| The main goal of this dissertation project is to develop and evaluate a novel approach to overcome the multidrug resistance in lung cancer cells/ tumors using a combination therapeutic strategy that involves silencing multidrug resistance genes and augmenting the efficacy of a chemotherapeutic agent. Currently, one of the most challenging aspects of lung cancer therapy is the rapid acquisition of multidrug resistant (MDR) phenotype. MDR develops due to multiple factors that include poor systemic drug delivery efficiency, inefficient drug residence at the tumor site, poor intracellular availability and micro environmental selection pressures that allow certain cells to survive despite aggressive chemotherapy. Although, the RNA interference therapy has emerged as a powerful strategy to down-regulate key genes, the intracellular delivery of siRNA to specific tumor site is still a major challenge that needs to be overcome before this experimental technique can be routinely used as a clinically-viable therapeutic strategy for lung cancer patients. To address this need, in the current study, a self-assembled hyaluronic acid nanoparticle system is designed with different functional blocks that are expected to circulate longer and specifically reaches the tumor cell by receptor mediated endocytosis via its receptors that are over expressed in the tumor cell surface. With efficient delivery of siRNA directed against MDR genes using the HA based nanoparticle system described, the reversal of drug resistance and enhancement of sensitivity to chemotherapeutic drugs was achieved. Anti-MDR strategies may thus show the highest clinical efficacy when administered in combination with conventional chemotherapeutic regimens. |
