Thermal-sensitive lipid nanoparticles potentiate anti-PD therapy through enhancing drug penetration and T lymphocytes infiltration in metastatic tumor. (1st December 2021)

• Record Type: Journal Article
• Authors: Tan, Ya-Nan; Li, Yong-Peng; Huang, Jian-Dong; Luo, Min; Li, Shan-Shan; Lee, Anne Wing-Mui; Hu, Fu-Qiang; Guan, Xin-Yuan
• Is Part Of: Cancer letters. Volume 522(2021)
• Page Start: 238
• Page End: 254
• Publication Date: 2021-12-01
• Subjects: Anti-PD therapy -- Responsive drug release -- Laser-enhanced immunotherapy -- Cold tumor -- Tumor metastasis; Cancer -- Periodicals; Neoplasms -- Periodicals; Cancer -- Périodiques; Electronic journals; 616.994
• DOI: 10.1016/j.canlet.2021.09.031
• Languages: English
• ISSNs: 0304-3835

Abstract

Abstract: The response rate of anti-PD therapy in most cancer patients remains low. Therapeutic drug and tumor-infiltrating lymphocytes (TILs) are usually obstructed by the stromal region within tumor microenvironment (TME) rather than distributed around tumor cells, thus unable to induce the immune response of cytotoxic T cells. Here, we constructed the cationic thermosensitive lipid nanoparticles IR780/DPPC/BMS by introducing cationic NIR photosensitizer IR-780 iodide (IR780) modified lipid components, thermosensitive lipid DPPC and PD-1/PD-L1 inhibitor BMS202 (BMS). Upon laser irradiation, IR780/DPPC/BMS penetrated into deep tumor, and reduced cancer-associated fibroblasts (CAFs) around tumor cells to remodel the spatial distribution of TILs in TME. Interestingly, the cationic IR780/DPPC/BMS could capture released tumor-associated antigens (TAAs), thereby enhancing the antigen-presenting ability of DCs to activate cytotoxic T lymphocytes. Moreover, IR780/DPPC/BMS initiated gel-liquid crystal phase transition under laser irradiation, accelerating the disintegration of lipid bilayer structure and leading to the responsive release of BMS, which would reverse the tumor immunosuppression state by blocking PD-1/PD-L1 pathway for a long term. This combination treatment can synergistically exert the antitumor immune response and inhibit the tumor growth and metastasis. Highlights: The lipid nanoparticles IR780/DPPC/BMS with antigen-capturing and NIR-responsive drug release capabilities was developed for enhanced anti-PD therapy in cancer treatment. IR780/DPPC/BMS selectively targeted to tumor tissues and penetrated into deep tumors upon NIR-laser irradiation. The local hyperthermia can reduce the extracellular matrix (ECM) barrier in tumor microenvironment, thus increasing the tumor-infiltrating lymphocytes (TILs). Laser-induced hyperthermia can trigger the responsive release of PD-1/PD-L1 inhibitor BMS, which will reverse the tumor immunosuppression state for a long term.