pH-degradable imidazoquinoline-ligated nanogels for lymph node-focused immune activation
pH-degradable imidazoquinoline-ligated nanogels for lymph node-focused immune activation
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DOI：
10.1073/pnas.1600816113
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发表时间：
2016-07-19
影响因子：
11.1
通讯作者：
De Geest, Bruno G.
中科院分区：
文献类型：
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作者：
Nuhn, Lutz;Vanparijs, Nane;De Geest, Bruno G.
Toll 样受体 (TLR) 激动剂是先天免疫系统的有效激活剂，有望作为疫苗佐剂和抗癌免疫治疗。不幸的是，它们以可溶形式很容易进入体循环并引起全身炎症毒性。在这里，我们证明，通过将基于咪唑喹啉的小分子 TLR7/8 激动剂与 50 nm 尺寸的可降解聚合物纳米凝胶共价连接，激动剂在体外培养的树突状细胞中激活 TLR7/8 的效力在很大程度上得以保留。重要的是，咪唑喹啉连接的纳米凝胶将体内免疫激活集中在引流淋巴结上，同时显着减少全身炎症。机理研究揭示了纳米凝胶普遍被动扩散到引流淋巴结。此外，小鼠免疫研究表明，相对于可溶性 TLR7/8 激动剂，咪唑喹啉连接的纳米凝胶可诱导针对结核抗原的优异抗体和 T 细胞反应。这种方法为增强小分子 TLR 激动剂在各种应用中的治疗效果提供了可能性。
Agonists of Toll-like receptors (TLRs) are potent activators of the innate immune system and hold promise as vaccine adjuvant and for anticancer immunotherapy. Unfortunately, in soluble form they readily enter systemic circulation and cause systemic inflammatory toxicity. Here we demonstrate that by covalent ligation of a small-molecule imidazoquinoline-based TLR7/8 agonist to 50-nm-sized degradable polymeric nanogels the potency of the agonist to activate TLR7/8 in in vitro cultured dendritic cells is largely retained. Importantly, imidazoquinoline-ligated nanogels focused the in vivo immune activation on the draining lymph nodes while dramatically reducing systemic inflammation. Mechanistic studies revealed a prevalent passive diffusion of the nanogels to the draining lymph node. Moreover, immunization studies in mice have shown that relative to soluble TLR7/8 agonist, imidazoquinoline-ligated nanogels induce superior antibody and T-cell responses against a tuberculosis antigen. This approach opens possibilities to enhance the therapeutic benefit of small-molecule TLR agonist for a variety of applications.