Lipid-enveloped zinc phosphate hybrid nanoparticles for codelivery of H-2Kb and H-2Db-restricted antigenic peptides and monophosphoryl lipid A to induce antitumor immunity against melanoma

Abstract

Nanoimmunotherapy, the application of nanotechnology for sustained and targeted delivery of antigens to dendritic cells (DCs), has attracted much attention in stimulating antigen-specific immune response for antitumor therapy. In order to in situ deliver antigens to DCs for efficient antigen presentation and subsequent induction of strong cytotoxic T lymphocytes (CTL) response, here we developed a multi-peptide (TRP2180–188 and HGP10025–33) and toll-like receptor 4 agonist (monophosphoryl lipid A) codelivery system based on lipid-coated zinc phosphate hybrid nanoparticles (LZnP NPs). This delivery system equips with the chelating property of zinc to realize the high encapsulation efficiency with antigenic peptides and the influence on immune system with adjuvant-like feature. The combination of H-2Kb and H-2Db-restricted peptides could provide multiple epitopes as the target of specific MHC alleles, making tumor more difficult to escape from the surveillance of immune system. The formulated LZnP nano-vaccine with the size of 30nm and outer leaflet lipid exhibited antitumor immunity as the secretion of cytokines in vitro and increased CD8+ T cell response from IFN-γ ELISPOT analysis ex vivo. The antitumor effects were further evidenced from the prophylactic, therapeutic and metastatic melanoma tumor models compared with free antigens and single peptide-loaded nano-vaccines. These results validate the benefit of LZnP-based vaccine for antitumor immunity and indicate that co-delivery of tumor antigens along with adjuvant may be an optimized strategy for tumor immunotherapy.