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 multifunctional 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 additionally 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 still represents an important medical need. Second, many newly discovered or synthesized proapoptotic 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 formulating a combination of new agents into self-assembling pharmaceutical nanocarriers (lipid-core micelles) specifically targeted to and into cancer cells. Such formulations will allow for an efficient solubilization of a poorly soluble proapoptotic 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.
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 completion 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.
|Essex, S; Navarro, G; Sabhachandani, P et al. (2015) Phospholipid-modified PEI-based nanocarriers for in vivo siRNA therapeutics against multidrug-resistant tumors. Gene Ther 22:257-66|
|Abouzeid, Abraham H; Patel, Niravkumar R; Torchilin, Vladimir P (2014) Polyethylene glycol-phosphatidylethanolamine (PEG-PE)/vitamin E micelles for co-delivery of paclitaxel and curcumin to overcome multi-drug resistance in ovarian cancer. Int J Pharm 464:178-84|
|Xu, Jing; Singh, Amit; Amiji, Mansoor M (2014) Redox-responsive targeted gelatin nanoparticles for delivery of combination wt-p53 expressing plasmid DNA and gemcitabine in the treatment of pancreatic cancer. BMC Cancer 14:75|
|Perche, F; Biswas, S; Wang, T et al. (2014) Hypoxia-targeted siRNA delivery. Angew Chem Int Ed Engl 53:3362-6|
|Zhu, Lin; Perche, Federico; Wang, Tao et al. (2014) Matrix metalloproteinase 2-sensitive multifunctional polymeric micelles for tumor-specific co-delivery of siRNA and hydrophobic drugs. Biomaterials 35:4213-22|
|Bedi, Deepa; Gillespie, James W; Petrenko, Valery A (2014) Selection of pancreatic cancer cell-binding landscape phages and their use in development of anticancer nanomedicines. Protein Eng Des Sel 27:235-43|
|Sarisozen, Can; Abouzeid, Abraham H; Torchilin, Vladimir P (2014) The effect of co-delivery of paclitaxel and curcumin by transferrin-targeted PEG-PE-based mixed micelles on resistant ovarian cancer in 3-D spheroids and in vivo tumors. Eur J Pharm Biopharm 88:539-50|
|Torchilin, Vladimir P (2014) Multifunctional, stimuli-sensitive nanoparticulate systems for drug delivery. Nat Rev Drug Discov 13:813-27|
|Kommagalla, Yadagiri; Cornea, Sinziana; Riehle, Robert et al. (2014) Optimization of the anti-cancer activity of phosphatidylinositol-3 kinase pathway inhibitor PITENIN-1: switching a thiourea with 1,2,3-triazole. Medchemcomm 5:1359-1363|
|Ganta, Srinivas; Singh, Amit; Patel, Niravkumar R et al. (2014) Development of EGFR-targeted nanoemulsion for imaging and novel platinum therapy of ovarian cancer. Pharm Res 31:2490-502|
Showing the most recent 10 out of 38 publications