Core-Coordinated Elliptic Polymer Nanoparticles Loading Copper(II) and Chlorambucil for Cooperative Chemodynamic/Chemotherapy

Abstract

Chemodynamic therapy (CDT) reflects an innovative cancer treatment modality; however, to enhance its relatively low therapeutic efficiency, rational combination with extra therapeutic modes is highly appreciated. Here, core-coordinated amphiphilic, elliptic polymer nanoparticles (Cu/CBL-POEGEA NPs) are constructed via the self-assembly of a glutathione (GSH)-responsive polymer-drug conjugate, bearing side-chain acylthiourea (ATU) motifs which behave as ligands capable of coordinating Cu(II), such a design is featured by combined chemo (CT)/CDT with dual GSH depletion collectively triggered by the Cu(II) reduction reaction and disulfide bond breakage. To do so, an amphiphilic random copolymer poly[oligo(ethylene glycol)ethyl acrylate-<i>co</i>-thiourea] [P(OEGEA-<i>co</i>-ATU)] is synthesized, followed by conjugation of chlorambucil (CBL) to ATU motifs linked via a disulfide bond, thus yielding the targeted P[OEGEA-<i>co</i>-(ATU-<i>g</i>-CBL)]. In such a system, hydrophilic POEGEA serves as the biocompatible section and ATU motifs coordinate Cu(II), resulting in core-coordinated elliptic Cu/CBL-POEGEA NPs. Benefitting from the GSH-induced reduction reaction, Cu(II) is converted into Cu(I) and subsequently react with endogenous H₂O₂ to create ^•OH, realizing GSH-depletion-promoted CDT. Additionally, the disulfide bond endows GSH-responsive CBL release and provokes further GSH decline, finally realizing combined CDT/CT toward enhancing antitumor outcomes, and <i>in vitro</i> as well as <i>in vivo</i> studies indeed reveal remarkable efficacy. Such a system can provide valuable advantages to create novel nanomedicines toward cascade antitumor therapy.