期刊
JOURNAL OF MEDICINAL CHEMISTRY
卷 55, 期 24, 页码 11013-11021出版社
AMER CHEMICAL SOC
DOI: 10.1021/jm3014713
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资金
- Australian Microscopy & Microanalysis Research Facility (AMMRF) node at the University of Sydney
- Australian Research Council [DP0773953, DP110100461]
- Swiss National Science Foundation
- Australian Research Council [DP0773953] Funding Source: Australian Research Council
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.
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