis of JDs and JGDs and their biol. activity and applications after assembly in aq. media.
- 27Bertrand, N.; Wu, J.; Xu, X.; Kamaly, N.; Farokhzad, O. Cancer nanotechnology: the impact of passive and active targeting in the era of modern cancer biology. Adv. Drug Delivery Rev. 2014, 66, 2– 25, DOI: 10.1016/j.addr.2013.11.009Google Scholar27https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2cXisV2hug%253D%253D&md5=0980da1a1b75cde64cc1cf82184e01b7Cancer nanotechnology: The impact of passive and active targeting in the era of modern cancer biologyBertrand, Nicolas; Wu, Jun; Xu, Xiaoyang; Kamaly, Nazila; Farokhzad, Omid C.Advanced Drug Delivery Reviews (2014), 66 (), 2-25CODEN: ADDREP; ISSN:0169-409X. (Elsevier B.V.)Cancer nanotherapeutics are progressing at a steady rate; research and development in the field has experienced an exponential growth since early 2000's. The path to the commercialization of oncol. drugs is long and carries significant risk; however, there is considerable excitement that nanoparticle technologies may contribute to the success of cancer drug development. The pace at which pharmaceutical companies have formed partnerships to use proprietary nanoparticle technologies has considerably accelerated. It is now recognized that by enhancing the efficacy and/or tolerability of new drug candidates, nanotechnol. can meaningfully contribute to create differentiated products and improve clin. outcome. This review describes the lessons learned since the commercialization of the first-generation nanomedicines including DOXIL and Abraxane. It explores our current understanding of targeted and non-targeted nanoparticles that are under various stages of development, including BIND-014 and MM-398. It highlights the opportunities and challenges faced by nanomedicines in contemporary oncol., where personalized medicine is increasingly the mainstay of cancer therapy. We revisit the fundamental concepts of enhanced permeability and retention effect (EPR) and explore the mechanisms proposed to enhance preferential "retention" in the tumor, whether using active targeting of nanoparticles, binding of drugs to their tumoral targets or the presence of tumor assocd. macrophages. The overall objective of this review is to enhance our understanding in the design and development of therapeutic nanoparticles for treatment of cancers.
- 28Dai, L.; Liu, J.; Luo, Z.; Li, M.; Cai, K. Tumor therapy: targeted drug delivery system. J. Mater. Chem. B 2016, 4, 6758– 6772, DOI: 10.1039/C6TB01743FGoogle Scholar28https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC28XhsVWktr3F&md5=43534ec2f361c7181059c074132608d4Tumor therapy: targeted drug delivery systemsDai, Liangliang; Liu, Junjie; Luo, Zhong; Li, Menghuan; Cai, KaiyongJournal of Materials Chemistry B: Materials for Biology and Medicine (2016), 4 (42), 6758-6772CODEN: JMCBDV; ISSN:2050-7518. (Royal Society of Chemistry)Recently, targeted drug delivery systems (TDDSs) have been extensively studied as a promising therapeutic for tumor therapy. In this review, we investigate the typical targeting mechanisms of TDDSs, covering both passively and actively targeting DDSs for tumor therapy. We highlight the popular active targeting strategies for different sites of action, including tumor cytomembrane or various organelles. Finally, we present some recent representative TDDSs that are under testing in preclin./clin. trials and have shown excellent clin. potential as the alternate treatment strategy for tumor therapy. Although TDDSs are proving to be promising therapeutic nanoplatforms for tumor therapy, extended investigations should be considered in the landscape for highly efficient tumor therapy with good biosafety.
- 29Davis, M.; Zuckerman, J.; Choi, C.; Seligson, D.; Tolcher, A.; Alabi, C.; Yen, Y.; Heidel, J.; Ribas, A. Evidence of RNAi in humans from systemically administered siRNA via targeted nanoparticles. Nature 2010, 464, 1067– 1070, DOI: 10.1038/nature08956Google Scholar29https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3cXjs1ehur8%253D&md5=b49a61e3acc1245274c2314fb6bcc99aEvidence of RNAi in humans from systemically administered siRNA via targeted nanoparticlesDavis, Mark E.; Zuckerman, Jonathan E.; Choi, Chung-Hang J.; Seligson, David; Tolcher, Anthony; Alabi, Christopher A.; Yen, Yun; Heidel, Jeremy D.; Ribas, AntoniNature (London, United Kingdom) (2010), 464 (7291), 1067-1070CODEN: NATUAS; ISSN:0028-0836. (Nature Publishing Group)Therapeutics that are designed to engage RNA interference (RNAi) pathways have the potential to provide new, major ways of imparting therapy to patients. Long, double-stranded RNAs were first shown to mediate RNAi in Caenorhabditis elegans, and the potential use of RNAi for human therapy has been demonstrated by the finding that small interfering RNAs (siRNAs; approx. 21-base-pair double-stranded RNA) can elicit RNAi in mammalian cells without producing an interferon response. We are at present conducting the first in-human phase I clin. trial involving the systemic administration of siRNA to patients with solid cancers using a targeted, nanoparticle delivery system. Here we provide evidence of inducing an RNAi mechanism of action in a human from the delivered siRNA. Tumor biopsies from melanoma patients obtained after treatment show the presence of intracellularly localized nanoparticles in amts. that correlate with dose levels of the nanoparticles administered (this is, to our knowledge, a first for systemically delivered nanoparticles of any kind). Furthermore, a redn. was found in both the specific mRNA (M2 subunit of ribonucleotide reductase (RRM2)) and the protein (RRM2) levels when compared to pre-dosing tissue. Most notably, we detect the presence of an mRNA fragment that demonstrates that siRNA-mediated mRNA cleavage occurs specifically at the site predicted for an RNAi mechanism from a patient who received the highest dose of the nanoparticles. Together, these data demonstrate that siRNA administered systemically to a human can produce a specific gene inhibition (redn. in mRNA and protein) by an RNAi mechanism of action.
- 30Sugahara, K.; Teesalu, T.; Karmali, P.; Kotamraju, V.; Agemy, L.; Greenwald, D.; Ruoslahti, E. Co-administration of a tumor-penetrating peptide enhances the efficacy of cancer drugs. Science 2010, 328, 1031– 1035, DOI: 10.1126/science.1183057Google ScholarThere is no corresponding record for this reference.
- 31Wong, P.; Tang, K.; Coulter, A.; Tan, S.; Baker, J.; Choi, S. Multivalent dendrimer vectors with DNA intercalation motifs for gene delivery. Biomacromolecules 2014, 15, 4134– 4415, DOI: 10.1021/bm501169sGoogle Scholar31https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2cXhs1yisr7K&md5=8c21541c6d33bbcad02f41564d5fe0d6Multivalent Dendrimer Vectors with DNA Intercalation Motifs for Gene DeliveryWong, Pamela T.; Tang, Kenny; Coulter, Alexa; Tang, Shengzhuang; Baker, James R.; Choi, Seok KiBiomacromolecules (2014), 15 (11), 4134-4145CODEN: BOMAF6; ISSN:1525-7797. (American Chemical Society)Poly(amido amine) (PAMAM) dendrimers constitute an important class of nonviral, cationic vectors in gene delivery. Here we report on a new concept for dendrimer vector design based on the incorporation of dual binding motifs: DNA intercalation, and receptor recognition for targeted delivery. We prepd. a series of dendrimer conjugates derived from a fifth generation (G5) PAMAM dendrimer, each conjugated with multiple folate (FA) or riboflavin (RF) ligands for cell receptor targeting, and with 3,8-diamino-6-phenylphenanthridinium ("DAPP")-derived ligands for anchoring a DNA payload. Polyplexes of each dendrimer with calf thymus dsDNA were made and characterized by surface plasmon resonance (SPR) spectroscopy, dynamic light scattering (DLS) and zeta potential measurement. These studies provided evidence supporting polyplex formation based on the observation of tight DNA-dendrimer adhesion, and changes in particle size and surface charge upon coincubation. Further SPR studies to investigate the adhesion of the polyplex to a model surface immobilized with folate binding protein (FBP), demonstrated that the DNA payload has only a minimal effect on the receptor binding activity of the polyplex: KD = 0.22 nM for G5(FA)(DAPP) vs. 0.98 nM for its polyplex. Finally, we performed in vitro transfection assays to det. the efficiency of conjugate mediated delivery of a luciferase-encoding plasmid into the KB cancer cell line and showed that RF-conjugated dendrimers were 1 to 2 orders of magnitude more effective in enhancing luciferase gene transfection than a plasmid only control. In summary, this study serves as a proof of concept for DNA-ligand intercalation as a motif in the design of multivalent dendrimer vectors for targeted gene delivery.
- 32Sugahara, K.; Teesalu, T.; Karmali, P.; Kotamraju, V.; Agemy, L.; Girard, O.; Hanahan, D.; Mattrey, R.; Ruoslahti, E. Tissue-penetrating delivery of compounds and nanoparticles into tumors. Cancer Cell 2009, 16, 510– 520, DOI: 10.1016/j.ccr.2009.10.013Google Scholar32https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3cXht1eqsbY%253D&md5=f42c01e8e751526318903d28d70ce4c4Tissue-penetrating delivery of compounds and nanoparticles into tumorsSugahara, Kazuki N.; Teesalu, Tambet; Karmali, Priya Prakash; Kotamraju, Venkata Ramana; Agemy, Lilach; Girard, Olivier M.; Hanahan, Douglas; Mattrey, Robert F.; Ruoslahti, ErkkiCancer Cell (2009), 16 (6), 510-520CODEN: CCAECI; ISSN:1535-6108. (Cell Press)Poor penetration of drugs into tumors is a major obstacle in tumor treatment. We describe a strategy for peptide-mediated delivery of compds. deep into the tumor parenchyma that uses a tumor-homing peptide, iRGD (CRGDK/RGPD/EC). I.v. injected compds. coupled to iRGD bound to tumor vessels and spread into the extravascular tumor parenchyma, whereas conventional RGD peptides only delivered the cargo to the blood vessels. IRGD homes to tumors through a three-step process: the RGD motif mediates binding to αv integrins on tumor endothelium and a proteolytic cleavage then exposes a binding motif for neuropilin-1, which mediates penetration into tissue and cells. Conjugation to iRGD significantly improved the sensitivity of tumor-imaging agents and enhanced the activity of an antitumor drug.
- 33Desgrosellier, J.; Cheresh, D. Integrins in cancer: biological implications and therapeutic opportunities. Nat. Rev. Cancer 2010, 10, 9– 22, DOI: 10.1038/nrc2748Google Scholar33https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD1MXhsF2hsLzI&md5=43d0b526ca38021e780aba991a58451bIntegrins in cancer: biological implications and therapeutic opportunitiesDesgrosellier, Jay S.; Cheresh, David A.Nature Reviews Cancer (2010), 10 (1), 9-22CODEN: NRCAC4; ISSN:1474-175X. (Nature Publishing Group)A review. The integrin family of cell adhesion receptors regulates a diverse array of cellular functions crucial to the initiation, progression and metastasis of solid tumors. The importance of integrins in several cell types that affect tumor progression has made them an appealing target for cancer therapy. Integrin antagonists, including the αvβ3 and αvβ5 inhibitor cilengitide, have shown encouraging activity in Phase II clin. trials and cilengitide is currently being tested in a Phase III trial in patients with glioblastoma. These exciting clin. developments emphasize the need to identify how integrin antagonists influence the tumor and its microenvironment.
- 34Marelli, U.; Rechenmacher, F.; Sobahi, T.; Mas-Moruno, C.; Kessler, H. Tumor targeting via integrin ligands. Front. Oncol. 2013, 3, 222– 233, DOI: 10.3389/fonc.2013.00222Google Scholar34https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BC2cflt1Gktg%253D%253D&md5=b09d0b738b25909e8b68d42d90ad638eTumor Targeting via Integrin LigandsMarelli Udaya Kiran; Rechenmacher Florian; Sobahi Tariq Rashad Ali; Mas-Moruno Carlos; Kessler HorstFrontiers in oncology (2013), 3 (), 222 ISSN:2234-943X.Selective and targeted delivery of drugs to tumors is a major challenge for an effective cancer therapy and also to overcome the side-effects associated with current treatments. Overexpression of various receptors on tumor cells is a characteristic structural and biochemical aspect of tumors and distinguishes them from physiologically normal cells. This abnormal feature is therefore suitable for selectively directing anticancer molecules to tumors by using ligands that can preferentially recognize such receptors. Several subtypes of integrin receptors that are crucial for cell adhesion, cell signaling, cell viability, and motility have been shown to have an upregulated expression on cancer cells. Thus, ligands that recognize specific integrin subtypes represent excellent candidates to be conjugated to drugs or drug carrier systems and be targeted to tumors. In this regard, integrins recognizing the RGD cell adhesive sequence have been extensively targeted for tumor-specific drug delivery. Here we review key recent examples on the presentation of RGD-based integrin ligands by means of distinct drug-delivery systems, and discuss the prospects of such therapies to specifically target tumor cells.
