ABSTRACT Passive‐targeting nanodelivery systems for cytotoxic drugs are often limited by the heterogeneity of the enhanced permeability and retention (EPR) effect, off‐target toxicity, and monotherapy resistance. Peptide‐drug conjugates (PDCs) offer a structurally precise and bio‐programmable strategy to compensate for these drawbacks. Herein, we report a structurally precise platinum (Pt)‐based PDC design that integrates axial‐ligand engineering with carrier‐free self‐assembly. Axial covalent modification of Pt IV with a hydrophobic alkyl chain and a cyclic RGD targeting peptide (c(RGD)fk) affords a structurally well‐defined amphiphilic prodrug that spontaneously assembles into stable lipid nanoparticles (NPt IV cRGD). These nanoparticles exhibited high α v β 3 integrin‐mediated selectivity, resulting in superior tumor accumulation. Within the reductive tumor microenvironment, the Pt IV center was converted to cytotoxic Pt II , resulting in pronounced DNA damage and a tumor growth inhibition rate of 78%, significantly outperforming cisplatin. Notably, systemic toxicity was markedly attenuated, as evidenced by minimal body weight loss and reduced hepatic and renal damage. This study establishes a structurally simplified PDC‐based chemotherapy paradigm for Pt drugs. By axially functionalizing a Pt IV prodrug with an active targeting peptide and leveraging its carrier‐free self‐assembly properties, this approach enhances antitumor efficacy while significantly minimizing off‐target toxicity.
Dong et al. (Fri,) studied this question.