Studies on Optimizing Delivery of Chemotherapeutics: from Informing in silico Drug Delivery Models to Developing Therapeutic Regimens to Overcome Hypoxia-mediated Resistance

The first part of the dissertation focuses on developing an experimentally-informed in silico tool to enable optimum design of nanocarriers’ properties for delivery of chemotherapy to solid tumors. We postulate that one of the major reasons contributing to the failure of successfully managing solid tumor growth is primarily the heterogeneous spatiotemporal microdistributions of ttherapeutics within the tumor volume; significant areas are left not being (adequately) exposed to therapeutics and, therefore, are likely not being killed. We showed that, the efficacy of a drug-carrier system is determined as the combined result of different processes, namely, transport, binding, drug release and drug availability at the active site(s). Parameters obtained by fitting the processes (binding, internalization, trafficking, release, killing etc.) to rate laws were used to experimentally inform the mathematical model. Since the focus of this study is on established tumors which develop acidic interstitial regions, in several of the processes mentioned above, parameters were found to be a function of the local pH. The developed tool is intended to serve as a guide to reduce the number of iterations in designing novel carrier systems. Using nanocarriers with properties chosen from the first part of the study, the second part of the dissertation focuses on overcoming the challenges in treating TNBCs arising due to the development of hypoxia. In vitro, on hypoxic TNBC cells cultured on monolayers, we demonstrated that cisplatin, a first line chemotherapy for TNBC, was still effective against these cells but at greater concentrations. We demonstrated that the diffusion-limited transport within spheroids favored the development of hypoxic conditions in their interstitium. We utilized TNBC cells with a permanent hypoxia fate-mapping switch to evaluate the effect of cisplatin’s dosing level, rate and/or dose scheduling on the growth and migration of normoxic and of hypoxic TNBC cells. We showed that the delivery carriers of cisplatin that enabled (1) fast exposure of cells to greater levels of therapy, and (2) uniform intra-tumoral micro distributions of the chemotherapeutic, resulted in greater extents of cell kill and in lower cell motility (migration potential) of both the hypoxic and the normoxic cell populations