- 35Teesalu, T.; Sugahara, K.; Kotamraju, V.; Ruoslahti, E. C-end rule peptides mediate neuropilin-1-dependent cell, vascular, and tissue penetration. Proc. Natl. Acad. Sci. U. S. A. 2009, 106, 16157– 16162, DOI: 10.1073/pnas.0908201106Google Scholar35https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD1MXht1OjsbbI&md5=3eb210213cfccc091c4aba949d437b42C-end rule peptides mediate neuropilin-1-dependent cell, vascular, and tissue penetrationTeesalu, Tambet; Sugahara, Kazuki N.; Kotamraju, Venkata Ramana; Erkki RuoslahtiProceedings of the National Academy of Sciences of the United States of America (2009), 106 (38), 16157-16162, S16157/1-S16157/15CODEN: PNASA6; ISSN:0027-8424. (National Academy of Sciences)Screening of phage libraries expressing random peptides for binding to prostate cancer cells primarily yielded peptides that had a C-terminal arginine (or rarely lysine) residue, usually in a consensus context R/KXXR/K. Phage expressing these sequences and synthetic nanoparticles coated with them bound to and were internalized into cells. The C-terminal arginine (or lysine) was essential to the activity; adding another amino acid, or even blocking the free carboxyl group of this arginine residue by amidation, eliminated the binding and internalizing activity. An internal R/KXXR/K can be exposed and switched on by a cleavage by a protease. The strict requirement for C-terminal exposure of the motif prompted the authors to term the phenomenon the C-end rule (CendR). Affinity chromatog. showed that the CendR peptides bind to neuropilin-1 (NRP-1) on the target cells. NRP-1 is a cell-surface receptor that plays an essential role in angiogenesis, regulation of vascular permeability, and the development of the nervous system. VEGF-A165 and other ligands of NRP-1 possess a C-terminal CendR sequence that interacts with the b1 domain of NRP-1 and causes cellular internalization and vascular leakage. The authors' CendR peptides have similar effects, particularly when made multivalent through coupling to a particle. The authors also noted a unique and important activity of these peptides: penetration and transportation through tissues. The peptides were able to take payloads up to the nanoparticle size scale deep into extravascular tissue. The authors' observations have implications in drug delivery and penetration of tissue barriers and tumors.
- 36Liu, X.; Liu, C.; Chen, C.; Bentobji, M.; Cheillan, F.; Piana, J.; Qu, F.; Rocchi, P.; Peng, L. Targeted delivery of Dicer-substrate siRNAs using a dual targeting peptide decorated dendrimer delivery system. Nanomedicine 2014, 10, 1627– 1636, DOI: 10.1016/j.nano.2014.05.008Google Scholar36https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2cXhtFOgtL3K&md5=27ce93c828721bcad7351c4edde95339Targeted delivery of Dicer-substrate siRNAs using a dual targeting peptide decorated dendrimer delivery systemLiu, Xiaoxuan; Liu, Cheng; Chen, Chao; Bentobji, Melanie; Cheillan, Francine Azario; Piana, Jeanne Thomassin; Qu, Fanqi; Rocchi, Palma; Peng, LingNanomedicine (New York, NY, United States) (2014), 10 (8), 1627-1636CODEN: NANOBF; ISSN:1549-9634. (Elsevier)Small interfering RNAs (siRNA) are emerging as novel therapeutic agents, providing competent delivery systems that are available. Dendrimers, a special family of synthetic macromols., represent an exciting delivery platform by virtue of their well-defined dendritic structure and unique multivalency and cooperativity confined within a nanoscale vol. Here, we report a Dicer-substrate siRNA (dsiRNA) which, when delivered using a structurally flexible triethanolamine-core poly(amidoamine) dendrimer of generation 5 as the nanocarrier, gives rise to a much greater RNAi response than that produced with conventional siRNA. Further decoration of the dsiRNA/dendrimer complexes with a dual targeting peptide simultaneously promoted cancer cell targeting through interacting with integrins and cell penetration via the interaction with neuropilin-1 receptors, which led to improved gene silencing and anticancer activity. Altogether, our results disclosed here open a new avenue for therapeutic implementation of RNAi using dendrimer nanovector based targeted delivery.
- 37Svenson, S. The dendrimer paradox--high medical expectations but poor clinical translation. Chem. Soc. Rev. 2015, 46, 4131– 4144, DOI: 10.1039/C5CS00288EGoogle ScholarThere is no corresponding record for this reference.
- 38Cao, Y.; Liu, X.; Peng, L. Molecular engineering of dendrimer nanovecters for siRNA delivery and gene silencing. Front. Chem. Sci. Eng. 2017, 11, 663– 675, DOI: 10.1007/s11705-017-1623-5Google Scholar38https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2sXlvFyjsLs%253D&md5=72a76c778f9c6878d0f125e3b57bcb88Molecular engineering of dendrimer nanovectors for siRNA delivery and gene silencingCao, Yu; Liu, Xiaoxuan; Peng, LingFrontiers of Chemical Science and Engineering (2017), 11 (4), 663-675CODEN: FCSEA3; ISSN:2095-0187. (Springer)A review. Small interfering RNA (siRNA) therapeutics hold great promise to treat a variety of diseases, as long as they can be delivered safely and effectively into cells. Dendrimers are appealing vectors for siRNA delivery by virtue of their well-defined mol. architecture and multivalent cooperativity. However, the clin. translation of RNA therapeutics mediated by dendrimer delivery is hampered by the lack of dendrimers that are of high quality to meet good manufg. practice std. In this context, we have developed small amphiphilic dendrimers that self-assemble into supramol. structures, which mimic high-generation dendrimers synthesized with covalent construction, yet are easy to produce in large amt. and superior quality. This short review presents a brief introduction to RNAi therapeutics, the obstacles to their delivery and the advantages of dendrimer delivery vectors as well as our bio-inspired structurally flexible dendrimers for siRNA delivery. We then highlight our efforts in creating selfassembling amphiphilic dendrimers to construct supramol. dendrimer nanosystems for effective siRNA delivery as well as the related structural alterations to enhance delivery efficiency. The advent of self-assembling supramol. dendrimer nanovectors holds great promise and heralds a new era of dendrimer-mediated delivery of RNA therapeutics in biomedical applications.
- 39Zhou, J.; Liu, J.; Cheng, C.; Patel, T.; Weller, C.; Piepmeier, J.; Jiang, Z.; Saltzman, W. Biodegradable poly(amine-co-ester) terpolymers for targeted gene delivery. Nat. Mater. 2012, 11, 82– 90, DOI: 10.1038/nmat3187Google Scholar39https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3MXhsFGkurfN&md5=937db7f417aafb60789ec0f760f27d49Biodegradable poly(amine-co-ester) terpolymers for targeted gene deliveryZhou, Jiangbing; Liu, Jie; Cheng, Christopher J.; Patel, Toral R.; Weller, Caroline E.; Piepmeier, Joseph M.; Jiang, Zhaozhong; Saltzman, W. MarkNature Materials (2012), 11 (1), 82-90CODEN: NMAACR; ISSN:1476-1122. (Nature Publishing Group)Many synthetic polycationic vectors for non-viral gene delivery show high efficiency in vitro, but their usually excessive charge d. makes them toxic for in vivo applications. Here we describe the synthesis of a series of high mol. wt. terpolymers with low charge d., and show that they exhibit efficient gene delivery, some surpassing the efficiency of the com. transfection reagents Polyethylenimine and Lipofectamine 2000. The terpolymers were synthesized via enzyme-catalyzed copolymn. of lactone with dialkyl diester and amino diol, and their hydrophobicity adjusted by varying the lactone content and by selecting a lactone comonomer of specific ring size. Targeted delivery of the pro-apoptotic TRAIL gene to tumor xenografts by one of the terpolymers results in significant inhibition of tumor growth, with minimal toxicity both in vitro and in vivo. Our findings suggest that the gene delivery ability of the terpolymers stems from their high mol. wt. and increased hydrophobicity, which compensates for their low charge d.
- 40Grandclement, C.; Borg, C. Neuropilins: a new target for cancer therapy. Cancers 2011, 3, 1899– 1928, DOI: 10.3390/cancers3021899Google ScholarThere is no corresponding record for this reference.
- 41Siegel, R.; Miller, K.; Jemal, A. Cancer Statistics, 2017. Ca-Cancer J. Clin. 2017, 67, 7– 30, DOI: 10.3322/caac.21387Google Scholar41https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BC1c7isFWgtA%253D%253D&md5=e439f3424d5a773e4ae289c392236ad6Cancer Statistics, 2017Siegel Rebecca L; Miller Kimberly D; Jemal AhmedinCA: a cancer journal for clinicians (2017), 67 (1), 7-30 ISSN:.Each year, the American Cancer Society estimates the numbers of new cancer cases and deaths that will occur in the United States in the current year and compiles the most recent data on cancer incidence, mortality, and survival. Incidence data were collected by the Surveillance, Epidemiology, and End Results Program; the National Program of Cancer Registries; and the North American Association of Central Cancer Registries. Mortality data were collected by the National Center for Health Statistics. In 2017, 1,688,780 new cancer cases and 600,920 cancer deaths are projected to occur in the United States. For all sites combined, the cancer incidence rate is 20% higher in men than in women, while the cancer death rate is 40% higher. However, sex disparities vary by cancer type. For example, thyroid cancer incidence rates are 3-fold higher in women than in men (21 vs 7 per 100,000 population), despite equivalent death rates (0.5 per 100,000 population), largely reflecting sex differences in the "epidemic of diagnosis." Over the past decade of available data, the overall cancer incidence rate (2004-2013) was stable in women and declined by approximately 2% annually in men, while the cancer death rate (2005-2014) declined by about 1.5% annually in both men and women. From 1991 to 2014, the overall cancer death rate dropped 25%, translating to approximately 2,143,200 fewer cancer deaths than would have been expected if death rates had remained at their peak. Although the cancer death rate was 15% higher in blacks than in whites in 2014, increasing access to care as a result of the Patient Protection and Affordable Care Act may expedite the narrowing racial gap; from 2010 to 2015, the proportion of blacks who were uninsured halved, from 21% to 11%, as it did for Hispanics (31% to 16%). Gains in coverage for traditionally underserved Americans will facilitate the broader application of existing cancer control knowledge across every segment of the population. CA Cancer J Clin 2017;67:7-30. © 2017 American Cancer Society.
- 42Grasso, C.; Wu, Y.; Robinson, D.; Cao, X.; Dhanasekaran, S.; Khan, A.; Quist, M.; Jing, X.; Lonigro, R.; Brenner, J.; Asangani, I.; Ateeq, B.; Chun, S.; Siddiqui, J.; Sam, L.; Anstett, M.; Mehra, R.; Prensner, J.; Palanisamy, N.; Ryslik, G.; Vandin, F.; Raphael, B.; Kunju, L.; Rhodes, D.; Pienta, K.; Chinnaiyan, A.; Tomlins, S. The mutational landscape of lethal castration-resistant prostate cancer. Nature 2012, 487, 239– 243, DOI: 10.1038/nature11125Google Scholar42https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC38XhtVWisLfP&md5=15b1780d9cd2189325baf4e4fec84687The mutational landscape of lethal castration-resistant prostate cancerGrasso, Catherine S.; Wu, Yi-Mi; Robinson, Dan R.; Cao, Xuhong; Dhanasekaran, Saravana M.; Khan, Amjad P.; Quist, Michael J.; Jing, Xiaojun; Lonigro, Robert J.; Brenner, J. Chad; Asangani, Irfan A.; Ateeq, Bushra; Chun, Sang Y.; Siddiqui, Javed; Sam, Lee; Anstett, Matt; Mehra, Rohit; Prensner, John R.; Palanisamy, Nallasivam; Ryslik, Gregory A.; Vandin, Fabio; Raphael, Benjamin J.; Kunju, Lakshmi P.; Rhodes, Daniel R.; Pienta, Kenneth J.; Chinnaiyan, Arul M.; Tomlins, Scott A.Nature (London, United Kingdom) (2012), 487 (7406), 239-243CODEN: NATUAS; ISSN:0028-0836. (Nature Publishing Group)Characterization of the prostate cancer transcriptome and genome has identified chromosomal rearrangements and copy no. gains and losses, including ETS gene family fusions, PTEN loss and androgen receptor (AR) amplification, which drive prostate cancer development and progression to lethal, metastatic castration-resistant prostate cancer (CRPC). However, less is known about the role of mutations. Here we sequenced the exomes of 50 lethal, heavily pre-treated metastatic CRPCs obtained at rapid autopsy (including three different foci from the same patient) and 11 treatment-naive, high-grade localized prostate cancers. We identified low overall mutation rates even in heavily treated CRPCs (2.00 per megabase) and confirmed the monoclonal origin of lethal CRPC. Integrating exome copy no. anal. identified disruptions of CHD1 that define a subtype of ETS gene family fusion-neg. prostate cancer. Similarly, we demonstrate that ETS2, which is deleted in approx. one-third of CRPCs (commonly through TMPRSS2:ERG fusions), is also deregulated through mutation. Furthermore, we identified recurrent mutations in multiple chromatin- and histone-modifying genes, including MLL2 (mutated in 8.6% of prostate cancers), and demonstrate interaction of the MLL complex with the AR, which is required for AR-mediated signaling. We also identified novel recurrent mutations in the AR collaborating factor FOXA1, which is mutated in 5 of 147 (3.4%) prostate cancers (both untreated localized prostate cancer and CRPC), and showed that mutated FOXA1 represses androgen signaling and increases tumor growth. Proteins that phys. interact with the AR, such as the ERG gene fusion product, FOXA1, MLL2, UTX (also known as KDM6A) and ASXL1 were found to be mutated in CRPC. In summary, we describe the mutational landscape of a heavily treated metastatic cancer, identify novel mechanisms of AR signaling deregulated in prostate cancer, and prioritize candidates for future study.
- 43Gundem, G.; Van, P.; Kremeyer, B.; Alexandrov, L.; Tubio, J.; Papaemmanuil, E.; Brewer, D.; Kallio, H.; Hoegnas, G.; Annala, M.; Kivinummi, K.; Goody, V.; Latimer, C.; O’Meara, S.; Dawson, K.; Isaacs, W.; Emmert-Buck, M.; Nykter, M.; Foster, C.; Kote-Jarai, Z.; Easton, D.; Whitaker, H.; Neal, D.; Cooper, C.; Eeles, R.; Visakorpi, T.; Campbell, P.; McDermott, U.; Wedge, D.; Bova, G. The evolutionary history of lethal metastatic prostate cancer. Nature 2015, 520, 353– 357, DOI: 10.1038/nature14347Google ScholarThere is no corresponding record for this reference.
