Simultaneous delivery of immune stimulatory gene and checkpoint blocker via targeted nanoparticles to strengthen antitumor immunity

Abstract

The functions of immune cells are regulated by stimulatory and inhibitory signals. Immune stimulating factors provoke the activation of immune cells and the release of cytotoxic cytokines such as interferon gamma (IFN-γ), which can induce overexpression of programmed cell death protein ligand-1 (PD-L1) on tumor cells, leading to immune evasion. Concurrent blockage of programmed cell death protein-1 (PD-1)/PD-L1 axis will counterbalance the immune suppression attributed to PD-L1 and further augment antitumor responses. Herein, a combined immunotherapy to enhance immune activation and reverse immunosuppression is developed for cancer treatment using a self-assembled nanocarrier-drug system. This study introduces the tumor-targeting RDMCM nanoparticles composed of (cyclo (Arg-Gly-Asp-D-Phe-Lys)-poly(ethylene glycol)-poly(ϵ-caprolactone)) (cRGD-PEG-PCL) copolymer, 1,2-Dioleoyl-3-trimethylammonium-propane (DOTAP) and methoxy PEG-PCL-methoxy PEG (MPEG-PCL-MPEG) copolymer to deliver IL-12 encoding plasmid (pIL-12) and PD-1/PD-L1 small molecular inhibitor (PD-1/PD-L1i) for cancer therapy. The RDMCM nanoparticles selectively deliver dual drugs to the tumor site by targeting the integrin αvβ3 receptor overexpressed on neoendothelial cells and tumor cells. We disclose that combined treatment can reshape tumor immune micro-environment, modulate lymphocytes, macrophages, natural killer (NK) cells and other immune cells, thus, to boost antitumor activities. Synergistic immunotherapy markedly retards tumor growth without causing significant toxicity or adverse effects. Collectively, the results indicate that the fabricated therapeutic nanoparticle will be a promising candidate for cancer immunotherapy.