Engineering Semicarbazide-Bearing Polypeptide Conjugates for Efficient Tumor Chemotherapy and Imaging of Tumor Metastasis

Polypeptide materials offer scalability, biocompatibility, and biodegradability, rendering them an ideal platform for biomedical applications. However, the preparation of polypeptides with specific functional groups, such as semicarbazide moieties, remains challenging. This work reports, for the first time, the straightforward synthesis of well-defined methoxy-terminated poly(ethylene glycol)-b-polypeptide hybrid block copolymers (HBCPs) containing semicarbazide moieties. This synthesis involves implementing the direct polymerization of environment-stable N-phenoxycarbonyl-functionalized alpha-amino acid (NPCA) precursors, thereby avoiding the handling of labile N-carboxyanhydride (NCA) monomers. The resulting HBCPs containing semicarbazide moieties enable facile functionalization with aldehyde/ketone derivatives, forming pH-cleavable semicarbazone linkages for tailored drug release. Particularly, the intracellular pH-triggered hydrolysis of semicarbazone moieties restores the initial semicarbazide residues, facilitating endo-lysosomal escape and thus improving therapeutic outcomes. Furthermore, the integration of the hypoxic probe (Ir(btpna)(bpy)2) into the pH-responsive nanomedicines allows sequential responses to acidic and hypoxic tumor microenvironments, enabling precise detection of metastatic tumors. The innovative approach for designing bespoke functional polypeptides holds promise for advanced drug delivery and precision therapeutics. This work reports the synthesis of well-defined polypeptides containing semicarbazide moieties via direct polymerization of N-phenoxycarbonyl-functionalized alpha-amino acid (NPCA) based monomers. These polypeptides can be further decorated with ketone/aldehyde-containing agents with the formation of pH-cleavable semicarbazone linkages. The intracellular acidic pH-triggered release promotes drug escape from endolysosomes and enhances anti-tumor efficacy, which can be also employed for highly sensitive detection of tumor lesions.image