- 44Lorente, D.; Mateo, J.; Perez-Lopez, R.; de, J.; Attard, G. Sequencing of agents in castration-resistant prostate cancer. Lancet Oncol. 2015, 16, 279– 292, DOI: 10.1016/S1470-2045(15)70033-1Google ScholarThere is no corresponding record for this reference.
- 45Cornford, P.; Dodson, A.; Parsons, K.; Desmond, A.; Woolfenden, A.; Fordham, M.; Neoptolemos, J.; Ke, Y.; Foster, C. Heat shock protein expression independently predicts clinical outcome in prostate cancer. Cancer Res. 2000, 60, 7099– 7105Google ScholarThere is no corresponding record for this reference.
- 46Rocchi, P.; So, A.; Kojima, S.; Signaevsky, M.; Beraldi, E.; Fazli, L.; Hurtado-Coll, A.; Yamanaka, K.; Gleave, M. Heat shock protein 27 increases after androgen ablation and plays a cytoprotective role in hormone-refractory prostate cancer. Cancer Res. 2004, 64, 6595– 6602, DOI: 10.1158/0008-5472.CAN-03-3998Google ScholarThere is no corresponding record for this reference.
- 47Jego, G.; Hazoume, A.; Seigneuric, R.; Garrido, C. Targeting heat shock proteins in cancer. Cancer Lett. 2013, 332, 275– 285, DOI: 10.1016/j.canlet.2010.10.014Google Scholar47https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3sXlvVWitLs%253D&md5=4e1dcc15387cbb33d4a2d18f5defdd16Targeting heat shock proteins in cancerJego, Gaetan; Hazoume, Adonis; Seigneuric, Renaud; Garrido, CarmenCancer Letters (New York, NY, United States) (2013), 332 (2), 275-285CODEN: CALEDQ; ISSN:0304-3835. (Elsevier)A review. Heat shock proteins (HSPs) HSP27, HSP70 and HSP90 are powerful chaperones. Their expression is induced in response to a wide variety of physiol. and environmental insults including anti-cancer chemotherapy, thus allowing the cell to survive to lethal conditions. Different functions of HSPs have been described to account for their cytoprotective function, including their role as mol. chaperones as they play a central role in the correct folding of misfolded proteins, but also their anti-apoptotic properties. HSPs are often overexpressed in cancer cells and this constitutive expression is necessary for cancer cells' survival. HSPs may have oncogene-like functions and likewise mediate "non-oncogene addiction" of stressed tumor cells that must adapt to a hostile microenvironment, thereby becoming dependent for their survival on HSPs. HSP-targeting drugs have therefore emerged as potential anti-cancer agents. This review describes the different mols. and approaches being used or proposed in cancer therapy based on the in inhibition of HSP90, HSP70 and HSP27.
- 48Wei, T.; Chen, C.; Liu, J.; Liu, C.; Posocco, P.; Liu, X.; Cheng, Q.; Huo, S.; Liang, Z.; Fermeglia, M.; Pricl, S.; Liang, X.; Rocchic, P.; Peng, L. Anticancer drug nanomicelles formed by self-assembling amphiphilic dendrimer to combat cancer drug resistance. Proc. Natl. Acad. Sci. U. S. A. 2015, 112, 2978– 2983, DOI: 10.1073/pnas.1418494112Google Scholar48https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2MXjtFemur4%253D&md5=ba3fcc69507c6da884cfeeabd95fb782Anticancer drug nanomicelles formed by self-assembling amphiphilic dendrimer to combat cancer drug resistanceWei, Tuo; Chen, Chao; Liu, Juan; Liu, Cheng; Posocco, Paola; Liu, Xiaoxuan; Cheng, Qiang; Huo, Shuaidong; Liang, Zicai; Fermeglia, Maurizio; Pricl, Sabrina; Liang, Xing-Jie; Rocchi, Palma; Peng, LingProceedings of the National Academy of Sciences of the United States of America (2015), 112 (10), 2978-2983CODEN: PNASA6; ISSN:0027-8424. (National Academy of Sciences)Drug resistance and toxicity constitute challenging hurdles for cancer therapy. The application of nanotechnol. for anticancer drug delivery is expected to address these issues and bring new hope for cancer treatment. In this context, we established an original nanomicellar drug delivery system based on an amphiphilic dendrimer (AmDM), which could generate supramol. micelles to effectively encapsulate the anticancer drug doxorubicin (DOX) with high drug-loading capacity (>40%), thanks to the unique dendritic structure creating large void space for drug accommodation. The resulting AmDM/DOX nanomicelles were able to enhance drug potency and combat doxorubicin resistance in breast cancer models by significantly enhancing cellular uptake while considerably decreasing efflux of the drug. In addn., the AmDM/DOX nanoparticles abolished significantly the toxicity related to the free drug. Collectively, our studies demonstrate that the drug delivery system based on nanomicelles formed with the self-assembling amphiphilic dendrimer constitutes a promising and effective drug carrier in cancer therapy.
- 49Posocco, P.; Liu, X.; Laurini, E.; Marson, D.; Chen, C.; Liu, C.; Fermeglia, M.; Rocchi, P.; Pricl, S.; Peng, L. Impact of siRNA overhangs for dendrimer-mediated siRNA delivery and gene silencing. Mol. Pharmaceutics 2013, 10, 3262– 3273, DOI: 10.1021/mp400329gGoogle Scholar49https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3sXhtVyjur%252FI&md5=bc7721f224b9006c6e075bf8a0ff401fImpact of siRNA Overhangs for Dendrimer-Mediated siRNA Delivery and Gene SilencingPosocco, Paola; Liu, Xiaoxuan; Laurini, Erik; Marson, Domenico; Chen, Chao; Liu, Cheng; Fermeglia, Maurizio; Rocchi, Palma; Pricl, Sabrina; Peng, LingMolecular Pharmaceutics (2013), 10 (8), 3262-3273CODEN: MPOHBP; ISSN:1543-8384. (American Chemical Society)Small interfering RNA (siRNA) have attracted considerable attention, as compelling therapeutics providing safe and competent delivery systems are available. Dendrimers are emerging as appealing siRNA delivery vectors thanks to their unique, well-defined architecture and the resulting cooperativity and multivalency confined within a nanostructure. We have recently disclosed the structurally flexible fifth-generation TEA-core PAMAM dendrimer (G5) as an effective nanocarrier for delivery of sticky siRNA bearing long complementary sequence overhangs (dA)n/(dT)n (n = 5 or 7). Here, using combined exptl./computational approaches, we successfully clarified (i) the underlying mechanisms of interaction between the dendrimer nanovector G5 and siRNA mols. bearing either complementary or noncomplementary sequence overhangs of different length and chem. and (ii) the impact of siRNA overhangs contributing toward the improved delivery potency. Using siRNA with complementary overhangs offer the best action in term of gene silencing through the formation of concatemers, i.e., supramol. structures resulting from synergistic and cooperative binding via (dA)n/(dT)n bridges (n = 5 or 7). On the other hand, although siRNA bearing long, noncomplementary overhangs (dA)n/(dA)n or (dT)n/(dT)n (n = 5 or 7) are endowed with considerably higher gene silencing potency than normal siRNA with (dT)2/(dT)2, they remain less effective than their sticky siRNA counterparts. The obsd. gene silencing potency depends on length, nature, and flexibility of the overhangs, which behave as a sort of clamps that hold and interact with the dendrimer nanovectors, thus impacting siRNA delivery performance and, ultimately, gene silencing. Our findings can be instrumental in designing siRNA entities with enhanced capability to achieve effective RNA interference for therapeutic applications.
- 50Albanyan, B.; Laurini, E.; Posocco, P.; Pricl, S.; Smith, D. Self-assembled multivalent (SAMul) polyanion binding—impact of hydrophobic modifications in the micellar core on DNA and heparin binding at the peripheral cationic ligands. Chem. - Eur. J. 2017, 23, 6391– 6397, DOI: 10.1002/chem.201700177Google Scholar50https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2sXlvVCgsLk%253D&md5=e971234081cca25156b7bcde61149d98Self-Assembled Multivalent (SAMul) Polyanion Binding-Impact of Hydrophobic Modifications in the Micellar Core on DNA and Heparin Binding at the Peripheral Cationic LigandsAlbanyan, Buthaina; Laurini, Erik; Posocco, Paola; Pricl, Sabrina; Smith, David K.Chemistry - A European Journal (2017), 23 (26), 6391-6397CODEN: CEUJED; ISSN:0947-6539. (Wiley-VCH Verlag GmbH & Co. KGaA)This paper reports a small family of cationic surfactants designed to bind polyanions such as DNA and heparin. Each mol. has the same hydrophilic cationic ligand and a hydrophobic aliph. group with eighteen carbon atoms with one, two, or three alkene groups within the hydrophobic chain (C18-1, C18-2 and C18-3). Dynamic light scattering indicates that more alkenes lead to geometric distortion, giving rise to larger self-assembled multivalent (SAMul) nanostructures. Mallard Blue and Ethidium Bromide dye displacement assays demonstrate that heparin and DNA have markedly different binding preferences, with heparin binding most effectively to C18-1, and DNA to C18-3, even though the mol. structural differences of these SAMul systems are buried in the hydrophobic core. Multiscale modeling suggests that adaptive heparin maximises enthalpically favorable interactions with C18-1, while shape-persistent DNA forms a similar no. of interactions with each ligand display, but with slightly less entropic cost for binding to C18-3-fundamental thermodn. differences in SAMul binding of heparin or DNA. This study therefore provides unique insight into electrostatic mol. recognition between highly charged nanoscale surfaces in biol. relevant systems.
- 51Fechner, L.; Albanyan, B.; Vieira, V.; Laurini, E.; Posocco, P.; Pricl, S.; Smith, D. Electrostatic binding of polyanions using self-assembled multivalent (SAMul) ligand displays - structure-activity effects on DNA/heparin binding. Chem. Sci. 2016, 7, 4653– 4659, DOI: 10.1039/C5SC04801JGoogle Scholar51https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC28Xms1Kks7o%253D&md5=2663d127c7871258d0687f089ec63624Electrostatic binding of polyanions using self-assembled multivalent (SAMul) ligand displays - structure-activity effects on DNA/heparin bindingFechner, Loryn E.; Albanyan, Buthaina; Vieira, Vania M. P.; Laurini, Erik; Posocco, Paola; Pricl, Sabrina; Smith, David K.Chemical Science (2016), 7 (7), 4653-4659CODEN: CSHCCN; ISSN:2041-6520. (Royal Society of Chemistry)This paper reports that modifying the ligands in self-assembled multivalent (SAMul) displays has an impact on apparent binding selectivity towards two nanoscale biol. polyanions - heparin and DNA. For the nanostructures assayed here, spermidine ligands are optimal for heparin binding but spermine ligands are preferred for DNA. Probing subtle differences in such nanoscale binding interfaces is a significant challenge, and as such, several exptl. binding assays - competition assays and isothermal calorimetry - are employed to confirm differences in affinity and provide thermodn. insights. Given the dynamic nature and hierarchical binding processes involved in SAMul systems, we employed multiscale modeling to propose reasons for the origins of polyanion selectivity differences. The modeling results, when expressed in thermodn. terms and compared with the exptl. data, suggest that DNA is a shape-persistent polyanion, and selectivity originates only from ligand preferences, whereas heparin is more flexible and adaptive, and as such, actively reinforces ligand preferences. As such, this study suggests that inherent differences between polyanions may underpin subtle binding selectivity differences, and that even simple electrostatic interfaces such as these can have a degree of tunability, which has implications for biol. control and regulation on the nanoscale.
- 52Qi, C.; Su, Y.; Peng, Y.; Tian, E.; Sun, G.; Zhou, J.; Sun, G.; Liu, X.; Chao, C.; Murai, K.; Zhao, C.; Azizian, K.; Yang, L.; Warden, C.; Wu, X.; D’Apuzzo, M.; Brown, C.; Badie, B.; Peng, L.; Riggs, D.; Rossi, J.; Shi, Y. Downregulation of TLX induces TET3 expression and inhibits glioblastoma stem cell self-renewal and tumorigenesis. Nat. Commun. 2016, 7, 10637– 10651, DOI: 10.1038/ncomms10637Google ScholarThere is no corresponding record for this reference.
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Abstract
Scheme 1
Scheme 1. Strategy for Active Delivery of siRNA Using an Amphiphilic Dendrimer AD Vector with the Dual Targeting Peptide: (A) Chemical Structure of the Amphiphilic Dendrimer AD; (B) The Targeting Peptide E16G6RGDK Composed of Three Distinct Functional Segments: RGDK as the Targeting Warhead, Oligo(glutamic acid) E16 as the Negatively Charged Sequence to Interact with Positively Charged siRNA/AD Complexes, and the Neutral Oligo(glycine) G6 as the Linker to Bridge the Targeting Unit and the siRNA Loading Complex; (C) Cartoon Illustration of the Formation of the siRNA/AD/E16G6RGDK Complexes for Targeted siRNA DeliveryFigure 1
Figure 1. Small and stable siRNA/AD/E16G6RGDK complexes formed by adding the peptide E16G6RGDK to the siRNA/AD complexes. (A) TEM imaging and (B) DLS analysis of the siRNA/AD/E16G6RGDK complexes (siRNA/AD at an N/P ratio of 10, AD/peptide at a molar ratio of 5.0). (C) Representative integrated ITC profiles for titration of the siRNA/AD complexes with the E16G6RGDK peptide in ultrapure water (T = 25 °C). The solid red lines are data fitted with a sigmoidal function. The inset shows the corresponding ITC raw data. All experiments were run in triplicate. (D) Agarose gel shift analysis of the siRNA/AD/E16G6RGDK complexes versus the siRNA/AD complexes (siRNA/AD at an N/P ratio of 10, AD/peptide ratio varying from 2.0 to 20). (E) The siRNA/AD/E16G6RGDK complexes are able to protect siRNA from RNase A digestion. (siRNA/AD at an N/P ratio of 10; AD/peptide ratio of 5.0).
