Active targeting redox-responsive mannosylated prodrug nanocolloids promote tumor recognition and cell internalization for enhanced colon cancer chemotherapy

Abstract

Despite the diversified therapeutic approaches for malignant tumors, chemotherapy remains the backbone of current cancer treatment. However, conventional chemotherapeutics was found to be associated with deficient recognition of tumor, low uptake efficiency, insolubility, short circulation, poor biocompatibility and low therapeutic outcomes. Herein, the active targeting redox-responsive mannosylated prodrug nanocolloids (HM NCs) were constructed for enhanced chemotherapy of colon cancer. HM NCs were prepared by the covalent cross-linking of 10-hydroxycamptothecin (HCPT) and mannose (MAN) via a redox-responsive cross-linker containing disulfide bonds, and modified with a moderate amount of polyethylene glycol (PEG). The large amount of mannose contained in HM NCs could actively target overexpressed mannose receptors on the surface of cancer cells and enhance cancer cell internalization through mannose receptor-mediated endocytosis. Owing to the combination of active targeting and the enhanced permeability and retention (EPR) passive targeting, HM NCs could effectively accumulate in tumors and high glutathione (GSH) in tumor microenvironment triggered cleavage of redox-responsive bonds and precise drug release. HM NCs exhibited superior antitumor activity both in vitro and in vivo and appreciably extended the mouse survival rate with good biocompatibility. The innovative HM NCs are expected to be conducive to overcoming the limitations of conventional chemotherapy for colon cancer and providing more choices for future clinical translation. STATEMENT OF SIGNIFICANCE: Despite the enhanced permeability and retention effect, the passive targeting can be interfered with by the complex biologic barriers in the body. In this study, an active targeting system (HM NCs) was constructed by covalent cross-linking of mannose and anticancer drug 10-hydroxycamptothecin via redox-responsive disulfide bonds for enhanced colon cancer chemotherapy. Mannosylation could promote hydrophilia and stability for prolonged blood circulation. Mannose could promote tumor recognition and cell internalization via mannose receptor-mediated endocytosis. High glutathione level could trigger the redox-responsive release of anticancer drugs and further induce cell apoptosis via DNA damage. The HM NCs exhibited superior antitumor activity both in vitro and in vivo and appreciably extended the mouse survival rate with good biocompatibility.

Keywords: Drug delivery system; Enhanced chemotherapy; Mannose; Prodrug nanocolloids; Redox-responsive; Tumor-targeting.