Fabrication of a Polymeric Inhibitor of Proximal Metabolic Enzymes in Hypoxia for Synergistic Inhibition of Cancer Cell Proliferation, Survival, and Migration.

Since conventional molecular targeted drugs often result in side effects, the development of novel molecular targeted drugs with both high efficacy and selectivity is desired. Simultaneous inhibition of metabolically and spatiotemporally related proteins/enzymes is a promising strategy for improving therapeutic interventions in cancer treatment. Herein, we report a poly-α-l-glutamate-based polymer inhibitor that simultaneously targets proximal transmembrane enzymes under hypoxia, namely, carbonic anhydrase IX (CAIX) and zinc-dependent metalloproteinases. A polymer incorporating two types of inhibitors more effectively inhibited the proliferation and migration of human breast cancer cells than a combination of two polymers functionalized exclusively with either inhibitor. Synergistic inhibition of cancer cells would occur owing to the hetero-multivalent interactions of the polymer with proximate enzymes on the cancer cell membrane. Our results highlight the potential of polymer-based cancer therapeutics.