Figure 2
Figure 2. (A) (Left) Cartoon showing the arrangement of the siRNA molecule (gray) and the four E16G6RGDK moieties (colored as in the right panel) on the AD nanomicelle (blue), as derived from the detailed atomistic molecular simulations. (Center) Equilibrated molecular dynamics (MD) snapshot of an siRNA/AD micelle in complex with four E16G6RGDK peptides numbered as E16G6RGDK1 to E16G6RGDK4 and colored as follows: E16G6RGDK1, tail (E16G6) sandy brown, head (RGDK) firebrick; E16G6RGDK2, tail light green, head olive drab; E16G6RGDK3, tail khaki, head golden rod; E16G6RGDK4, tail plum, head magenta. The siRNA molecule is portrayed with its van der Waals surface in gray. The AD micelle is shown in dark slate blue sticks and balls, while the four peptides are depicted as colored spheres, as above precised. Ions and counterions are shown as green and purple hollow spheres; water is shown as a light cyan surface. (Right) Zoomed-in view of the system in panel A showing the RGDK warhead group of E16G6RGDK4 protruding into the solvent as an example. (B) Radial distribution function as a function of the distance from the AD micelle center of mass for the AD positively charged terminal groups (dark slate blue) and for each of the four RGDK warhead groups. Colors as in panel A. (C) Electrostatic surface potential of the siRNA/AD micelle (left) and of the siRNA/AD/(E16G6RGDK)4 complex (right) as extracted from the equilibrated portion of the corresponding MD simulations. Dark blue represents a highly positively charged surface, while red represents a highly negatively charged surface. (D) Free energy of binding (ΔGb) of each E16G6RGDK peptide on the siRNA/AD micelle. Colors as in panel A. The empty color bars (left bar of each pair) represent the value of ΔGb for the entire peptide molecule, while the filled color bars (right bar of each pair) give the contribution to ΔGb from the negatively charged E16G6 tails only.
Figure 3
Figure 3. SiRNA/AD/E16G6RGDK complexes are effectively taken up by PC-3 prostate cancer cells via RGD/integrin and RGDK/neuropilin-1 (Nrp-1) receptor interactions and are then released from endosomes. (A) Flow cytometry analysis of the cellular uptake of siRNA/AD/E16G6RGDK complexes compared to siRNA/AD complexes using Cy5-labeled siRNA. (B) Flow cytometry analysis of the cellular uptake of siRNA/AD/E16G6RGDK complexes in the absence and presence of cyclic RGD (cRGD). (C) Confocal microscopic imaging of the cellular uptake of siRNA/AD/E16G6RGDK complexes in the absence and presence of Nrp-1-receptor antibody. (D) Confocal microscopic imaging of the endosomal escape of the siRNA/AD/E16G6RGDK complexes after incubation times of 0 (control), 0.5, 1.0, and 2.0 h. Red channel image shows the Cy5-labeled siRNA/AD/E16G6RGDK complexes, green channel image shows the endosomes marked by LysoTracker red, and blue channel image shows the nuclei of PC-3 cells stained by DAPI (C) or Hoechst33342 (D). The siRNA/AD/E16G6RGDK complexes were formed using 50 nM siRNA, an N/P ratio of 10, and AD/peptide molar ratio of 5.0. Data are presented as mean ± SD. **, p ≤ 0.01 as calculated by Student’s t test.
Figure 4
Figure 4. Targeted siRNA/AD/E16G6RGDK system is much more effective than the nontargeted siRNA/AD system for Hsp27 silencing and antiproliferation in PC-3 prostate cancer cells. Hsp27 silencing at (A) mRNA and (B) protein levels, determined using qRT-PCR and Western blotting, respectively. (C) The improved down-regulation of Hsp27 at the mRNA level by the targeting complexes is reduced in the presence of either cRGD or anti-Nrp-1-receptor antibody. (D) MTT assay of the antiproliferation effect of the complexes on PC-3 cells. Conditions used: 20 nM siRNA, N/P ratio of 10, AD/peptide molar ratio of 5.0. Data are presented as mean ± SD. **, p ≤ 0.01; ***, p ≤ 0.001 as calculated by Student’s t test.
Figure 5
Figure 5. Targeted siRNA/AD/E16G6RGDK delivery system (A, B) accumulates more efficiently in tumor tissues and (C, D) is much more potent than the nontargeted siRNA/AD system for gene silencing and anticancer activity in tumor xenograft mice. Cy5-siRNA/AD complexes and Cy5-siRNA/AD/E16G6RGDK complexes were administered to PC-3 xenograft mice via i.v. injection in PBS buffer (1.0 mg/kg siRNA, N/P ratio 5.0, AD/peptide molar ratio 5). (A) Fluorescence images of siRNAs accumulated in isolated tumors. (B) Fluorescence quantification analysis of tumors in (A) using imaging software. Data were normalized to the tumors from PBS-treated animals. PC-3 xenograft nude mice were administered twice per week with PBS buffer, siRNA/AD complexes, or siRNA/AD/E16G6RGDK complexes (0.25 mg/kg siRNA, N/P ratio 5.0, AD/peptide molar ratio 5). (C) Tumor growth assessed by measuring tumor size. (D) Cancer cell proliferation in tumor tissue revealed by immunohistochemistry using Ki67 staining. (E) Expression of Hsp27 protein in tumors quantified using Western blotting. (F) Mouse body weight monitoring during the treatment. Data are presented as mean ± SD. *, p ≤ 0.05; **, p ≤ 0.01, ***, p ≤ 0.001 as calculated by Student’s t test.
Figure 6
Figure 6. In vitro toxicity assessment of the targeted siRNA/AD/E16G6RGDK delivery system versus the nontargeted siRNA/AD system. Toxicity assessment using the MTT assay and LDH assay for (A, B) PC-3 prostate cancer cells and (C, D) human embryonic kidney (HEK 293) cells (20 nM siRNA, N/P ratio of 10, AD/peptide molar ratio of 5.0). (E) Left panel: Hemolysis assay of the siRNA/AD complexes and the siRNA/AD/E16G6RGDK complexes in comparison with AD alone at different concentrations of AD (0.50, 1.0, 2.5, 5.0, and 10 μM), which correspond to siRNA concentrations of 10, 20, 50, 100, and 200 nM. Right panel: Quantitative analysis of hemolysis determined by UV absorption at 540 nm. Data are presented as mean ± SD. ***, p ≤ 0.001 as calculated by Student’s t test.
Figure 7
Figure 7. In vivo toxicity assessment of the targeted siRNA/AD/E16G6RGDK delivery system versus the nontargeted siRNA/AD system. (A) Cytokine response in mice determined by quantifying the serum levels of IL-6, INF-γ, TNF-α, GM-CSF, MCP-1, KC, and IL-1β at 3 h postinjection using Luminex-detection technology according to the manufacturer’s protocol. Lipopolysaccharide (LPS) was used as the positive control. Data are presented as mean ± SEM. *, p < 0.05, ***, p < 0.001, versus PBS group, as calculated by Student’s t test. (B) Major serum biochemistry parameters measured in mouse serum collected at 24 h postinjection. Alanine transaminase (ALT), aspartate transaminase (AST), and alkaline phosphatase (ALP) are measured as U/L; total bilirubin (TBIL), urea, triacylglycerol (TG), and total cholesterol (TCHO) are measured as mmol/L; total protein (TP) is measured as g/L. Data are shown as mean ± SEM. (C) Histopathological analysis of major organs from mice treated with siRNA/AD and siRNA/AD/E16G6RGDK. Tissue samples were collected at 24 h postadministration. No significant histopathological changes were observed in any of the tissue sections. Images were enlarged 200 times with the microscope.
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- 12Lachelt, U.; Wagner, E. Nucleic acid therapeutics using polyplexes: a journey of 50 years (and beyond). Chem. Rev. 2015, 115, 11043– 11078, DOI: 10.1021/cr500679312https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BC2MjktVagtg%253D%253D&md5=f317ecbf3554fbcb4ebae59ef0d3d48fNucleic Acid Therapeutics Using Polyplexes: A Journey of 50 Years (and Beyond)Lachelt Ulrich; Wagner Ernst; Lachelt Ulrich; Wagner ErnstChemical reviews (2015), 115 (19), 11043-78 ISSN:.There is no expanded citation for this reference.
- 13Tseng, Y.; Mozumdar, S.; Huang, L. Lipid-based systemic delivery of siRNA. Adv. Drug Delivery Rev. 2009, 61, 721– 731, DOI: 10.1016/j.addr.2009.03.00313https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD1MXmsFyns7Y%253D&md5=535a7456fd5f7ab5503a19dfa7a66f7dLipid-based systemic delivery of siRNATseng, Yu-Cheng; Mozumdar, Subho; Huang, LeafAdvanced Drug Delivery Reviews (2009), 61 (9), 721-731CODEN: ADDREP; ISSN:0169-409X. (Elsevier B.V.)A review. RNAi technol. has brought a new category of treatments for various diseases including genetic diseases, viral diseases, and cancer. Despite the great versatility of RNAi that can down regulate almost any protein in the cells, the delicate and precise machinery used for silencing is the same. The major challenge indeed for RNAi-based therapy is the delivery system. In this review, we start with the uniqueness and mechanism of RNAi machinery and the utility of RNAi in therapeutics. Then we discuss the challenges in systemic siRNA delivery by dividing them into two categories-kinetic and phys. barriers. At the end, we discuss different strategies to overcome these barriers, esp. focusing on the step of endosome escape. Toxicity issues and current successful examples for lipid-based delivery are also included in the review.
- 14Wagner, E. Polymers for siRNA delivery: inspired by viruses to be targeted, dynamic, and precise. Acc. Chem. Res. 2012, 45, 1005– 1013, DOI: 10.1021/ar200223214https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3MXhs1GltrfO&md5=7b0c369312a3d10cb5a8f7fe5dd21f82Polymers for siRNA Delivery: Inspired by Viruses to be Targeted, Dynamic, and PreciseWagner, ErnstAccounts of Chemical Research (2012), 45 (7), 1005-1013CODEN: ACHRE4; ISSN:0001-4842. (American Chemical Society)A review. Synthetic small interfering RNA (siRNA) presents an exciting novel medical opportunity. Although researchers agree that siRNA could have a great therapeutic impact, the required extracellular and intracellular delivery of these mols. into the disease-assocd. target cells presents the primary roadblock for the broader translation of these mols. into medicines. Thus, the design of adequate delivery technologies has utmost importance. Viruses are natural masterpieces of nucleic acid delivery and present chemists and drug delivery experts with a template for the design of artificial carriers for synthetic nucleic acids such as siRNA. They have been developed into gene vectors and have provided convincing successes in gene therapy. Optimized by biol. evolution, viruses are programmed to be dynamic and bioresponsive as they enter living cells, and they carry out their functions in a precisely defined sequence. However, because they are synthesized within living cells and with naturally available nucleotides and amino acids, the chem. of viruses is limited. With the use of diverse synthetic mols. and macromols., chemists can provide delivery solns. beyond the scope of the natural evolution of viruses. This Account describes the design and synthesis of "synthetic siRNA viruses." These structures contain elements that mimic the delivery functions of viral particles and surface domains that shield against undesired biol. interactions and enable specific host cell receptor binding through the presentation of multiple targeting ligands. For example, cationic polymers can reversibly package one or more siRNA mols. into nanoparticle cores to protect them against a degradative bioenvironment. After internalization by receptor-mediated endocytosis into the acidifying endosomes of cells, synthetic siRNA can escape from these vesicles through the activation of membrane-disruption domains as viruses do and reach the cytoplasm, the location of RNA interference. This multistep task presents an attractive challenge for chemists. Similar to the design of prodrugs, the functional domains of these systems have to be activated in a dynamic mode, triggered by conformational changes or bond cleavages in the relevant microenvironment such as the acidic endosome or disulfide-reducing cytoplasm. These chem. analogs of viral domains are often synthetically simpler and more easily accessible mols. than viral proteins. Their precise assembly into multifunctional macromol. and supramol. structures is facilitated by improved anal. techniques, precise orthogonal conjugation chemistries, and sequence-defined polymer syntheses. The chem. evolution of microdomains using chem. libraries and macromol. and supramol. evolution could provide key strategies for optimizing siRNA carriers to selected medical indications.
- 15Wittrup, A.; Ai, A.; Liu, X.; Hamar, P.; Trifonova, R.; Charisse, K.; Manoharan, M.; Kirchhausen, T.; Lieberman, J. Visualizing lipid-formulated siRNA release from endosomes and target gene knockdown. Nat. Biotechnol. 2015, 33, 870– 876, DOI: 10.1038/nbt.329815https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2MXhtF2murjF&md5=1e896c5372fff738d373ef1deb2ac412Visualizing lipid-formulated siRNA release from endosomes and target gene knockdownWittrup, Anders; Ai, Angela; Liu, Xing; Hamar, Peter; Trifonova, Radiana; Charisse, Klaus; Manoharan, Muthiah; Kirchhausen, Tomas; Lieberman, JudyNature Biotechnology (2015), 33 (8), 870-876CODEN: NABIF9; ISSN:1087-0156. (Nature Publishing Group)A central hurdle in developing small interfering RNAs (siRNAs) as therapeutics is the inefficiency of their delivery across the plasma and endosomal membranes to the cytosol, where they interact with the RNA interference machinery. With the aim of improving endosomal release, a poorly understood and inefficient process, we studied the uptake and cytosolic release of siRNAs, formulated in lipoplexes or lipid nanoparticles, by live-cell imaging and correlated it with knockdown of a target GFP reporter. siRNA release occurred invariably from maturing endosomes within ∼5-15 min of endocytosis. Cytosolic galectins immediately recognized the damaged endosome and targeted it for autophagy. However, inhibiting autophagy did not enhance cytosolic siRNA release. Gene knockdown occurred within a few hours of release and required <2,000 copies of cytosolic siRNAs. The ability to detect cytosolic release of siRNAs and understand how it is regulated will facilitate the development of rational strategies for improving the cytosolic delivery of candidate drugs.
