A versatile method to deliver platinum (II) drugs via thiol-ene/yne click reaction of polypeptide

Amphiphilic poly(amino acid) as a platinum(Ⅱ) drug delivery platform. [Display omitted] •Novel vinyl- or alkynyl-substituted cysteine N-carboxyanhydride (NCA) monomers were synthesized, and their corresponding amphiphilic block copolymers of mPEG-poly(amino acid) were prepared.•A versatile method for functionalizing poly(amino acid) through thiol-ene/thiol-yne click reactions to deliver platinum (II) drugs was successfully developed.•This system uses thiol-ene/yne click reaction, which has the advantages of mild reaction, fast reaction rate and high yield.•Compared with traditional small molecule chemotherapeutic drugs, the drug delivery system exhibits comparable therapeutic efficacy in vitro. Platinum (II) demonstrates potent anticancer activity, but it is hampered by drawbacks such as poor solubility, facile decomposition, bone marrow suppression, and nephrotoxicity, which severely restrict its clinical use. To overcome these limitations, polymer prodrugs were developed by conjugation of platinum drugs onto polymers. The protective shield provided by polymers enables drugs to evade enzymatic degradation and immune system attacks in the physiological environment, achieving sustained release and long-term efficacy. In this study, we synthesized novel vinyl- or alkynyl-substituted cysteine N-carboxyanhydride (NCA) monomers, followed by the preparation of amphiphilic poly(ethylene glycol)-poly(amino-acid) copolymers through the copolymerization of PEG with the NCAs. Next, 1,2-didentate dicarboxylic groups were introduced into the side chains of the block copolymer by employing the “Thiol-ene” or “Thiol-yne” reactions. These carboxylic acid groups were then chelated with (1R,2R)-1,2-diaminocyclohexane platinum (II)(DACH-Pt) and simultaneously assembled into nanoparticles. The morphology and particle size were characterized using transmission electron microscopy (TEM) and dynamic light scattering (DLS). Remarkably, the chelation of platinum (II) led to a decrease in micellar size. In vitro drug release experiments demonstrated a significantly faster release rate in the intracellular environment (pH 5.0) compared to physiological conditions (pH 7.4). MTT assays confirmed the excellent biocompatibility of the polymer. Moreover, concentration-dependent inhibition of cancer cell growth was observed with poly(amino acid)-platinum (II) chelate micelles. Overall, these findings suggest that self-assembled nanoparticles of poly(amino acid)-platinum (II) chelates hold