Abstract
Docetaxel (DTX, 1) and paclitaxel (PTX, 2) are famous cytotoxic agents widely used in cancer therapy, however, their low specificity for tumor cells often results in severe systemic toxicity. Beyond conventional prodrug strategies, this study introduces a novel nanoconversion technology that chemically modifies DTX to form self-assembled nanoparticles (NPs), which subsequently convert into a paclitaxel-mimicking molecule (PTXm, 3). Hydrophilic acetylated Phe-Arg-Arg-Phe peptide ((Ac)FRRF, 4) and hydrophobic docetaxel were conjugated to prepare self-assembled (Ac)FRRF-DTX NPs. The selective cleavage of the Arg-Phe bond by cathepsin B, which is abundant in cancer cells, facilitated the nanoconversion of PTXm (3) from (Ac)FRRF-DTX NPs, demonstrating effective cytotoxic effects. Utilizing the cleavage site of peptide and specific sequences (ex. Arg-Arg-Phe), this approach does not simply act as a prodrug but allows the nanomaterial to transform into another cytotoxic biomolecule within tumors. (Ac)FRRF-DTX NPs exhibited remarkable physicochemical properties, superior anti-cancer efficacy, and low toxicity, showcasing an innovative conversion in peptide-conjugated nanomedicine. Unlike traditional prodrug chemistry, this tumor-specific nanoconversion process involves the biochemical transformation of DTX (1) into PTXm (3) via enzymatic action. Overall, this study provides an outstanding example of chemical drug molecular modification through the concept of nanoconversion.