- 16Lee, C.; MacKay, J.; Frechet, J.; Szoka, F. Designing dendrimers for biological applications. Nat. Biotechnol. 2005, 23, 1517– 1526, DOI: 10.1038/nbt117116https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2MXht1yisrnE&md5=d1306ae17979250c01f2fb51fa76a080Designing dendrimers for biological applicationsLee, Cameron C.; MacKay, John A.; Frechet, Jean M. J.; Szoka, Francis C.Nature Biotechnology (2005), 23 (12), 1517-1526CODEN: NABIF9; ISSN:1087-0156. (Nature Publishing Group)A review. Dendrimers are branched, synthetic polymers with layered architectures that show promise in several biomedical applications. By regulating dendrimer synthesis, it is possible to precisely manipulate both their mol. wt. and chem. compn., thereby allowing predictable tuning of their biocompatibility and pharmacokinetics. Advances in our understanding of the role of mol. wt. and architecture on the in vivo behavior of dendrimers, together with recent progress in the design of biodegradable chemistries, has enabled the application of these branched polymers as anti-viral drugs, tissue repair scaffolds, targeted carriers of chemotherapeutics and optical oxygen sensors. Before such products can reach the market, however, the field must not only address the cost of manuf. and quality control of pharmaceutical-grade materials, but also assess the long-term human and environmental health consequences of dendrimer exposure in vivo.
- 17Khandare, J.; Calderon, M.; Dagia, N.; Haag, R. Multifunctional dendritic polymers in nanomedicine: opportunities and challenges. Chem. Soc. Rev. 2012, 41, 2824– 2848, DOI: 10.1039/C1CS15242D17https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC38Xjs1CksLg%253D&md5=2096b686d6657325955ec41bbbc006f2Multifunctional dendritic polymers in nanomedicine: opportunities and challengesKhandare, Jayant; Calderon, Marcelo; Dagia, Nilesh M.; Haag, RainerChemical Society Reviews (2012), 41 (7), 2824-2848CODEN: CSRVBR; ISSN:0306-0012. (Royal Society of Chemistry)A review. Nanotechnol. has resulted in materials that have greatly improved the effectiveness of drug delivery because of their ability to control matter on the nanoscale. Advanced forms of nanomedicine have been synthesized for better pharmacokinetics to obtain higher efficacy, less systemic toxicity, and better targeting. These criteria have long been the goal in nanomedicine, in particular, for systemic applications in oncol. disorders. Now, the "holy grail" in nanomedicine is to design and synthesize new advanced macromol. nanocarriers and to translate them from lab to clinic. This review describes the current and future perspectives of nanomedicine with particular emphasis on the clin. targets in cancer and inflammation. The advanced forms of liposomes and polyethylene glycol (PEG) based nanocarriers, as well as dendritic polymer conjugates will be discussed with particular attention paid to designs, synthetic strategies, and chem. pathways. In this crit. review, we also report on the current status and perspective of dendritic polymer nanoconjugate platforms (e.g. polyamidoamine dendrimers and dendritic polyglycerols) for cellular localization and targeting of specific tissues (192 refs.).
- 18Liu, X.; Rocchi, P.; Peng, L. Dendrimers as non-viral vectors for siRNA delivery. New J. Chem. 2012, 36, 256– 263, DOI: 10.1039/C1NJ20408DThere is no corresponding record for this reference.
- 19Liu, X.; Liu, C.; Catapano, C.; Peng, L.; Zhou, J.; Rocchi, P. Structurally flexible triethanolamine-core poly(amidoamine) dendrimers as effective nanovectors to deliver RNAi-based therapeutics. Biotechnol. Adv. 2014, 32, 844– 852, DOI: 10.1016/j.biotechadv.2013.08.001There is no corresponding record for this reference.
- 20Reebye, V.; Sætrom, P.; Mintz, P.; Huang, K.; Swiderski, P.; Peng, L.; Liu, C.; Liu, X.; Lindkaer-Jensen, S.; Zacharoulis, D. Novel RNA oligonucleotide improves liver function and inhibits liver carcinogenesis in vivo. Hepatology 2014, 59, 216– 227, DOI: 10.1002/hep.26669There is no corresponding record for this reference.
- 21Yu, T.; Liu, X.; Bolcato-Bellemin, A.; Wang, Y.; Liu, C.; Erbacher, P.; Qu, F.; Rocchi, P.; Behr, J.; Peng, L. An amphiphilic dendrimer for effective delivery of small interfering RNA and gene silencing in vitro and in vivo. Angew. Chem., Int. Ed. 2012, 51, 8478– 8484, DOI: 10.1002/anie.20120392021https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC38XhtVyjs7rO&md5=176386f529e80f5778008b8aba3c2714An Amphiphilic Dendrimer for Effective Delivery of Small Interfering RNA and Gene Silencing In Vitro and In VivoYu, Tianzhu; Liu, Xiaoxuan; Bolcato-Bellemin, Anne-Laure; Wang, Yang; Liu, Cheng; Erbacher, Patrick; Qu, Fanqi; Rocchi, Palma; Behr, Jean-Paul; Peng, LingAngewandte Chemie, International Edition (2012), 51 (34), 8478-8484, S8478/1-S8478/33CODEN: ACIEF5; ISSN:1433-7851. (Wiley-VCH Verlag GmbH & Co. KGaA)An amphiphilic dendrimer bearing a hydrophobic alkyl chain and hydrophilic poly(amidoamine) dendrons is able to combine the advantageous features of lipid and dendrimers vectors to deliver a heat shock protein 27 siRNA and produce potent gene silencing and anticancer activity in vitro and in vivo in a prostate cancer model. This dendrimer can be used alternatively for treating various diseases.
- 22Liu, X.; Zhou, J.; Yu, T.; Chen, C.; Cheng, Q.; Sengupta, K.; Huang, Y.; Li, H.; Liu, C.; Wang, Y.; Posocco, P.; Wang, M.; Cui, Q.; Giorgio, S.; Fermeglia, M.; Qu, F.; Pricl, S.; Shi, Y.; Liang, Z.; Rocchi, P.; Rossi, J.; Peng, L. Adaptive amphiphilic dendrimer-based nanoassemblies as robust and versatile siRNA delivery systems. Angew. Chem., Int. Ed. 2014, 53, 11822– 11827, DOI: 10.1002/anie.20140676422https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2cXhsFCisrvF&md5=5cb14bd9e508eb76c4b008b6752ed806Adaptive Amphiphilic Dendrimer-Based Nanoassemblies as Robust and Versatile siRNA Delivery SystemsLiu, Xiaoxuan; Zhou, Jiehua; Yu, Tianzhu; Chen, Chao; Cheng, Qiang; Sengupta, Kheya; Huang, Yuanyu; Li, Haitang; Liu, Cheng; Wang, Yang; Posocco, Paola; Wang, Menghua; Cui, Qi; Giorgio, Suzanne; Fermeglia, Maurizio; Qu, Fanqi; Pricl, Sabrina; Shi, Yanhong; Liang, Zicai; Rocchi, Palma; Rossi, John J.; Peng, LingAngewandte Chemie, International Edition (2014), 53 (44), 11822-11827CODEN: ACIEF5; ISSN:1433-7851. (Wiley-VCH Verlag GmbH & Co. KGaA)SiRNA delivery remains a major challenge in RNAi-based therapy. Here, we report for the first time that an amphiphilic dendrimer is able to self-assemble into adaptive supramol. assemblies upon interaction with siRNA, and effectively delivers siRNAs to various cell lines, including human primary and stem cells, thereby outperforming the currently available nonviral vectors. In addn., this amphiphilic dendrimer is able to harness the advantageous features of both polymer and lipid vectors and hence promotes effective siRNA delivery. Our study demonstrates for the first time that dendrimer-based adaptive supramol. assemblies represent novel and versatile means for functional siRNA delivery, heralding a new age of dendrimer-based self-assembled drug delivery in biomedical applications.
- 23Chen, C.; Posocco, P.; Liu, X.; Cheng, Q.; Laurini, E.; Zhou, J.; Liu, C.; Wang, Y.; Tang, J.; Col, V.; Yu, T.; Giorgio, S.; Fermeglia, M.; Qu, F.; Liang, Z.; Rossi, J.; Liu, M.; Rocchi, P.; Pricl, S.; Peng, L. siRNA delivery: mastering dendrimer self-assembly for efficient siRNA delivery: from conceptual design to in vivo efficient gene silencing. Small 2016, 12, 3667– 3676, DOI: 10.1002/smll.201503866There is no corresponding record for this reference.
- 24Liu, X.; Wang, Y.; Chen, C.; Tintaru, A.; Cao, Y.; Liu, J.; Ziarelli, F.; Tang, J.; Guo, H.; Rosas, R.; Giorgio, S.; Charle, L.; Rocchi, P.; Peng, L. A fluorinated bola-amphiphilic dendrimer for on-demand delivery of siRNA, via specific response to reactive oxygen species. Adv. Funct. Mater. 2016, 26, 8594– 8603, DOI: 10.1002/adfm.20160419224https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC28XhslGitLjE&md5=931ea4546e4a792fc32c41dd25b69a8aA Fluorinated Bola-Amphiphilic Dendrimer for On-Demand Delivery of siRNA, via Specific Response to Reactive Oxygen SpeciesLiu, Xiaoxuan; Wang, Yang; Chen, Chao; Tintaru, Aura; Cao, Yu; Liu, Juan; Ziarelli, Fabio; Tang, Jingjie; Guo, Hongbo; Rosas, Roseline; Giorgio, Suzanne; Charles, Laurence; Rocchi, Palma; Peng, LingAdvanced Functional Materials (2016), 26 (47), 8594-8603CODEN: AFMDC6; ISSN:1616-301X. (Wiley-VCH Verlag GmbH & Co. KGaA)Functional materials capable of responding to stimuli intrinsic to diseases are extremely important for specific drug delivery at the disease site. However, developing on-demand stimulus-responsive vectors for targeted delivery is highly challenging. Here, a stimulus-responsive fluorinated bola-amphiphilic dendrimer is reported for on-demand delivery of small interfering RNA (siRNA) in response to the characteristic high level of reactive oxygen species (ROS) in cancer cells. This dendrimer bears a ROS-sensitive thioacetal in the hydrophobic core and pos. charged poly(amidoamine) dendrons at the terminals, capable of interacting and compacting the neg. charged siRNA into nanoparticles to protect the siRNA and promote cellular uptake. The ROS-sensitive feature of this dendrimer boosts specific and efficient disassembly of the siRNA/vector complexes in ROS-rich cancer cells for effective siRNA delivery and gene silencing. Moreover, the fluorine tags in the vector enable 19F-NMR anal. of the ROS-responsive delivery process. In addn., this ingenious and distinct bola-amphiphilic dendrimer is also able to combine the advantageous delivery features of both lipid and dendrimer vectors. Therefore, it represents an innovative on-demand stimulus-responsive delivery platform.
- 25Percec, V.; Wilson, D.; Leowanawat, P.; Wilson, C.; Hughes, A.; Kaucher, M.; Hammer, D.; Levine, D.; Kim, A.; Bates, F. Self-assembly of Janus dendrimers into uniform dendrimersomes and other complex architectures. Science 2010, 328, 1009– 1014, DOI: 10.1126/science.118554725https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3cXmtFCnsLo%253D&md5=f27fa5e6ae26f177e85c36ca5e46047eSelf-Assembly of Janus Dendrimers into Uniform Dendrimersomes and Other Complex ArchitecturesPercec, Virgil; Wilson, Daniela A.; Leowanawat, Pawaret; Wilson, Christopher J.; Hughes, Andrew D.; Kaucher, Mark S.; Hammer, Daniel A.; Levine, Dalia H.; Kim, Anthony J.; Bates, Frank S.; Davis, Kevin P.; Lodge, Timothy P.; Klein, Michael L.; De Vane, Russell H.; Aqad, Emad; Rosen, Brad M.; Argintaru, Andreea O.; Sienkowska, Monika J.; Rissanen, Kari; Nummelin, Sami; Ropponen, JarmoScience (Washington, DC, United States) (2010), 328 (5981), 1009-1014CODEN: SCIEAS; ISSN:0036-8075. (American Association for the Advancement of Science)Self-assembled nanostructures obtained from natural and synthetic amphiphiles serve as mimics of biol. membranes and enable the delivery of drugs, proteins, genes, and imaging agents. Yet the precise mol. arrangements demanded by these functions are difficult to achieve. Libraries of amphiphilic Janus dendrimers, prepd. by facile coupling of tailored hydrophilic and hydrophobic branched segments, have been screened by cryogenic transmission electron microscopy, revealing a rich palette of morphologies in water, including vesicles, denoted dendrimersomes, cubosomes, disks, tubular vesicles, and helical ribbons. Dendrimersomes marry the stability and mech. strength obtainable from polymersomes with the biol. function of stabilized phospholipid liposomes, plus superior uniformity of size, ease of formation, and chem. functionalization. This modular synthesis strategy provides access to systematic tuning of mol. structure and of self-assembled architecture.
