Drug Resistance in Cancer Therapy

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DESCRIPTION (provided by applicant): This aim of this exploratory proposal is to investigate the efficacy of our recently developed nanoparticle formulation to overcome the problem of drug resistance in cancer therapy. Modified nanoparticles are seen to localize in and around the nucleus following their cellular uptake and are retained inside the cells i.e. they do not undergo exocytosis. Hence, it is hypothesized that modified nanoparticles would deliver the encapsulated drug directly to the nucleus without its exposure to the membrane-bound efflux transporters and cytoplasmic factors (e.g., degradation or accumulation of drug in acidic vesicles) that limit the nuclear delivery of antineoplastic agents in resistant cells. Hence, direct nuclear delivery of the drug using modified nanoparticles would overcome the problem of drug resistance and hence the therapy would be more effective in tumor regression. We will use doxorubicin as a model antineoplastic agent because it acts by intercalating with the nuclear DNA. To test the above hypothesis, we will measure the antiproliferative activity (IC50) of the drug in normal and drug resistant breast cancer cell lines and also determine drug levels in various intracellular compartments (nucleus, cytoplasm, endo-lysosomes) to understand the mechanism of greater drug efficacy with modified nanoparticles. To test the suitability of modified nanoparticles for in vivo administration, we will study their biocompatibility, biodistribution, and then determine their efficacy for tumor regression in a murine model of breast cancer progression via intravenous administration. The specific aims of the proposal are: 1) to test the hypothesis that modified nanoparticles are effective in targeting doxorubicin to the nucleus, and hence in overcoming the problem of drug resistance and 2) to demonstrate that modified nanoparticles are effective in tumor regression in a murine model of breast cancer induced using sensitive (MCF-7) and resistant (MCF-7/Adr) cells. The nanoparticle formulation investigated in this proposal could be used as an effective delivery mechanism for several classes of therapeutics for which the target is nucleus.