Microtechnologies for mimicking tumor-imposed transport limitations and developing targeted cancer therapies

Intravenously delivered cancer drugs face transport limitations at the tumor site and cannot reach all parts of tumors at therapeutically effective concentrations. Transport limitations also prevent oxygen from distributing evenly in tumors resulting in hypoxia, which plays a critical role in cancer progression. In this dissertation, I present the development of micro-devices that mimic transport limitations of drugs and nutrients on three dimensional tumor tissues, enable visualization and quantification of the ensuing gradients, and enable simple analysis and mathematical modeling of obtained data. To measure the independent effects of oxygen gradients on tumor tissues, an oxygen delivery device that used microelectrodes to generate oxygen directly underneath three-dimensional tumor cylindroids was developed. Supplying oxygen for 60 hours eliminated the necrotic region typically found in the center of cylindroids. Dead cells were observed moving away from the location of oxygen delivery. These measurements show that oxygen gradients are an important determinant of cell viability and rearrangement. Another micro-device was developed to mimic the delivery and systemic clearance of therapeutic agents. This microfluidic device consisted of cuboidal tumor tissue subjected to continuous medium perfusion along one face. The device was used to measure the spatiotemporal dynamics of the accumulation of therapeutic bacteria in tumors. Suspensions of Salmonella typhimurium and Escherichia coli strains were delivered to tumor tissues for 1 hour. Bacterial motility strongly correlated (R2 = 99.3%) with the extent of tissue accumulation. Based on spatio-temporal profiles and a mathematical model of motility and growth, bacterial dispersion was found to be necessary for deep penetration into tissue. These results show that motility is critical for effective distribution of bacteria in tumors. The microfluidic device was further used to mimic the delivery and clearance of equal concentrations of doxorubicin and liposome-encapsulated doxorubicin (Doxil). A pharmacokinetic/pharmacodynamic model incorporating mechanisms of tissue-level diffusion and binding was developed and experimental data was fit to this model. Doxorubicin was found to have the optimal diffusivity and binding for maximizing therapeutic effect. Doxil was severely limited by low intratumor drug release. These results show that in-vitro models mimicking tissue-level transport limitations more accurately predict the therapeutic response of drugs