Development of protein-binding bifunctional linkers for a new generation of dual-acting prodrugs.

The aim of this work was to develop a new bifunctional maleimide linker for the development of dual-acting prodrugs that incorporate two pharmaceutically different anticancer agents independently bound by enzymatically cleavable substrates. The linker consists of a carboxyl group in one arm and an activated 1,6-self-immolative para-aminobenzyloxycarbonyl spacer together with a cathepsin B cleavable dipeptide Phe-Lys in the other. Aided with this linker, we have prepared a thiol-binding prodrug that contains the anticancer drugs doxorubicin and paclitaxel. Bound to the cysteine-34 position of albumin, it was cleaved efficiently by cathepsin B releasing the free drugs.