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J Med Chem. 2014 Mar 27;57(6):2303-14. doi: 10.1021/jm401644v. Epub 2014 Mar 6.

Macromolecular prodrug that provides the irinotecan (CPT-11) active-metabolite SN-38 with ultralong half-life, low C(max), and low glucuronide formation.

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ProLynx , 455 Mission Bay Boulevard South, Suite 145, San Francisco, California 94158, United States.


We have recently reported a chemical approach for half-life extension that utilizes β-eliminative linkers to attach amine-containing drugs or prodrugs to macromolecules. The linkers release free drug or prodrug over periods ranging from a few hours to over 1 year. We adapted these linkers for use with phenol-containing drugs. Here, we prepared PEG conjugates of the irinotecan (CPT-11) active metabolite SN-38 via a phenyl ether that release the drug with predictable long half-lives. Pharmacokinetic studies in the rat indicate that, in contrast to other SN-38 prodrugs, the slowly released SN-38 shows a very low C(max), is kept above target concentrations for extended periods, and forms very little SN-38 glucuronide (the precursor of enterotoxic SN-38). The low SN-38 glucuronide is attributed to low hepatic uptake of SN-38. These macromolecular prodrugs have unique pharmacokinetic profiles that may translate to less intestinal toxicity and interpatient variability than the SN-38 prodrugs thus far studied.

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