Synthetic Polymeric Mixed Micelles Targeting Lymph Nodes Trigger Enhanced Cellular and Humoral Immune Responses
Synthetic Polymeric Mixed Micelles Targeting Lymph Nodes Trigger Enhanced Cellular and Humoral Immune Responses
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靶向淋巴结的合成聚合物混合胶束触发增强的细胞和体液免疫反应
DOI：
10.1021/acsami.7b14004
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发表时间：
2018-01-24
影响因子：
9.5
通讯作者：
Chen, Dawei
中科院分区：
文献类型：
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作者：
Li, Chenxi;Zhang, Xiaoxu;Chen, Dawei
淋巴结（LN）是癌症疫苗的关键靶点，因为抗原呈递和T细胞介导的免疫应答的启动主要发生在这些位置，这一点已被广泛接受。本研究采用两亲性二嵌段共聚物聚（2-乙基-2-恶唑啉）-聚（D，L-丙交酯）（PEOz-PLA）与羧基末端的Pluronic F127构建了混合胶束[羧基化纳米颗粒（NPs）]，用于将抗原卵清蛋白（OVA）和Toll样受体-7激动剂CL 264（Carboxylated-NPs/OVA/CL 264）共递送至LN驻留的树突状细胞（DCs）。结果表明，自组装混合胶束的小的，小于60 nm的尺寸使它们能够迅速渗透到淋巴管中，并在皮下注射后到达引流淋巴结。此外，用羧基进行的表面修饰赋予了羧基化-NPs内吞受体靶向能力，允许羧基化-NPs/OVA/CL 264通过清道夫受体介导的途径被DC内化。由于CL 264在早期内体中的刺激将导致比在晚期内体/溶酶体中更有效的免疫应答，因此调节混合胶束中PEOz-PLA与羧化-Pluronic F127的质量比以将包封的CL 264释放到早期内体，导致DC的共刺激分子的表达和刺激的细胞因子的分泌增加。此外，PEOz的胶束壳外的掺入有效地增强了MHC I抗原的呈递，通过促进内体逃逸和抗原的胞质释放。这又在体内诱发有效的免疫应答，包括抗原特异性T细胞应答的活化、抗原特异性IgG抗体的产生和细胞毒性T淋巴细胞应答的产生。最后，在E.G7-OVA荷瘤小鼠中用共递送系统免疫不仅可以显著抑制肿瘤生长，而且可以显著延长荷瘤小鼠的存活。综上所述，羧化-NPs/OVA/CL 264作为进一步免疫治疗的有效抗肿瘤疫苗具有巨大的临床应用潜力。
It has been widely accepted that lymph nodes (LNs) are critical targets of cancer vaccines because antigen presentation and initiation of T-cell-mediated immune responses occur primarily at these locations. In this study, amphiphilic diblock copolymer poly(2-ethyl-2-oxazoline)-poly-(D,L-lactide) (PEOz-PLA) combined with carboxylterminated-Pluronic F127 was used to construct mixed micelles [carboxylated-nanoparticles (NPs)] for codelivery of antigen ovalbumin (OVA) and Toll-like receptor-7 agonist CL264 (carboxylated-NPs/OVA/CL264) to the LN-resident dendritic cells (DCs). The results showed that the small, sub-60 nm size of the self-assembled mixed micelles enables them to rapidly penetrate into lymphatic vessels and reach draining lymph nodes after subcutaneous injection. Furthermore, the surface modification with carboxylic groups imparted the carboxylated-NPs with endocytic receptor-targeting ability, allowing for DC internalization of carboxylated-NPs/OVA/CL264 via the scavenger receptor-mediated pathway. Because stimulation of CL264 in early endosomes will lead to a more effective immune response than that in late endo/lysosomes, the mass ratio of PEOz-PLA to carboxylated-Pluronic F127 in the mixed micelles was adjusted to release the encapsulated CL264 to the early endosome, resulting in increased expression of costimulatory molecules and secretion of stimulited cytokines by DCs. Moreover, the incorporation of PEOz outside the micellar shell effectively augmented MHC I antigen presentation through facilitating endosome escape and cytosolic release of antigens. This in turn evoked potent immune responses in vivo, including activation of antigen-specific T-cell responses, production of antigen-specific IgG antibodies, and generation of cytotoxic T-lymphocyte responses. Finally, immunization with the codelivery system in E.G7-OVA tumor-bearing mice could not only significantly inhibit tumor growth but also markedly prolong the survival of tumor-bearing mice. Taken together, carboxylated-NPs/OVA/CL264 have demonstrated great potential for clinical applications as an effective antitumor vaccine for further immunotherapy.