A surge of platinum(IV) compounds are utilized or investigated in cancer treatment but their therapeutic outcomes have been greatly compromised by remaining adverse effects and limited antitumor performance, attributable to nonspecific distribution and insufficient activation in tumor site. Herein, we designed a series of disulfide bond introduced Pt(IV)-lipid prodrugs with different branch length, all of which are able to self-stabilize into nanomedicine and be activated by high intracellular glutathione (GSH) level. The impact of precise modification of these prodrugs on their assembly stability, pharmacokinetics and cytotoxicity was probed to establish a connection between chemical structure and antiproliferation efficiency. With optimal assembly manner and delivery efficacy, the longest axial branched Pt(IV) prodrug CSS18 exhibited the most impressive therapeutic outcome, providing a potential path to more efficient nanocarriers for chemotherapeutic agents by chemical modulation and, giving insights into the rational design of reduction responsive platinum delivery system.
Keywords: Antitumor performance; Chemical modification; Disulfide bond; Pt(IV) prodrug; Self-stabilization.
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