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

Abstract

Despite the broad antitumor spectrum of cisplatin, its therapeutic efficacy in cancer treatment is compromised by the 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 the effective delivery of Pt(IV) prodrugs capable of reversing cisplatin resistance through the disulfide-group-based GSH-scavenging process, as described herein, is a promising route by which to overcome limitations associated with tumor resistance. Following systematic screening, the optimized NPs (referred to as CP5 NPs) showed a small particle size (76.2 nm), high loading of Pt(IV) prodrugs (15.50% Pt), a sharp response to GSH, the 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 the growth of cisplatin-resistant xenograft tumors with an inhibition rate of 83.32% while alleviating serious side effects associated with cisplatin. The GSH-scavenging nanoplatform is therefore a promising route by which to enhance the therapeutic index of Pt drugs used currently in cancer treatment.

Host−guest complexation-mediated codelivery of anticancer drug and photosensitizer for cancer photochemotherapy

“…4F). Drug efflux was one of the possible reasons for the invalidation of chemotherapy against A2780CIS cells (33)(34)(35). Compared with A2780 cells, more drugs were pumped out from A2780CIS cells for both free cisplatin and MNPs (Fig.…”

Cysteine‐Based Biomaterials as Drug Nanocarriers

“…Additionally, in order to reverse the drug resistance of tumor cells and decrease the systemic side effects of cisplatin in normal tissues, Ling et al. designed a unique poly(disulfide amide) polymer nanoparticle (NP) platform to deliver Pt(IV) prodrugs effectively and release platinum (Pt) ions rapidly in the tumor microenvironment via an S─S group‐based GSH‐scavenging process . Moreover, this NP platform was able to induce a higher apoptosis of cisplatin‐resistant A2780cis cells and inhibit the proliferation of cisplatin‐resistant xenograft tumors effectively while decreasing the serious side effects associated with cisplatin.…”

Novel synthesis of platinum complexes and their intracellular delivery to tumor cells by means of magnetic nanoparticles

“…[14][15][16][17] Some of these systems have also been successfully tested in animal models, showing a remarkable reduction of unwanted side effects and decreased drug resistance. 13,[18][19][20][21] The composition of the carrier together with the structure of the drug dictates the loading capability and the release profile of the drug itself. 22 In addition, its ability to tune size and surface chemistry of nanoparticles also allows the control of their circulation time, biodistribution, immune sequestration and clearance.…”