- 26Sherman, S.; Xiao, Q.; Percec, V. Mimicking complex biological membranes and their programmable glycan ligands with dendrimersomes and glycodendrimersomes. Chem. Rev. 2017, 117, 6538– 6631, DOI: 10.1021/acs.chemrev.7b0009726https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2sXmtVyqur8%253D&md5=7448c0318ceb9b46a0b12963822a166bMimicking Complex Biological Membranes and Their Programmable Glycan Ligands with Dendrimersomes and GlycodendrimersomesSherman, Samuel E.; Xiao, Qi; Percec, VirgilChemical Reviews (Washington, DC, United States) (2017), 117 (9), 6538-6631CODEN: CHREAY; ISSN:0009-2665. (American Chemical Society)A review. Synthetic vesicles have been assembled and co-assembled from phospholipids, their modified versions, and other single amphiphiles into liposomes, and from block copolymers into polymersomes. Their time-consuming synthesis and prepn. as stable, monodisperse, and biocompatible liposomes and polymersomes called for the elaboration of new synthetic methodologies. Amphiphilic Janus dendrimers (JDs) and glycodendrimers (JGDs) represent the most recent self-assembling amphiphiles capable of forming monodisperse, stable, and multifunctional unilamellar and multilamellar onion-like vesicles denoted dendrimersomes (DSs) and glycodendrimersomes (GDSs), dendrimercubosomes (DCs), glycodendrimercubosomes (GDCs), and other complex architectures. Amphiphilic JDs consist of hydrophobic dendrons connected to hydrophilic dendrons and can be thought of as monodisperse oligomers of a single amphiphile. They can be functionalized with a variety of mols. such as dyes, and, in the case of JGDs, with carbohydrates. Their iterative modular synthesis provides efficient access to sequence control at the mol. level, resulting in topologies with specific epitope sequence and d. DSs, GDSs, and other architectures from JDs and JGDs serve as powerful tools for mimicking biol. membranes and for biomedical applications such as targeted drug and gene delivery and theranostics. This Review covers all aspects of the synthesis of JDs and JGDs and their biol. activity and applications after assembly in aq. media.
- 27Bertrand, N.; Wu, J.; Xu, X.; Kamaly, N.; Farokhzad, O. Cancer nanotechnology: the impact of passive and active targeting in the era of modern cancer biology. Adv. Drug Delivery Rev. 2014, 66, 2– 25, DOI: 10.1016/j.addr.2013.11.00927https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2cXisV2hug%253D%253D&md5=0980da1a1b75cde64cc1cf82184e01b7Cancer nanotechnology: The impact of passive and active targeting in the era of modern cancer biologyBertrand, Nicolas; Wu, Jun; Xu, Xiaoyang; Kamaly, Nazila; Farokhzad, Omid C.Advanced Drug Delivery Reviews (2014), 66 (), 2-25CODEN: ADDREP; ISSN:0169-409X. (Elsevier B.V.)Cancer nanotherapeutics are progressing at a steady rate; research and development in the field has experienced an exponential growth since early 2000's. The path to the commercialization of oncol. drugs is long and carries significant risk; however, there is considerable excitement that nanoparticle technologies may contribute to the success of cancer drug development. The pace at which pharmaceutical companies have formed partnerships to use proprietary nanoparticle technologies has considerably accelerated. It is now recognized that by enhancing the efficacy and/or tolerability of new drug candidates, nanotechnol. can meaningfully contribute to create differentiated products and improve clin. outcome. This review describes the lessons learned since the commercialization of the first-generation nanomedicines including DOXIL and Abraxane. It explores our current understanding of targeted and non-targeted nanoparticles that are under various stages of development, including BIND-014 and MM-398. It highlights the opportunities and challenges faced by nanomedicines in contemporary oncol., where personalized medicine is increasingly the mainstay of cancer therapy. We revisit the fundamental concepts of enhanced permeability and retention effect (EPR) and explore the mechanisms proposed to enhance preferential "retention" in the tumor, whether using active targeting of nanoparticles, binding of drugs to their tumoral targets or the presence of tumor assocd. macrophages. The overall objective of this review is to enhance our understanding in the design and development of therapeutic nanoparticles for treatment of cancers.
- 28Dai, L.; Liu, J.; Luo, Z.; Li, M.; Cai, K. Tumor therapy: targeted drug delivery system. J. Mater. Chem. B 2016, 4, 6758– 6772, DOI: 10.1039/C6TB01743F28https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC28XhsVWktr3F&md5=43534ec2f361c7181059c074132608d4Tumor therapy: targeted drug delivery systemsDai, Liangliang; Liu, Junjie; Luo, Zhong; Li, Menghuan; Cai, KaiyongJournal of Materials Chemistry B: Materials for Biology and Medicine (2016), 4 (42), 6758-6772CODEN: JMCBDV; ISSN:2050-7518. (Royal Society of Chemistry)Recently, targeted drug delivery systems (TDDSs) have been extensively studied as a promising therapeutic for tumor therapy. In this review, we investigate the typical targeting mechanisms of TDDSs, covering both passively and actively targeting DDSs for tumor therapy. We highlight the popular active targeting strategies for different sites of action, including tumor cytomembrane or various organelles. Finally, we present some recent representative TDDSs that are under testing in preclin./clin. trials and have shown excellent clin. potential as the alternate treatment strategy for tumor therapy. Although TDDSs are proving to be promising therapeutic nanoplatforms for tumor therapy, extended investigations should be considered in the landscape for highly efficient tumor therapy with good biosafety.
- 29Davis, M.; Zuckerman, J.; Choi, C.; Seligson, D.; Tolcher, A.; Alabi, C.; Yen, Y.; Heidel, J.; Ribas, A. Evidence of RNAi in humans from systemically administered siRNA via targeted nanoparticles. Nature 2010, 464, 1067– 1070, DOI: 10.1038/nature0895629https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3cXjs1ehur8%253D&md5=b49a61e3acc1245274c2314fb6bcc99aEvidence of RNAi in humans from systemically administered siRNA via targeted nanoparticlesDavis, Mark E.; Zuckerman, Jonathan E.; Choi, Chung-Hang J.; Seligson, David; Tolcher, Anthony; Alabi, Christopher A.; Yen, Yun; Heidel, Jeremy D.; Ribas, AntoniNature (London, United Kingdom) (2010), 464 (7291), 1067-1070CODEN: NATUAS; ISSN:0028-0836. (Nature Publishing Group)Therapeutics that are designed to engage RNA interference (RNAi) pathways have the potential to provide new, major ways of imparting therapy to patients. Long, double-stranded RNAs were first shown to mediate RNAi in Caenorhabditis elegans, and the potential use of RNAi for human therapy has been demonstrated by the finding that small interfering RNAs (siRNAs; approx. 21-base-pair double-stranded RNA) can elicit RNAi in mammalian cells without producing an interferon response. We are at present conducting the first in-human phase I clin. trial involving the systemic administration of siRNA to patients with solid cancers using a targeted, nanoparticle delivery system. Here we provide evidence of inducing an RNAi mechanism of action in a human from the delivered siRNA. Tumor biopsies from melanoma patients obtained after treatment show the presence of intracellularly localized nanoparticles in amts. that correlate with dose levels of the nanoparticles administered (this is, to our knowledge, a first for systemically delivered nanoparticles of any kind). Furthermore, a redn. was found in both the specific mRNA (M2 subunit of ribonucleotide reductase (RRM2)) and the protein (RRM2) levels when compared to pre-dosing tissue. Most notably, we detect the presence of an mRNA fragment that demonstrates that siRNA-mediated mRNA cleavage occurs specifically at the site predicted for an RNAi mechanism from a patient who received the highest dose of the nanoparticles. Together, these data demonstrate that siRNA administered systemically to a human can produce a specific gene inhibition (redn. in mRNA and protein) by an RNAi mechanism of action.
- 30Sugahara, K.; Teesalu, T.; Karmali, P.; Kotamraju, V.; Agemy, L.; Greenwald, D.; Ruoslahti, E. Co-administration of a tumor-penetrating peptide enhances the efficacy of cancer drugs. Science 2010, 328, 1031– 1035, DOI: 10.1126/science.1183057There is no corresponding record for this reference.
- 31Wong, P.; Tang, K.; Coulter, A.; Tan, S.; Baker, J.; Choi, S. Multivalent dendrimer vectors with DNA intercalation motifs for gene delivery. Biomacromolecules 2014, 15, 4134– 4415, DOI: 10.1021/bm501169s31https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2cXhs1yisr7K&md5=8c21541c6d33bbcad02f41564d5fe0d6Multivalent Dendrimer Vectors with DNA Intercalation Motifs for Gene DeliveryWong, Pamela T.; Tang, Kenny; Coulter, Alexa; Tang, Shengzhuang; Baker, James R.; Choi, Seok KiBiomacromolecules (2014), 15 (11), 4134-4145CODEN: BOMAF6; ISSN:1525-7797. (American Chemical Society)Poly(amido amine) (PAMAM) dendrimers constitute an important class of nonviral, cationic vectors in gene delivery. Here we report on a new concept for dendrimer vector design based on the incorporation of dual binding motifs: DNA intercalation, and receptor recognition for targeted delivery. We prepd. a series of dendrimer conjugates derived from a fifth generation (G5) PAMAM dendrimer, each conjugated with multiple folate (FA) or riboflavin (RF) ligands for cell receptor targeting, and with 3,8-diamino-6-phenylphenanthridinium ("DAPP")-derived ligands for anchoring a DNA payload. Polyplexes of each dendrimer with calf thymus dsDNA were made and characterized by surface plasmon resonance (SPR) spectroscopy, dynamic light scattering (DLS) and zeta potential measurement. These studies provided evidence supporting polyplex formation based on the observation of tight DNA-dendrimer adhesion, and changes in particle size and surface charge upon coincubation. Further SPR studies to investigate the adhesion of the polyplex to a model surface immobilized with folate binding protein (FBP), demonstrated that the DNA payload has only a minimal effect on the receptor binding activity of the polyplex: KD = 0.22 nM for G5(FA)(DAPP) vs. 0.98 nM for its polyplex. Finally, we performed in vitro transfection assays to det. the efficiency of conjugate mediated delivery of a luciferase-encoding plasmid into the KB cancer cell line and showed that RF-conjugated dendrimers were 1 to 2 orders of magnitude more effective in enhancing luciferase gene transfection than a plasmid only control. In summary, this study serves as a proof of concept for DNA-ligand intercalation as a motif in the design of multivalent dendrimer vectors for targeted gene delivery.
- 32Sugahara, K.; Teesalu, T.; Karmali, P.; Kotamraju, V.; Agemy, L.; Girard, O.; Hanahan, D.; Mattrey, R.; Ruoslahti, E. Tissue-penetrating delivery of compounds and nanoparticles into tumors. Cancer Cell 2009, 16, 510– 520, DOI: 10.1016/j.ccr.2009.10.01332https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3cXht1eqsbY%253D&md5=f42c01e8e751526318903d28d70ce4c4Tissue-penetrating delivery of compounds and nanoparticles into tumorsSugahara, Kazuki N.; Teesalu, Tambet; Karmali, Priya Prakash; Kotamraju, Venkata Ramana; Agemy, Lilach; Girard, Olivier M.; Hanahan, Douglas; Mattrey, Robert F.; Ruoslahti, ErkkiCancer Cell (2009), 16 (6), 510-520CODEN: CCAECI; ISSN:1535-6108. (Cell Press)Poor penetration of drugs into tumors is a major obstacle in tumor treatment. We describe a strategy for peptide-mediated delivery of compds. deep into the tumor parenchyma that uses a tumor-homing peptide, iRGD (CRGDK/RGPD/EC). I.v. injected compds. coupled to iRGD bound to tumor vessels and spread into the extravascular tumor parenchyma, whereas conventional RGD peptides only delivered the cargo to the blood vessels. IRGD homes to tumors through a three-step process: the RGD motif mediates binding to αv integrins on tumor endothelium and a proteolytic cleavage then exposes a binding motif for neuropilin-1, which mediates penetration into tissue and cells. Conjugation to iRGD significantly improved the sensitivity of tumor-imaging agents and enhanced the activity of an antitumor drug.
- 33Desgrosellier, J.; Cheresh, D. Integrins in cancer: biological implications and therapeutic opportunities. Nat. Rev. Cancer 2010, 10, 9– 22, DOI: 10.1038/nrc274833https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD1MXhsF2hsLzI&md5=43d0b526ca38021e780aba991a58451bIntegrins in cancer: biological implications and therapeutic opportunitiesDesgrosellier, Jay S.; Cheresh, David A.Nature Reviews Cancer (2010), 10 (1), 9-22CODEN: NRCAC4; ISSN:1474-175X. (Nature Publishing Group)A review. The integrin family of cell adhesion receptors regulates a diverse array of cellular functions crucial to the initiation, progression and metastasis of solid tumors. The importance of integrins in several cell types that affect tumor progression has made them an appealing target for cancer therapy. Integrin antagonists, including the αvβ3 and αvβ5 inhibitor cilengitide, have shown encouraging activity in Phase II clin. trials and cilengitide is currently being tested in a Phase III trial in patients with glioblastoma. These exciting clin. developments emphasize the need to identify how integrin antagonists influence the tumor and its microenvironment.
- 34Marelli, U.; Rechenmacher, F.; Sobahi, T.; Mas-Moruno, C.; Kessler, H. Tumor targeting via integrin ligands. Front. Oncol. 2013, 3, 222– 233, DOI: 10.3389/fonc.2013.0022234https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BC2cflt1Gktg%253D%253D&md5=b09d0b738b25909e8b68d42d90ad638eTumor Targeting via Integrin LigandsMarelli Udaya Kiran; Rechenmacher Florian; Sobahi Tariq Rashad Ali; Mas-Moruno Carlos; Kessler HorstFrontiers in oncology (2013), 3 (), 222 ISSN:2234-943X.Selective and targeted delivery of drugs to tumors is a major challenge for an effective cancer therapy and also to overcome the side-effects associated with current treatments. Overexpression of various receptors on tumor cells is a characteristic structural and biochemical aspect of tumors and distinguishes them from physiologically normal cells. This abnormal feature is therefore suitable for selectively directing anticancer molecules to tumors by using ligands that can preferentially recognize such receptors. Several subtypes of integrin receptors that are crucial for cell adhesion, cell signaling, cell viability, and motility have been shown to have an upregulated expression on cancer cells. Thus, ligands that recognize specific integrin subtypes represent excellent candidates to be conjugated to drugs or drug carrier systems and be targeted to tumors. In this regard, integrins recognizing the RGD cell adhesive sequence have been extensively targeted for tumor-specific drug delivery. Here we review key recent examples on the presentation of RGD-based integrin ligands by means of distinct drug-delivery systems, and discuss the prospects of such therapies to specifically target tumor cells.
