Targeting Tumor Hypoxia with Potent Vascular Disrupting Agents

Abstract

Current therapeutic methods highlight the use of vascular disrupting agents (VDAs) in anti-cancer therapy. Through a binding interaction with the colchicine binding site on beta-tubulin, VDAs function as inhibitors of tubulin polymerization, resulting in morphological changes to the endothelial cells lining tumor-feeding vessels, which selectively disrupts blood flow to tumors and results in tumor necrosis. An active area of research inquiry centers on methods to further enhance selectivity of therapeutic agents and strategies towards tumors and targets within the tumor microenvironment, including vasculature. Bioreductively activatable prodrug conjugates (BAPCs) represent one such strategy. BAPCs utilize potent anti-cancer agents as prodrugs to selectively target tumor hypoxia. In order to reduce toxicity and enhance targeting, VDAs are coupled with bioreductive triggers to mask the ability of the resultant BAPCs to interact with the tubulin-microtubule protein system. Under hypoxic conditions which are inherent to many solid tumor cancers, the trigger compounds are cleaved, thus releasing the cytotoxic VDAs site-specific to the tumor. Synthetic pathways for these BAPCs have been developed to effectively couple highly active VDAs with bioreductive triggers.