Tumor-specific biochemical nanoconversion of self-assembled peptide-conjugated paclitaxel-docetaxel-based nanoparticles

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.