451087 Modeling: A Tool for Experimentalists. Design, Synthesis and Evaluation of Self-Assembling Dendrons for Gene/Drug Delivery
1) Anticancer drug nanomicelles formed by self-assembling amphiphilic dendrimer able to overcome drug resistance in cancer cell 
Drug resistance and toxicity constitute challenging hurdles for cancer therapy. The application of nanotechnology 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 supramolecular micelles to effectively encapsulate the anticancer drug doxorubicin (DOX) with high drug-loading capacity (>40%). The resulting AmDM/DOX nanomicelles were able to enhance drug potency and contrast doxorubicin resistance in breast cancer models by significantly enhancing cellular uptake while considerably decreasing efflux of the drug. In addition, 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.
2) Chameleon self-assembling nanovectors for efficient siRNA delivery in vitro and in vivo 
Small interfering RNA (siRNA) delivery remains a major challenge in RNAi-based therapy. Through the combined action of in silico/experimental efforts, we designed and produced for the first time an amphiphilic dendrimer AD able to self-assemble into adaptive supramolecular assemblies upon interaction with siRNA. The resulting nanovectors can effectively deliver siRNAs to various cell lines, including human primary and stem cells, thereby outperforming the currently available non-viral vectors. Most importantly, however, AD-mediated gene silencing was successfully achieved also in vivo.
 P. Posocco, E. Laurini, V. Dal Col, D. Marson, K. Karatasos, M. Fermeglia and S. Pricl, “Tell me something that I do not know. Multiscale molecular modeling of dendrimer/dendron organization and self-assembly for gene therapy,” Curr. Med. Chem., vol. 19, pp. 5062-5087, 2012.
 T. Wei, C. Chen, J. Liu, C. Liu, P. Posocco, X. Liu Q. Cheng, S. Huo, Z. Liang, M. Fermeglia, S. Pricl, X. J.Liang, P. Rocchi, L. Peng, “Anticancer drug nanomicelles formed by self-assembling amphiphilic dendrimer to combat cancer drug resistance,” Proc. Natl. Acad. Sci. USA, vol. 112, pp. 2978-2983. 2015.
 D. Marson, E. Laurini, P. Posocco, M. Fermeglia, S. Pricl, “Cationic carbosilane dendrimers and oligonucleotide binding: an energetic affair,” Nanoscale, 7, pp. 3876-87, 2015.
 X. Liu, J. Zhou, T. Yu, C. Chen, Q. Cheng, K. Sengupta, Y. Huang, H. Li, C. Liu, Y. Wang, P. Posocco, M. Wang, Q. Cui, S. Giorgio, M. Fermeglia, F. Qu, S. Pricl, Y. Shi, Z. Liang, P. Rocchi, J. J. Rossi, L. Peng, “Adaptive amphiphilic dendrimer-based nanoassemblies as robust and versatile siRNA delivery systems,” Angew. Chem. Int. Ed. Engl., vol. 53, pp. 11822-11827, 2014.
 S. Kala, A. S. Mak, X. Liu, P. Posocco, S. Pricl, L. Peng, A. S. Wong, “Combination of dendrimer-nanovector-mediated small interfering RNA delivery to target Akt with the clinical anticancer drug paclitaxel for effective and potent anticancer activity in treating ovarian cancer,” J. Med. Chem., vol. 57, pp. 2634-42, 2014.
 P. Posocco, X. Liu, E. Laurini, D. Marson, C. Chen, C. Liu, M. Fermeglia, P. Rocchi, S. Pricl, L. Peng, “Impact of siRNA overhangs for dendrimer-mediated siRNA delivery and gene silencing,” Mol. Pharm., vol. 10, pp. 3262-3273, 2013.
 X. Liu, C. Liu, E. Laurini, P. Posocco, S. Pricl, F. Qu, P. Rocchi, L. Peng, “Efficient delivery of sticky siRNA and potent gene silencing in a prostate cancer model using a generation 5 triethanolamine-core PAMAM dendrimer,” Mol. Pharm., vol. 9, 470-81, 2012.
 X. Liu, J. Wu, M. Yammine, J. Zhou, P. Posocco, S. Viel, C. Liu, F. Ziarelli, M. Fermeglia, S. Pricl, G. Victorero, C. Nguyen, P. Erbacher, J. P. Behr, L. Peng, “Structurally flexible triethanolamine core PAMAM dendrimers are effective nanovectors for DNA transfection in vitro and in vivo to the mouse thymus,” Bioconjug. Chem., vol. 22, 2461-2473, 2011.
 A. Barnard, P. Posocco, S. Pricl, M. Calderon, R. Haag, M. E. Hwang, V. M. Shum, D. W. Pack, D. K. Smith, “Degradable self-assembling dendrons for gene delivery: experimental and theoretical insights into the barriers to cellular uptake,” J. Am. Chem. Soc., vol. 133, pp. 20288-20300, 2011.
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