中文摘要：研究表明一种TLR4促进剂MPLA和TLR9促进剂CpG能够有效地协同装载到人工合成的高密度脂蛋白纳米盘上，从而形成一种佐剂系统ND-MPLA/CpG，这种佐剂系统能够与蛋白、多肽等多种亚单位抗原结合。与两种佐剂单独联合或一种佐剂与纳米盘联合相比，ND-MPLA/CpG能够促进树突状细胞激活。更重要的是，当用ND-MPLA/CpG传递的混合蛋白免疫小鼠时，能够促进产生强大的系统免疫反应，包括抗蛋白酶枯草杆菌蛋白酶（PCSK9）的IgG反应的诱导，从而使得血浆总胆固醇含量降低了17-30%。同时，在多肿瘤鼠类模型中，ND-MPLA/CpG能够表现出强大的抗肿瘤作用。与未装载纳米盘的自由佐剂相比，ND-MPLA/CpG与卵黄抗体结合能够提高抗原特异性CD8+ T细胞反应8倍以上，且差异显著，并能促进B16F10-OVA黑素瘤的衰退。ND-MPLA/CpG与E7多肽抗原集合能够激发产生近20% 的E7特异性CD8+ T细胞反应，并能促进已确诊的TC-1肿瘤细胞的完全衰退。总而言之，本研究结果表明，双重TLR促进剂纳米盘是一种简单、功能多样的佐剂系统，在疫苗制备和肿瘤免疫疗法方面具有巨大的应用潜力。
外文摘要：Recent studies have shown that certain combinations of Toll-like receptor (TLR) agonists can induce synergistic immune activation. However, it remains challenging to achieve such robust responses in vivo in a manner that is effective, facile, and amenable for clinical translation. Here, we show that MPLA, a TLR4 agonist, and CpG, a TLR9 agonist, can be efficiently co-loaded into synthetic high-density lipoprotein nanodiscs, forming a potent adjuvant system (ND-MPLA/CpG) that can be readily combined with a variety of subunit antigens, including proteins and peptides. ND-MPLA/CpG significantly enhanced activation of dendritic cells, compared with free dual adjuvants or nanodiscs delivering a single TLR agonist. Importantly, mice immunized with physical mixtures of protein antigens ND-MPLA/CpG generated strong humoral responses, including induction of IgG responses against protein convertase subtilisin/kexin 9 (PCSK9), leading to 17-30% reduction of the total plasma cholesterol levels. Moreover, ND-MPLA/CpG exerted strong anti-tumor efficacy in multiple murine tumor models. Compared with free adjuvants, ND-MPLA/CpG admixed with ovalbumin markedly improved antigen-specific CD8+ T cell responses by 8-fold and promoted regression of B16F10-OVA melanoma (P < 0.0001). Furthermore, ND-MPLA/CpG admixed with E7 peptide antigen elicited similar to 20% E7-specific CD8+ T cell responses and achieved complete regression of established TC-1 tumors in all treated animals. Taken together, our work highlights the simplicity, versatility, and potency of dual TLR agonist nanodiscs for applications in vaccines and cancer immunotherapy.
外文关键词：Vaccine； Nanoparticle； Adjuvant； Cancer； Immunotherapy
作者：Kuai, R； Sun, XQ； Yuan, WM； Ochyl, LJ； Xu, Y； Najafabadi, AH； Scheetz, L； Yu, MZ； Balwani, I； Schwendeman, A； Moon, JJ
作者单位：美国密歇根大学
期刊名称：JOURNAL OF CONTROLLED RELEASE
期刊影响因子：7.56
出版年份：2018
出版刊次：7
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