Simultaneous delivery of immune stimulatory gene and checkpoint blocker via targeted nanoparticles to strengthen antitumor immunity. (March 2022)

• Record Type: Journal Article
• Authors: Hu, Y.; Liu, X.; Ran, M.; Yang, T.; Li, T.; Wu, Y.; Lin, Y.; Qian, Z.; Gao, X.
• Is Part Of: Materials today nano. Volume 17(2022)
• Publication Date: 2022-03
• Subjects: IL-12 -- Immune checkpoint blockage -- Nanomedicine -- Tumor immune micro-environment -- Cancer immunotherapy; Nanoscience -- Periodicals; Nanotechnology -- Periodicals; Nanotechnology; Nanoscience; Nanotechnology -- Periodicals; Periodicals; Periodical; Electronic journals; Electronic journals; 620.5
• DOI: 10.1016/j.mtnano.2021.100151
• Languages: English
• ISSNs: 2588-8420

Abstract

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. Graphical abstract: The tumor-targeting nanoparticles composed of (cyclo (Arg-Gly-Asp-D-Phe-Lys)-poly (ethylene glycol)–poly(ϵ-caprolactone)) (cRGD-PEG-PCL) copolymers, 1, 2-Dioleoyl-3-trimethylammonium-propane (DOTAP) and methoxy PEG-PCL-methoxy PEG (MPEG-PCL-MPEG) copolymers are developed to incorporate immune stimulating gene and checkpoint blocker, and selectively deliver them to tumor sites. The combined immunotherapy boosts antitumor activities to eliminate tumor by remodeling immune micro-environment. Image 1 Highlights: Simultaneous delivery of immune stimulatory gene and immune checkpoint blocker is achieved by self-assembled RDMCM nanoparticles. RDMCM nanoparticles selectively deliver dual drugs to the tumor site by targeting cyclo(Arg-Gly-Asp-D-Phe-Lys) (cRGD)-binding integrins. Combinatorial immunotherapy exhibits excellent antitumor efficacy in tumor therapy. Synergistic treatment reshapes the immune micro-environment involving multiple immune cells to boost antitumor activities.