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.