- 35Teesalu, T.; Sugahara, K.; Kotamraju, V.; Ruoslahti, E. C-end rule peptides mediate neuropilin-1-dependent cell, vascular, and tissue penetration. Proc. Natl. Acad. Sci. U. S. A. 2009, 106, 16157– 16162, DOI: 10.1073/pnas.090820110635https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD1MXht1OjsbbI&md5=3eb210213cfccc091c4aba949d437b42C-end rule peptides mediate neuropilin-1-dependent cell, vascular, and tissue penetrationTeesalu, Tambet; Sugahara, Kazuki N.; Kotamraju, Venkata Ramana; Erkki RuoslahtiProceedings of the National Academy of Sciences of the United States of America (2009), 106 (38), 16157-16162, S16157/1-S16157/15CODEN: PNASA6; ISSN:0027-8424. (National Academy of Sciences)Screening of phage libraries expressing random peptides for binding to prostate cancer cells primarily yielded peptides that had a C-terminal arginine (or rarely lysine) residue, usually in a consensus context R/KXXR/K. Phage expressing these sequences and synthetic nanoparticles coated with them bound to and were internalized into cells. The C-terminal arginine (or lysine) was essential to the activity; adding another amino acid, or even blocking the free carboxyl group of this arginine residue by amidation, eliminated the binding and internalizing activity. An internal R/KXXR/K can be exposed and switched on by a cleavage by a protease. The strict requirement for C-terminal exposure of the motif prompted the authors to term the phenomenon the C-end rule (CendR). Affinity chromatog. showed that the CendR peptides bind to neuropilin-1 (NRP-1) on the target cells. NRP-1 is a cell-surface receptor that plays an essential role in angiogenesis, regulation of vascular permeability, and the development of the nervous system. VEGF-A165 and other ligands of NRP-1 possess a C-terminal CendR sequence that interacts with the b1 domain of NRP-1 and causes cellular internalization and vascular leakage. The authors' CendR peptides have similar effects, particularly when made multivalent through coupling to a particle. The authors also noted a unique and important activity of these peptides: penetration and transportation through tissues. The peptides were able to take payloads up to the nanoparticle size scale deep into extravascular tissue. The authors' observations have implications in drug delivery and penetration of tissue barriers and tumors.
- 36Liu, X.; Liu, C.; Chen, C.; Bentobji, M.; Cheillan, F.; Piana, J.; Qu, F.; Rocchi, P.; Peng, L. Targeted delivery of Dicer-substrate siRNAs using a dual targeting peptide decorated dendrimer delivery system. Nanomedicine 2014, 10, 1627– 1636, DOI: 10.1016/j.nano.2014.05.00836https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2cXhtFOgtL3K&md5=27ce93c828721bcad7351c4edde95339Targeted delivery of Dicer-substrate siRNAs using a dual targeting peptide decorated dendrimer delivery systemLiu, Xiaoxuan; Liu, Cheng; Chen, Chao; Bentobji, Melanie; Cheillan, Francine Azario; Piana, Jeanne Thomassin; Qu, Fanqi; Rocchi, Palma; Peng, LingNanomedicine (New York, NY, United States) (2014), 10 (8), 1627-1636CODEN: NANOBF; ISSN:1549-9634. (Elsevier)Small interfering RNAs (siRNA) are emerging as novel therapeutic agents, providing competent delivery systems that are available. Dendrimers, a special family of synthetic macromols., represent an exciting delivery platform by virtue of their well-defined dendritic structure and unique multivalency and cooperativity confined within a nanoscale vol. Here, we report a Dicer-substrate siRNA (dsiRNA) which, when delivered using a structurally flexible triethanolamine-core poly(amidoamine) dendrimer of generation 5 as the nanocarrier, gives rise to a much greater RNAi response than that produced with conventional siRNA. Further decoration of the dsiRNA/dendrimer complexes with a dual targeting peptide simultaneously promoted cancer cell targeting through interacting with integrins and cell penetration via the interaction with neuropilin-1 receptors, which led to improved gene silencing and anticancer activity. Altogether, our results disclosed here open a new avenue for therapeutic implementation of RNAi using dendrimer nanovector based targeted delivery.
- 37Svenson, S. The dendrimer paradox--high medical expectations but poor clinical translation. Chem. Soc. Rev. 2015, 46, 4131– 4144, DOI: 10.1039/C5CS00288EThere is no corresponding record for this reference.
- 38Cao, Y.; Liu, X.; Peng, L. Molecular engineering of dendrimer nanovecters for siRNA delivery and gene silencing. Front. Chem. Sci. Eng. 2017, 11, 663– 675, DOI: 10.1007/s11705-017-1623-538https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2sXlvFyjsLs%253D&md5=72a76c778f9c6878d0f125e3b57bcb88Molecular engineering of dendrimer nanovectors for siRNA delivery and gene silencingCao, Yu; Liu, Xiaoxuan; Peng, LingFrontiers of Chemical Science and Engineering (2017), 11 (4), 663-675CODEN: FCSEA3; ISSN:2095-0187. (Springer)A review. Small interfering RNA (siRNA) therapeutics hold great promise to treat a variety of diseases, as long as they can be delivered safely and effectively into cells. Dendrimers are appealing vectors for siRNA delivery by virtue of their well-defined mol. architecture and multivalent cooperativity. However, the clin. translation of RNA therapeutics mediated by dendrimer delivery is hampered by the lack of dendrimers that are of high quality to meet good manufg. practice std. In this context, we have developed small amphiphilic dendrimers that self-assemble into supramol. structures, which mimic high-generation dendrimers synthesized with covalent construction, yet are easy to produce in large amt. and superior quality. This short review presents a brief introduction to RNAi therapeutics, the obstacles to their delivery and the advantages of dendrimer delivery vectors as well as our bio-inspired structurally flexible dendrimers for siRNA delivery. We then highlight our efforts in creating selfassembling amphiphilic dendrimers to construct supramol. dendrimer nanosystems for effective siRNA delivery as well as the related structural alterations to enhance delivery efficiency. The advent of self-assembling supramol. dendrimer nanovectors holds great promise and heralds a new era of dendrimer-mediated delivery of RNA therapeutics in biomedical applications.
- 39Zhou, J.; Liu, J.; Cheng, C.; Patel, T.; Weller, C.; Piepmeier, J.; Jiang, Z.; Saltzman, W. Biodegradable poly(amine-co-ester) terpolymers for targeted gene delivery. Nat. Mater. 2012, 11, 82– 90, DOI: 10.1038/nmat318739https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3MXhsFGkurfN&md5=937db7f417aafb60789ec0f760f27d49Biodegradable poly(amine-co-ester) terpolymers for targeted gene deliveryZhou, Jiangbing; Liu, Jie; Cheng, Christopher J.; Patel, Toral R.; Weller, Caroline E.; Piepmeier, Joseph M.; Jiang, Zhaozhong; Saltzman, W. MarkNature Materials (2012), 11 (1), 82-90CODEN: NMAACR; ISSN:1476-1122. (Nature Publishing Group)Many synthetic polycationic vectors for non-viral gene delivery show high efficiency in vitro, but their usually excessive charge d. makes them toxic for in vivo applications. Here we describe the synthesis of a series of high mol. wt. terpolymers with low charge d., and show that they exhibit efficient gene delivery, some surpassing the efficiency of the com. transfection reagents Polyethylenimine and Lipofectamine 2000. The terpolymers were synthesized via enzyme-catalyzed copolymn. of lactone with dialkyl diester and amino diol, and their hydrophobicity adjusted by varying the lactone content and by selecting a lactone comonomer of specific ring size. Targeted delivery of the pro-apoptotic TRAIL gene to tumor xenografts by one of the terpolymers results in significant inhibition of tumor growth, with minimal toxicity both in vitro and in vivo. Our findings suggest that the gene delivery ability of the terpolymers stems from their high mol. wt. and increased hydrophobicity, which compensates for their low charge d.
- 40Grandclement, C.; Borg, C. Neuropilins: a new target for cancer therapy. Cancers 2011, 3, 1899– 1928, DOI: 10.3390/cancers3021899There is no corresponding record for this reference.
- 41Siegel, R.; Miller, K.; Jemal, A. Cancer Statistics, 2017. Ca-Cancer J. Clin. 2017, 67, 7– 30, DOI: 10.3322/caac.2138741https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BC1c7isFWgtA%253D%253D&md5=e439f3424d5a773e4ae289c392236ad6Cancer Statistics, 2017Siegel Rebecca L; Miller Kimberly D; Jemal AhmedinCA: a cancer journal for clinicians (2017), 67 (1), 7-30 ISSN:.Each year, the American Cancer Society estimates the numbers of new cancer cases and deaths that will occur in the United States in the current year and compiles the most recent data on cancer incidence, mortality, and survival. Incidence data were collected by the Surveillance, Epidemiology, and End Results Program; the National Program of Cancer Registries; and the North American Association of Central Cancer Registries. Mortality data were collected by the National Center for Health Statistics. In 2017, 1,688,780 new cancer cases and 600,920 cancer deaths are projected to occur in the United States. For all sites combined, the cancer incidence rate is 20% higher in men than in women, while the cancer death rate is 40% higher. However, sex disparities vary by cancer type. For example, thyroid cancer incidence rates are 3-fold higher in women than in men (21 vs 7 per 100,000 population), despite equivalent death rates (0.5 per 100,000 population), largely reflecting sex differences in the "epidemic of diagnosis." Over the past decade of available data, the overall cancer incidence rate (2004-2013) was stable in women and declined by approximately 2% annually in men, while the cancer death rate (2005-2014) declined by about 1.5% annually in both men and women. From 1991 to 2014, the overall cancer death rate dropped 25%, translating to approximately 2,143,200 fewer cancer deaths than would have been expected if death rates had remained at their peak. Although the cancer death rate was 15% higher in blacks than in whites in 2014, increasing access to care as a result of the Patient Protection and Affordable Care Act may expedite the narrowing racial gap; from 2010 to 2015, the proportion of blacks who were uninsured halved, from 21% to 11%, as it did for Hispanics (31% to 16%). Gains in coverage for traditionally underserved Americans will facilitate the broader application of existing cancer control knowledge across every segment of the population. CA Cancer J Clin 2017;67:7-30. © 2017 American Cancer Society.
- 42Grasso, C.; Wu, Y.; Robinson, D.; Cao, X.; Dhanasekaran, S.; Khan, A.; Quist, M.; Jing, X.; Lonigro, R.; Brenner, J.; Asangani, I.; Ateeq, B.; Chun, S.; Siddiqui, J.; Sam, L.; Anstett, M.; Mehra, R.; Prensner, J.; Palanisamy, N.; Ryslik, G.; Vandin, F.; Raphael, B.; Kunju, L.; Rhodes, D.; Pienta, K.; Chinnaiyan, A.; Tomlins, S. The mutational landscape of lethal castration-resistant prostate cancer. Nature 2012, 487, 239– 243, DOI: 10.1038/nature1112542https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC38XhtVWisLfP&md5=15b1780d9cd2189325baf4e4fec84687The mutational landscape of lethal castration-resistant prostate cancerGrasso, Catherine S.; Wu, Yi-Mi; Robinson, Dan R.; Cao, Xuhong; Dhanasekaran, Saravana M.; Khan, Amjad P.; Quist, Michael J.; Jing, Xiaojun; Lonigro, Robert J.; Brenner, J. Chad; Asangani, Irfan A.; Ateeq, Bushra; Chun, Sang Y.; Siddiqui, Javed; Sam, Lee; Anstett, Matt; Mehra, Rohit; Prensner, John R.; Palanisamy, Nallasivam; Ryslik, Gregory A.; Vandin, Fabio; Raphael, Benjamin J.; Kunju, Lakshmi P.; Rhodes, Daniel R.; Pienta, Kenneth J.; Chinnaiyan, Arul M.; Tomlins, Scott A.Nature (London, United Kingdom) (2012), 487 (7406), 239-243CODEN: NATUAS; ISSN:0028-0836. (Nature Publishing Group)Characterization of the prostate cancer transcriptome and genome has identified chromosomal rearrangements and copy no. gains and losses, including ETS gene family fusions, PTEN loss and androgen receptor (AR) amplification, which drive prostate cancer development and progression to lethal, metastatic castration-resistant prostate cancer (CRPC). However, less is known about the role of mutations. Here we sequenced the exomes of 50 lethal, heavily pre-treated metastatic CRPCs obtained at rapid autopsy (including three different foci from the same patient) and 11 treatment-naive, high-grade localized prostate cancers. We identified low overall mutation rates even in heavily treated CRPCs (2.00 per megabase) and confirmed the monoclonal origin of lethal CRPC. Integrating exome copy no. anal. identified disruptions of CHD1 that define a subtype of ETS gene family fusion-neg. prostate cancer. Similarly, we demonstrate that ETS2, which is deleted in approx. one-third of CRPCs (commonly through TMPRSS2:ERG fusions), is also deregulated through mutation. Furthermore, we identified recurrent mutations in multiple chromatin- and histone-modifying genes, including MLL2 (mutated in 8.6% of prostate cancers), and demonstrate interaction of the MLL complex with the AR, which is required for AR-mediated signaling. We also identified novel recurrent mutations in the AR collaborating factor FOXA1, which is mutated in 5 of 147 (3.4%) prostate cancers (both untreated localized prostate cancer and CRPC), and showed that mutated FOXA1 represses androgen signaling and increases tumor growth. Proteins that phys. interact with the AR, such as the ERG gene fusion product, FOXA1, MLL2, UTX (also known as KDM6A) and ASXL1 were found to be mutated in CRPC. In summary, we describe the mutational landscape of a heavily treated metastatic cancer, identify novel mechanisms of AR signaling deregulated in prostate cancer, and prioritize candidates for future study.
