Multifunctional Immunoliposomes Combining Catalase and PD-L1 Antibodies Overcome Tumor Hypoxia and Enhance Immunotherapeutic Effects Against Melanoma

Abstract

Yu Hei,1 Binhong Teng,2,3 Ziqian Zeng,2,3 Siqi Zhang,3 Qian Li,3 Jijia Pan,3 Zuyuan Luo,3 Chunyang Xiong,1 Shicheng Wei2,3 1Department of Mechanics and Engineering Science, College of Engineering, Peking University, Beijing, People’s Republic of China; 2Department of Oral and Maxillofacial Surgery, School and Hospital of Stomatology, Peking University, Beijing, People’s Republic of China; 3Laboratory of Biomaterials and Regenerative Medicine, Academy for Advanced Interdisciplinary Studies, Peking University, Beijing, People’s Republic of ChinaCorrespondence: Chunyang XiongDepartment of Mechanics and Engineering Science, College of Engineering, Peking University, Beijing, People’s Republic of ChinaTel [phone]Email [email protected] WeiDepartment of Oral and Maxillofacial Surgery, School and Hospital of Stomatology, Peking University, Beijing, People’s Republic of ChinaTel [phone]Email [email protected]: Immune checkpoint blockades (ICBs) are a promising treatment for cancers such as melanoma by blocking important inhibitory pathways that enable tumor cells to evade immune attack. Programmed death ligand 1 monoclonal antibodies (aPDL1s) can be used as an ICB to significantly enhance the effectiveness of tumor immunotherapy by blocking the PD-1/PD-L1 inhibitory pathway. However, the effectiveness of aPDL1s may be limited by low selectivity in vivo and immunosuppressed tumor microenvironment including hypoxia.Purpose: To overcome the limitations, we develop a multifunctional immunoliposome, called CAT@aPDL1-SSL, with catalase (CAT) encapsulated inside to overcome tumor hypoxia and aPDL1s modified on the surface to enhance immunotherapeutic effects against melanoma.Methods: The multifunctional immunoliposomes (CAT@aPDL1-SSLs) are prepared using the film dispersion/post-insertion method. The efficacy of CAT@aPDL1-SSLs is verified by multiple experiments in vivo and in vitro.Results: The results of this study suggest that the multifunctional immunoliposomes preserve and protect the enzyme activity of CAT and ameliorate tumor hypoxia. Moreover, the enhanced cellular uptake of CAT@aPDL1-SSLs in vitro and their in vivo biodistribution suggest that CAT@aPDL1-SSLs have great targeting ability,resulting in improved delivery and accumulation of immunoliposomes in tumor tissue.Finally, by activating and increasing the infiltration of CD8+ T cells at the tumor site, CAT@aPDL1-SSLs inhibit the growth of tumor and prolong survival time of mice,with low systemic toxicity.Conclusion: In conclusion, the multifunctional immunoliposomes developed and proposed in this study are a promising candidate for melanoma immunotherapy, and could potentially be combined with other cancer therapies like radiotherapy and chemotherapy to produce positive outcomes.Keywords: immunotherapy, programmed death ligand 1 monoclonal antibodies, aPDL1s, tumor hypoxia, melanoma, liposomes

Keywords

• immunotherapy
• programmed death ligand 1 monoclonal antibodies (apdl1s)
• tumor hypoxia
• melanoma
• liposomes