Dual Targeting of Hypoxic and Acidic Tumor Environments with a Cobalt(III) Chaperone Complex

作者：Yamamoto Natsuho; Renfrew Anna K; Kim Byung J; Bryce Nicole S^*; Hambley Trevor W

来源：Journal of Medicinal Chemistry, 2012, 55(24): 11013-11021.

DOI：10.1021/jm3014713

The rational design of prodrugs for selective accumulation and activation in tumor microenvironments is one of the most promising strategies for minimizing the toxicity of anticancer drugs. Manipulation of the charge of the prodrug represents a potential mechanism to selectively deliver the prodrug to the acidic tumor microenvironment. Here we present delivery of a fluorescent coumarin using a cobalt(III) chaperone to target hypoxic regions, and charged ligands for pH selectivity. Protonation or deprotonation of the complexes over a physiologically relevant pH range resulted in pH dependent accumulation of the fluorophore in colon cancer cells. Furthermore, in a spheroid solid tumor model, the anionic complexes exhibited preferential release of the fluorophore in the acidic/hypoxic region. By fine-tuning the physicochemical properties of the cobalt-chaperone moiety, we have demonstrated selective drug release in the acidic and hypoxic tumor microenvironment.

• 出版日期2012-12-27