Glutathione-scavenging Poly(disulfide amide) Nanoparticles for Effective Delivery of Pt(IV) Prodrugs and Reversal of Cisplatin Resistance

Xiang Ling, Xing Chen, Imogen Riddell, Wei Tao, Junqing Wang, Geoffrey Hollett, Stephen J. Lippard, Farokhzad Omid C., Jinjun Shi, Jun Wu

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    Abstract

    Despite the broad antitumor spectrum of cisplatin, its therapeutic efficacy in cancer treatment is compromised by development of drug resistance in tumor cells and systemic side effects. A close correlation has been drawn between cisplatin resistance in tumor cells and increased levels of intracellular thiol-containing species, especially glutathione (GSH). The construction of a unique nanoparticle (NP) platform composed of poly(disulfide amide) polymers with a high disulfide density for effective delivery of Pt(IV) prodrugs capable of reversing cisplatin resistance through disulfide group-based GSH-scavenging process, as described herein, is a promising route to overcome limitations associated with tumor resistance. Following systematic screening, the optimized NPs (referred to as CP5 NPs) showed high loading of Pt(IV) prodrugs, sharp response to GSH, rapid release of platinum (Pt) ions, and notable apoptosis of cisplatin-resistant A2780cis cells. CP5 NPs also exhibited long blood circulation and high tumor accumulation after intravenous injection. Moreover, in vivo efficacy and safety results showed that CP5 NPs effectively inhibited growth of cisplatin-resistant xenograft tumors, while alleviating serious side effects associated with cisplatin. The GSH-scavenging nanoplatform is therefore a promising route to enhance the therapeutic index of Pt drugs used currently in cancer treatment.
    Original languageEnglish
    JournalNano Letters
    Early online date14 Jun 2018
    DOIs
    Publication statusPublished - 2018

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