Conjugation of CD40-binding peptide to glycol chitosan nanoparticle for localized delivery of tumor microenvironment modulator

Abstract

Cancer immunotherapy focuses on helping the immune system fight and control cancer and has rapidly progressed in the recent years. Agonistic CD40 monoclonal antibodies have been proposed as a new therapeutic method that enhances anticancer immunity by various mechanisms that alter the immune-suppressive tumor microenvironment. Previous researches have shown that CD40 binding not only causes tumor cell death but also activates macrophages to rapidly penetrate tumors, become tumoricidal and promote the reduction of tumor stroma. In this study, in order to avoid unwanted systemic side effects while maintaining the anti-tumor effects of CD40 antibody, localized delivery of agonistic CD40-binding peptide (CD40p) that mimics a portion of human CD40 ligand was achieved by conjugating CD40p to hydrophobically modified glycol chitosan nanoparticles (CD40p-CNP). The immunomodulatory nanoparticles showed cytotoxicity against human cancer cells and enhanced phagocytic activity of macrophages in vitro. Systemic injection of CD40p-CNP into tumor-bearing mice resulted in tumor-targeted delivery and significant inhibition of tumor growth that was similar to the effect of local injection of CD40p. Also, the potential of localized cancer immunotherapy via CD40-dependent mechanism that targets tumor stroma in the treatment of cancer was demonstrated. The primary findings of this study provide a new platform to treat cancer through localized delivery of immunotherapeutic agents via systemic injection of nanoparticle which can also be combined with other treatment modalities to facilitate its effect.