- 43Gundem, G.; Van, P.; Kremeyer, B.; Alexandrov, L.; Tubio, J.; Papaemmanuil, E.; Brewer, D.; Kallio, H.; Hoegnas, G.; Annala, M.; Kivinummi, K.; Goody, V.; Latimer, C.; O’Meara, S.; Dawson, K.; Isaacs, W.; Emmert-Buck, M.; Nykter, M.; Foster, C.; Kote-Jarai, Z.; Easton, D.; Whitaker, H.; Neal, D.; Cooper, C.; Eeles, R.; Visakorpi, T.; Campbell, P.; McDermott, U.; Wedge, D.; Bova, G. The evolutionary history of lethal metastatic prostate cancer. Nature 2015, 520, 353– 357, DOI: 10.1038/nature14347There is no corresponding record for this reference.
- 44Lorente, D.; Mateo, J.; Perez-Lopez, R.; de, J.; Attard, G. Sequencing of agents in castration-resistant prostate cancer. Lancet Oncol. 2015, 16, 279– 292, DOI: 10.1016/S1470-2045(15)70033-1There is no corresponding record for this reference.
- 45Cornford, P.; Dodson, A.; Parsons, K.; Desmond, A.; Woolfenden, A.; Fordham, M.; Neoptolemos, J.; Ke, Y.; Foster, C. Heat shock protein expression independently predicts clinical outcome in prostate cancer. Cancer Res. 2000, 60, 7099– 7105There is no corresponding record for this reference.
- 46Rocchi, P.; So, A.; Kojima, S.; Signaevsky, M.; Beraldi, E.; Fazli, L.; Hurtado-Coll, A.; Yamanaka, K.; Gleave, M. Heat shock protein 27 increases after androgen ablation and plays a cytoprotective role in hormone-refractory prostate cancer. Cancer Res. 2004, 64, 6595– 6602, DOI: 10.1158/0008-5472.CAN-03-3998There is no corresponding record for this reference.
- 47Jego, G.; Hazoume, A.; Seigneuric, R.; Garrido, C. Targeting heat shock proteins in cancer. Cancer Lett. 2013, 332, 275– 285, DOI: 10.1016/j.canlet.2010.10.01447https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3sXlvVWitLs%253D&md5=4e1dcc15387cbb33d4a2d18f5defdd16Targeting heat shock proteins in cancerJego, Gaetan; Hazoume, Adonis; Seigneuric, Renaud; Garrido, CarmenCancer Letters (New York, NY, United States) (2013), 332 (2), 275-285CODEN: CALEDQ; ISSN:0304-3835. (Elsevier)A review. Heat shock proteins (HSPs) HSP27, HSP70 and HSP90 are powerful chaperones. Their expression is induced in response to a wide variety of physiol. and environmental insults including anti-cancer chemotherapy, thus allowing the cell to survive to lethal conditions. Different functions of HSPs have been described to account for their cytoprotective function, including their role as mol. chaperones as they play a central role in the correct folding of misfolded proteins, but also their anti-apoptotic properties. HSPs are often overexpressed in cancer cells and this constitutive expression is necessary for cancer cells' survival. HSPs may have oncogene-like functions and likewise mediate "non-oncogene addiction" of stressed tumor cells that must adapt to a hostile microenvironment, thereby becoming dependent for their survival on HSPs. HSP-targeting drugs have therefore emerged as potential anti-cancer agents. This review describes the different mols. and approaches being used or proposed in cancer therapy based on the in inhibition of HSP90, HSP70 and HSP27.
- 48Wei, T.; Chen, C.; Liu, J.; Liu, C.; Posocco, P.; Liu, X.; Cheng, Q.; Huo, S.; Liang, Z.; Fermeglia, M.; Pricl, S.; Liang, X.; Rocchic, P.; Peng, L. Anticancer drug nanomicelles formed by self-assembling amphiphilic dendrimer to combat cancer drug resistance. Proc. Natl. Acad. Sci. U. S. A. 2015, 112, 2978– 2983, DOI: 10.1073/pnas.141849411248https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2MXjtFemur4%253D&md5=ba3fcc69507c6da884cfeeabd95fb782Anticancer drug nanomicelles formed by self-assembling amphiphilic dendrimer to combat cancer drug resistanceWei, Tuo; Chen, Chao; Liu, Juan; Liu, Cheng; Posocco, Paola; Liu, Xiaoxuan; Cheng, Qiang; Huo, Shuaidong; Liang, Zicai; Fermeglia, Maurizio; Pricl, Sabrina; Liang, Xing-Jie; Rocchi, Palma; Peng, LingProceedings of the National Academy of Sciences of the United States of America (2015), 112 (10), 2978-2983CODEN: PNASA6; ISSN:0027-8424. (National Academy of Sciences)Drug resistance and toxicity constitute challenging hurdles for cancer therapy. The application of nanotechnol. for anticancer drug delivery is expected to address these issues and bring new hope for cancer treatment. In this context, we established an original nanomicellar drug delivery system based on an amphiphilic dendrimer (AmDM), which could generate supramol. micelles to effectively encapsulate the anticancer drug doxorubicin (DOX) with high drug-loading capacity (>40%), thanks to the unique dendritic structure creating large void space for drug accommodation. The resulting AmDM/DOX nanomicelles were able to enhance drug potency and combat doxorubicin resistance in breast cancer models by significantly enhancing cellular uptake while considerably decreasing efflux of the drug. In addn., the AmDM/DOX nanoparticles abolished significantly the toxicity related to the free drug. Collectively, our studies demonstrate that the drug delivery system based on nanomicelles formed with the self-assembling amphiphilic dendrimer constitutes a promising and effective drug carrier in cancer therapy.
- 49Posocco, P.; Liu, X.; Laurini, E.; Marson, D.; Chen, C.; Liu, C.; Fermeglia, M.; Rocchi, P.; Pricl, S.; Peng, L. Impact of siRNA overhangs for dendrimer-mediated siRNA delivery and gene silencing. Mol. Pharmaceutics 2013, 10, 3262– 3273, DOI: 10.1021/mp400329g49https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3sXhtVyjur%252FI&md5=bc7721f224b9006c6e075bf8a0ff401fImpact of siRNA Overhangs for Dendrimer-Mediated siRNA Delivery and Gene SilencingPosocco, Paola; Liu, Xiaoxuan; Laurini, Erik; Marson, Domenico; Chen, Chao; Liu, Cheng; Fermeglia, Maurizio; Rocchi, Palma; Pricl, Sabrina; Peng, LingMolecular Pharmaceutics (2013), 10 (8), 3262-3273CODEN: MPOHBP; ISSN:1543-8384. (American Chemical Society)Small interfering RNA (siRNA) have attracted considerable attention, as compelling therapeutics providing safe and competent delivery systems are available. Dendrimers are emerging as appealing siRNA delivery vectors thanks to their unique, well-defined architecture and the resulting cooperativity and multivalency confined within a nanostructure. We have recently disclosed the structurally flexible fifth-generation TEA-core PAMAM dendrimer (G5) as an effective nanocarrier for delivery of sticky siRNA bearing long complementary sequence overhangs (dA)n/(dT)n (n = 5 or 7). Here, using combined exptl./computational approaches, we successfully clarified (i) the underlying mechanisms of interaction between the dendrimer nanovector G5 and siRNA mols. bearing either complementary or noncomplementary sequence overhangs of different length and chem. and (ii) the impact of siRNA overhangs contributing toward the improved delivery potency. Using siRNA with complementary overhangs offer the best action in term of gene silencing through the formation of concatemers, i.e., supramol. structures resulting from synergistic and cooperative binding via (dA)n/(dT)n bridges (n = 5 or 7). On the other hand, although siRNA bearing long, noncomplementary overhangs (dA)n/(dA)n or (dT)n/(dT)n (n = 5 or 7) are endowed with considerably higher gene silencing potency than normal siRNA with (dT)2/(dT)2, they remain less effective than their sticky siRNA counterparts. The obsd. gene silencing potency depends on length, nature, and flexibility of the overhangs, which behave as a sort of clamps that hold and interact with the dendrimer nanovectors, thus impacting siRNA delivery performance and, ultimately, gene silencing. Our findings can be instrumental in designing siRNA entities with enhanced capability to achieve effective RNA interference for therapeutic applications.
- 50Albanyan, B.; Laurini, E.; Posocco, P.; Pricl, S.; Smith, D. Self-assembled multivalent (SAMul) polyanion binding—impact of hydrophobic modifications in the micellar core on DNA and heparin binding at the peripheral cationic ligands. Chem. - Eur. J. 2017, 23, 6391– 6397, DOI: 10.1002/chem.20170017750https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2sXlvVCgsLk%253D&md5=e971234081cca25156b7bcde61149d98Self-Assembled Multivalent (SAMul) Polyanion Binding-Impact of Hydrophobic Modifications in the Micellar Core on DNA and Heparin Binding at the Peripheral Cationic LigandsAlbanyan, Buthaina; Laurini, Erik; Posocco, Paola; Pricl, Sabrina; Smith, David K.Chemistry - A European Journal (2017), 23 (26), 6391-6397CODEN: CEUJED; ISSN:0947-6539. (Wiley-VCH Verlag GmbH & Co. KGaA)This paper reports a small family of cationic surfactants designed to bind polyanions such as DNA and heparin. Each mol. has the same hydrophilic cationic ligand and a hydrophobic aliph. group with eighteen carbon atoms with one, two, or three alkene groups within the hydrophobic chain (C18-1, C18-2 and C18-3). Dynamic light scattering indicates that more alkenes lead to geometric distortion, giving rise to larger self-assembled multivalent (SAMul) nanostructures. Mallard Blue and Ethidium Bromide dye displacement assays demonstrate that heparin and DNA have markedly different binding preferences, with heparin binding most effectively to C18-1, and DNA to C18-3, even though the mol. structural differences of these SAMul systems are buried in the hydrophobic core. Multiscale modeling suggests that adaptive heparin maximises enthalpically favorable interactions with C18-1, while shape-persistent DNA forms a similar no. of interactions with each ligand display, but with slightly less entropic cost for binding to C18-3-fundamental thermodn. differences in SAMul binding of heparin or DNA. This study therefore provides unique insight into electrostatic mol. recognition between highly charged nanoscale surfaces in biol. relevant systems.
- 51Fechner, L.; Albanyan, B.; Vieira, V.; Laurini, E.; Posocco, P.; Pricl, S.; Smith, D. Electrostatic binding of polyanions using self-assembled multivalent (SAMul) ligand displays - structure-activity effects on DNA/heparin binding. Chem. Sci. 2016, 7, 4653– 4659, DOI: 10.1039/C5SC04801J51https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC28Xms1Kks7o%253D&md5=2663d127c7871258d0687f089ec63624Electrostatic binding of polyanions using self-assembled multivalent (SAMul) ligand displays - structure-activity effects on DNA/heparin bindingFechner, Loryn E.; Albanyan, Buthaina; Vieira, Vania M. P.; Laurini, Erik; Posocco, Paola; Pricl, Sabrina; Smith, David K.Chemical Science (2016), 7 (7), 4653-4659CODEN: CSHCCN; ISSN:2041-6520. (Royal Society of Chemistry)This paper reports that modifying the ligands in self-assembled multivalent (SAMul) displays has an impact on apparent binding selectivity towards two nanoscale biol. polyanions - heparin and DNA. For the nanostructures assayed here, spermidine ligands are optimal for heparin binding but spermine ligands are preferred for DNA. Probing subtle differences in such nanoscale binding interfaces is a significant challenge, and as such, several exptl. binding assays - competition assays and isothermal calorimetry - are employed to confirm differences in affinity and provide thermodn. insights. Given the dynamic nature and hierarchical binding processes involved in SAMul systems, we employed multiscale modeling to propose reasons for the origins of polyanion selectivity differences. The modeling results, when expressed in thermodn. terms and compared with the exptl. data, suggest that DNA is a shape-persistent polyanion, and selectivity originates only from ligand preferences, whereas heparin is more flexible and adaptive, and as such, actively reinforces ligand preferences. As such, this study suggests that inherent differences between polyanions may underpin subtle binding selectivity differences, and that even simple electrostatic interfaces such as these can have a degree of tunability, which has implications for biol. control and regulation on the nanoscale.
- 52Qi, C.; Su, Y.; Peng, Y.; Tian, E.; Sun, G.; Zhou, J.; Sun, G.; Liu, X.; Chao, C.; Murai, K.; Zhao, C.; Azizian, K.; Yang, L.; Warden, C.; Wu, X.; D’Apuzzo, M.; Brown, C.; Badie, B.; Peng, L.; Riggs, D.; Rossi, J.; Shi, Y. Downregulation of TLX induces TET3 expression and inhibits glioblastoma stem cell self-renewal and tumorigenesis. Nat. Commun. 2016, 7, 10637– 10651, DOI: 10.1038/ncomms10637There is no corresponding record for this reference.
Supporting Information
Supporting Information
The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/jacs.8b10021.
Materials and methods as well as all experimental protocols for TEM, DLS, computational details, ITC, cell uptake and endosome release, siRNA delivery, gene silencing, anticancer activity and toxicity, etc. (PDF)
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