Intracellular Delivery of Cancer-Targeting Antibody-Drug Conjugates

Thesis (Ph.D.)--University of Washington, 2013The use of cancer targeted antibody-drug conjugates aims to reduce the adverse affects of current therapies by selectively seeking and destroying tumor cells. Current systems employ targeted monoclonal antibodies conjugated to chemotoxins which have good cancer cell specificity, but suffer from early decomposition, normal tissue exposure, and limited drug potency in solid tumors. An alternative to chemotherapeutics is the use of proapoptotic peptides that reach the cystosol for action with enhanced specificity and activity in the most chemoresistant cancer cells. {\bf The overall goal of our research is to develop a cancer-targeted intracellular delivery vehicle using monoclonal antibodies for targeting, pH-responsive polymers for endosomal escape, and proapoptotic peptides for cell death.} The ability of pH-responsive polymers to alter the endosomal/lysosomal trafficking pathway of antibodies was evaluated by ratiometric fluorescence and subcellular fractionation studies. A novel diblock copolymer that self-assembles into micelles was developed to address micelle stability, in vivo circulation, and therapeutic activity both in several cancer cell lines, and activity in a tumor-xenograft mouse model