DUAL-AGENT NANOPARTICLES TO OVERCOME DRUG RESISTANCE

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DESCRIPTION (provided by applicant): Overexpression of drug transporters, drug metabolizing enzymes, anti-apoptotic factors or other cellular proteins results in the development of drug resistance. Lack of an effective and safe approach to overcome drug resistance is a critical problem, because, until such an approach is available, it will not be possible to develop effective therapies for drug-resistant tumors. The long-term goal is to enable the effectiveness of drugs against drug-resistant tumors through the use of nanoparticles capable of targeting desired therapies to the tumor tissue. The objective of this R21 grant application is to acquire advanced preliminary data regarding the efficacy of simultaneous gene silencing and drug delivery using biodegradable nanoparticles to overcome drug resistance. Two cellular proteins (P-glycoprotein and Heat shock protein 70) that contribute to the development of drug resistance will be targeted for gene silencing. The central hypothesis of the proposed research is that dual-agent nanoparticles will sustain the cellular delivery of siRNA and paclitaxel, resulting in enhanced paclitaxel accumulation and cytotoxicity, and ultimately, regression of resistant tumor. The rationale for the proposed research is that, once the preliminary data demonstrating the efficacy of nanoparticles is acquired, subsequent definitive investigations on nanoparticle-mediated dual-therapy approach will ensue. The specific aims of the proposed research are to (1) Formulate dual-agent nanoparticles that demonstrate sustained cytotoxicity, (2) Determine kinetics of tumor-targeting with dual-agent nanoparticles in vivo, and (3) Establish the in vivo anti-tumor efficacy of dual-agent nanoparticles. In aim 1, the effect of dose of siRNA and paclitaxel released from nanoparticles on cytotoxicity in MDR tumor cells will be determined in vitro. In aim 2, kinetics of nanoparticle accumulation in tumor tissue following intravenous administration of nanoparticles formulations will be determined in a mouse xenograft tumor model. In aim 3, dose-dependency of tumor regression with dual-agent nanoparticles will be determined in a mouse model of resistant tumor. The proposed studies are significant, because they are expected to provide the foundation for subsequent definitive studies of the therapeutic efficacy of dual-agent nanoparticles against tumor drug resistance. Chemotherapy resistance is a frequent phenomenon in cancer cells. The significance of this problem is highlighted by the estimations that up to 500,000 new cases of cancer each year will eventually exhibit drug-resistant phenotype. The proposed research is expected to positively affect human health, because, it is expected to lead to the development of an effective approach for the treatment of drug resistant tumors.