Combination anticancer nanopreparations of novel proapoptotic drug and siRNA The current project is an integral part of our CCNE proposal which aims to develop, characterize in vitro, test in animal models, and scale up in an industrial setting a broad set of novel multifuncfional nanocarriers for targeted delivery of various drugs including DNA, siRNA, and diagnostic agents to solid tumors in vivo for the purposes of cancer therapy and diagnostics, especially for multidrug resistant (MDR) tumors. Within the general program, this proposal will cover a combination nanopreparations containing a novel, powerful proapoptotic agent, siRNA [to downregulate cancer cell defense mechanisms (such as Pgp)], and Tumor necrosis factor-Related Apoptosis-inducing Ligand (TRAIL), a cytokine of the TNFa family, a novel promising, selective anti-cancer agent. This combination micellar preparation will be addifionally modified with a tumor-specific targeting antibody (for systemic administration) or with the cell-penetrating TAT peptide (TATp) for intratumoral administration). Our proposal is based on several interrelated challenges. First, effective therapy of a cancer, especially in the case of MDR tumors sfill represents an important medical need. Second, many newly discovered or synthesized proapoptofic anticancer agents, which could serve as an effective means to treat cancer in combination with TRIAL by upregulating apopototic mechanisms in cancer cells, cannot now serve as practical drugs because of their poor solubility and low stability in vivo. Third, siRNAs (that downregulate tumor defense mechanisms) have very low stability in the body and multiple delivery problems. We propose to overcome these challenges by formulafing a combination of new agents into self-assembling pharmaceutical nanocarriers (lipid-core micelles) specifically targeted to and into cancer cells. Such formulafions will allow for an efficient solubilizafion of a pooriy soluble proapoptofic drug, stabilization of the drug or a siRNA in the body, and their efficient co-delivery together with TRIAL into targeted tumors. Thus, within the overarching organizing framework, this proposal will provide multifunctional micellar combinations of nanopreparations to specifically deliver a proapoptotic drug, a siRNA, and TRIAL to various tumors, particularly, to MDR tumors.

Public Health Relevance

This project addresses a well-known limitation on tumor drug treatment and imaging of a diagnosed tumor: the inability to get sufficient anti-cancer drug to a well-defined target. This project's complefion will generate effective drug carriers that will make possible clinical application of known anti-cancer agents and provide the means for the rapid clinical development of highly effective therapeutic anti-cancer agents.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Specialized Center--Cooperative Agreements (U54)
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Special Emphasis Panel (ZCA1-GRB-S)
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Northeastern University
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Petrenko, Valery A; Gillespie, James W (2017) Paradigm shift in bacteriophage-mediated delivery of anticancer drugs: from targeted 'magic bullets' to self-navigated 'magic missiles'. Expert Opin Drug Deliv 14:373-384
Pattni, Bhushan S; Jhaveri, Aditi; Dutta, Ivy et al. (2017) Targeting energy metabolism of cancer cells: Combined administration of NCL-240 and 2-DG. Int J Pharm 532:149-156
Singh, Amit; Xu, Jing; Mattheolabakis, George et al. (2016) EGFR-targeted gelatin nanoparticles for systemic administration of gemcitabine in an orthotopic pancreatic cancer model. Nanomedicine 12:589-600
Su, Mei-Ju; Aldawsari, Hibah; Amiji, Mansoor (2016) Pancreatic Cancer Cell Exosome-Mediated Macrophage Reprogramming and the Role of MicroRNAs 155 and 125b2 Transfection using Nanoparticle Delivery Systems. Sci Rep 6:30110
Sriraman, Shravan Kumar; Pan, Jiayi; Sarisozen, Can et al. (2016) Enhanced Cytotoxicity of Folic Acid-Targeted Liposomes Co-Loaded with C6 Ceramide and Doxorubicin: In Vitro Evaluation on HeLa, A2780-ADR, and H69-AR Cells. Mol Pharm 13:428-37
Gillespie, James W; Wei, Lixia; Petrenko, Valery A (2016) Selection of Lung Cancer-Specific Landscape Phage for Targeted Drug Delivery. Comb Chem High Throughput Screen 19:412-22
Patel, Niravkumar R; Piroyan, Aleksandr; Nack, Abbegial H et al. (2016) Design, Synthesis, and Characterization of Folate-Targeted Platinum-Loaded Theranostic Nanoemulsions for Therapy and Imaging of Ovarian Cancer. Mol Pharm 13:1996-2009
Zhang, Yilin; Sriraman, Shravan Kumar; Kenny, Hilary A et al. (2016) Reversal of Chemoresistance in Ovarian Cancer by Co-Delivery of a P-Glycoprotein Inhibitor and Paclitaxel in a Liposomal Platform. Mol Cancer Ther 15:2282-2293
Han, Lei; Liu, Pei; Petrenko, Valery A et al. (2016) A Label-Free Electrochemical Impedance Cytosensor Based on Specific Peptide-Fused Phage Selected from Landscape Phage Library. Sci Rep 6:22199
Sriraman, Shravan Kumar; Salzano, Giusseppina; Sarisozen, Can et al. (2016) Anti-cancer activity of doxorubicin-loaded liposomes co-modified with transferrin and folic acid. Eur J Pharm Biopharm 105:40-9

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