Glutathione-responsive conjugates of hyperbranched polyoxidized glutathione and camptothecin for cancer therapy

Abstract

Camptothecin (CPT) is a highly potent antitumor agent with severe systemic toxicity in clinical application. To employ the endogenous molecule of oxidized glutathione (GSSG) as carrier for CPT delivery could simultaneously avoid the carrier’s accumulative toxicity and drug’s systemic toxicity. The poly-GSSG was conjugated with CPT to develop a glutathione-responsive nanomedicine (Poly GSSG-CPT). The structure of poly GSSG-CPT was confirmed through FT-IR, NMR, and MALDI-TOF analyses. The cumulative CPT release rate from Poly GSSG-CPT reached 97.9% at 120 h in a 10 mg·mL-1 glutathione (GSH) environment measured by UV-Vis spectroscopy. CCK-8 assays and flow cytometry experiments exhibited similar cell inhibitory effects between Poly GSSG-CPT and CPT. Furthermore, laser scanning confocal microscopy (CLSM) and in vivo imaging (IVIS) showed that Poly GSSG-CPT could localize to cell nuclei within 6 h and accumulate in tumor tissue within 48 h. Tumor-bearing mice studies and histopathological analyses confirmed that Poly GSSG-CPT could significantly enhance antitumor efficacy and reduce systemic toxicity compared to free CPT. Altogether, the nanomedicine of Poly GSSG-CPT based on GSSG and CPT showed the superior stability in aqueous environment, higher tumor inhibition ability and lower side effects in vivo, demonstrating that the endogenous molecule as carriers is a better choice for developing nanomedicine with higher therapeutic efficacy and lower systemic toxicity