Mukundan Shilpaa, Guan Dongli, Singleton Amy, Yang Yunlong, Li Matthew, Parekkadan Biju
Department of Biomedical Engineering, Rutgers, The State University of New Jersey, Piscataway, New Jersey, USA.
Department of Surgery, Center for Surgery, Innovation, and Bioengineering, Massachusetts General Hospital, Harvard Medical School and the Shriners Hospitals for Children, Boston, Massachusetts, USA.
Am J Adv Drug Deliv. 2018;6(1):21-32.
Despite recent breakthroughs in melanoma treatment with anti-PD-1 immunotherapy, innovative approaches are needed to improve off-target effects. In this study, we report a T cell mimetic microparticle delivery of soluble PD1 aiming at providing a carrier substrate for future combinatorial and targeting efforts. Microparticles of sizes varying from (5 μm to-7 μm) were conjugated with soluble mouse or human PD-1 through nearly irreversible binding between streptavidin and biotin. PD-1 conjugated microparticles (PDMPs) suppressed 3-dimensional tumor growth of human A375 and mouse B16-F10 melanoma cells compared to control microparticles conjugated with the Fc portion of human IgG1 (IgG1MPs). This can be attributed to competitive inhibition by PDMPs on a melanoma cell-intrinsic PD-1/PD-L1 pathway. A single, local administration of mPDMPs in a B16-F10 mouse melanoma model inhibited tumor growth significantly compared to control IgMPs at the same dose. CD45+ immune cells were found to infiltrate tumors treated with mPDMPs as a mechanism for tumor control. These results collectively suggest that PDMPs can target the melanoma cell-intrinsic PD-1/PD-L1 pathway and that these artificial T cell mimetics can be the scaffold for further improvements in anti-tumor immunotherapy.
尽管抗PD-1免疫疗法在黑色素瘤治疗方面取得了近期突破，但仍需要创新方法来改善脱靶效应。在本研究中，我们报告了一种可溶性PD1的T细胞模拟微粒递送方法，旨在为未来的联合治疗和靶向治疗提供载体底物。通过链霉亲和素和生物素之间几乎不可逆的结合，将大小从5μm到7μm不等的微粒与可溶性小鼠或人PD-1偶联。与与人IgG1的Fc部分偶联的对照微粒（IgG1MPs）相比，PD-1偶联微粒（PDMPs）抑制了人A375和小鼠B16-F10黑色素瘤细胞的三维肿瘤生长。这可归因于PDMPs对黑色素瘤细胞内在PD-1/PD-L1通路的竞争性抑制。在B16-F10小鼠黑色素瘤模型中，与相同剂量的对照IgMPs相比，单次局部注射mPDMPs可显著抑制肿瘤生长。发现CD45+免疫细胞浸润用mPDMPs治疗的肿瘤，作为肿瘤控制的一种机制。这些结果共同表明，PDMPs可以靶向黑色素瘤细胞内在的PD-1/PD-L1通路，并且这些人工T细胞模拟物可以作为进一步改善抗肿瘤免疫疗法的支架。
