Redox-responsive nanomedicine of doxorubicin-conjugated poly-L-glutathione oxidized for cancer therapy

Abstract

BackgroundDoxorubicin (Dox) is a potent anticancer drug with severe side effects to normal tissues. To fabricate a nanomedicine with Dox is a better method to address the side effects of Dox in normal tissues. However, nanomedicines with unapproved materials could not be easily applied in clinic, hence, a nanomedicine fabricated by endogenous materials is a potential method to increase the possibility of clinical application. MethodsIn this study, a redox-responsive nanomedicine with clinical-applied anticancer of Dox and endogenous molecule of l-glutathione oxidized (GSSG) was prepared for cancer therapy.: The carboxyl and amino groups in l-glutathione oxidized can be reacted itself to form the poly-l-glutathione oxidized peptide-like polymer. Meanwhile, the Dox were conjugated in poly-l-glutathione oxidized polymer by amnio group in Dox and the structure of Dox-conjugated poly-l-glutathione oxidized polymer (Dox-Poly GSSG) was confirmed by FT-IR, NMR and MALDIT-TOF. Afterward, the drug loading of Dox (22 %) in poly-GSSG was measured by UV–vis and the accumulative Dox release rate of Dox-Poly GSSG is 46 % in 5 mg/mL reduced glutathione (GSH) environment at 72 h The size stability of Dox-Poly GSSG in PBS and PBS with GSH was evaluated by dynamic laser scatter (DLS) and transmit emission microscopy (TEM). Furthermore, cell viabilities of Dox-Poly GSSG were similar with free Dox evaluated by CCK-8 assay and flow cytometry experiment, respectively. The distribution of Dox-Poly GSSG in nuclei and tumor tissues was evaluated by Confocal laser scanning microscope and in vivo imaging system, respectively. Significant FindingsThe drug release results showed that the Dox could be controllable released in high concentration of GSH in tumor tissues. The tumor inhibition, H&E and TUNEL experiments showed that the Dox-Poly GSSG group can significantly inhibit the tumor growth compared to saline group and avoid major side effects to normal tissues compared to free Dox. This redox-responsive nanomedicine with clinical-applied anticancer of Dox and endogenous molecule of GSSG is a potential candidate for clinical application.