Polymeric Nanoparticles Integrated from Discrete Organoplatinum(II) Metallacycle by Stepwise Post-assembly Polymerization for Synergistic Cancer Therapy

Post-assembly modification is a useful tool for producing discrete metallasupramolecular structures. However, the simple structural transformation by facile covalent reactions greatly impedes the development of functional organometallic materials. Herein, we describe the successful outcome by means of coordination-driven self-assembly and post-assembly reversible addition–fragmentation chain-transfer polymerization in preparing an amphiphilic supramolecular block copolymer Pt-PBEMA-b-POEGMA possessing H2O2-responsive diblock copolymers arms and a well-defined metallacycle core. The polymer self-assembles into nanoparticles (Pt NPs), which are able to encapsulate palmitoyl ascorbate (PA) and doxorubicin (DOX). After being internalized by cancer cells, PA serves as a prooxidant to elevate the H2O2 concentration through cascade reactions to reverse the amphiphilicity of Pt-PBEMA-b-POEGMA through a H2O2-responsive removal of the hydrophobic domains, thus promoting the release of DOX. Meanwhile, the released quinone methide depletes the intracellular glutathione to decrease the antioxidation ability of cancer cells, realizing synergistic anticancer efficacy. Due to the sophisticated design and the enhanced permeability and retention effect, the nanomedicine codelivering PA and DOX highly accumulates in the tumor site. In vitro and in vivo results show the excellent antitumor performance of Pt NPs@PA/DOX, which greatly suppresses tumor growth after intravenous administration with negligible systemic toxicity.