Nanotechnology-based Strategies To Enhance Chemo-and Radiation Therapy In Breast Cancer

A major cause of cancer treatment failure is multidrug resistance (MDR) and radioresistance to standard therapies. Overexpression of ATP-binding cassette (ABC) transport proteins by cancer cells, which actively transport anti-cancer agents (e.g. doxorubicin, Dox) out of the cells against concentration gradients, is a major barrier to effective chemotherapy. Low levels of oxygen in tumors are responsible for radioresistance contributing to the failure of radiation therapy (RT) of solid tumors. This thesis concerns the development and evaluation of three nanoparticle delivery systems for overcoming tumor resistance to chemo- and radiotherapy. System 1: polymer lipid hybrid nanoparticles (PLN), co-loaded with a synergistic combination of anticancer agents Dox and mitomycin C (MMC) (DMsPLN), were found to overcome multiple membrane efflux pumps mediated MDR in vitro. Systemic administration of DMsPLN significantly enhanced therapeutic efficacy in orthotopic tumor models of Dox-sensitive and resistant human breast cancer cells, with low systemic toxicity compared to a clinically used liposomal formulation of Dox. System 2: cyclic Arg-Gly-Asp (RGD), a ligand that binds with αvβ3 intergin receptors preferentially expressed in angiogenic tumor blood vessels and certain cancer cells, was conjugated to DMsPLN. The Integrin-targeted RGD-DMsPLN resulted in a significant reduction in lung metastases of human breast cancer cells without producing drug-associated systemic toxicity as observed in mice treated with free Dox-MMC solutions. System 3: Manganese dioxide nanoparticles (MnO2 NPs) were developed and the reactivity of MnO2 towards peroxides was utilized to regulate the tumor microenvironment in a murine breast tumor. Intratumoral administration of MnO2 NPs simultaneously increased tumor oxygenation by 45%, and tumor pH from pH 6.7 to pH 7.2 by reacting with endogenous H2O2 produced within the tumor. Combination treatment of the tumors with NPs and ionizing radiation significantly inhibited breast tumor growth, increased DNA double strand breaks and cancer cell death as compared to RT alone. The design and application of these three novel nanotechnology platforms, in pharmaceutically acceptable NP formulations, provide promising therapeutic strategies for enhanced chemo- and radiation therapy of breast cancer.Ph.D.2016-11-30 00:00:0