Lymph-Node-Targeted Cholesterolized TLR7 Agonist Liposomes Provoke a Safe and Durable Antitumor Response,Nano Letters

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Lymph-Node-Targeted Cholesterolized TLR7 Agonist Liposomes Provoke a Safe and Durable Antitumor Response
Nano Letters ( IF 9.6 ) Pub Date : 2021-09-17 , DOI: 10.1021/acs.nanolett.1c01968
Dandan Wan ₁ , Haiying Que ₁ , Li Chen ₁ , Tianxia Lan ₁ , Weiqi Hong ₁ , Cai He ₁ , Jingyun Yang ₁ , Yuquan Wei ₁ , Xiawei Wei ₁

Affiliation

Toll-like receptor (TLR) agonists as the potent stimulants of an innate immune system hold promises for applications in anticancer immunotherapy. However, most of them are limited in the clinical translation due to the uncontrolled systemic inflammatory response. In the current study, 1V209, a small molecule TLR7 agonist, was conjugated with cholesterol (1V209-Cho) and prepared into liposomes (1V209-Cho-Lip). 1V209-Cho-Lip exerted minimal toxic effects and enhanced the transportation ability in lymph nodes (LNs) compared with 1V209. 1V209-Cho-Lip treatment inhibited tumor progression in CT26 colorectal cancer, 4T1 breast cancer, and Pan02 pancreatic ductal cancer models through inducing effective DC activation and eliciting CD8⁺ T cell responses. Furthermore, 1V209-Cho-Lip induced tumor-specific memory immunity to inhibit cancer recurrence and metastasis. These results indicate that cholesterol conjugation with 1V209 is an effective approach to target lymph nodes and to reduce the adverse effects. This work provides a rational basis for the distribution optimization of TLR agonists for potential clinical use.

中文翻译：

靶向淋巴结的胆固醇化 TLR7 激动剂脂质体可激发安全且持久的抗肿瘤反应

Toll 样受体 (TLR) 激动剂作为先天免疫系统的强效刺激剂，有望用于抗癌免疫治疗。然而，由于不受控制的全身炎症反应，它们中的大多数在临床转化中受到限制。在目前的研究中，小分子 TLR7 激动剂 1V209 与胆固醇 (1V209-Cho) 结合并制备成脂质体 (1V209-Cho-Lip)。与 1V209 相比，1V209-Cho-Lip 发挥最小的毒性作用并增强淋巴结 (LN) 的转运能力。1V209-Cho-Lip 治疗通过诱导有效的 DC 激活和引发 CD8 ⁺抑制 CT26 结直肠癌、4T1 乳腺癌和 Pan02 胰腺导管癌模型的肿瘤进展T 细胞反应。此外，1V209-Cho-Lip 诱导肿瘤特异性记忆免疫以抑制癌症复发和转移。这些结果表明，胆固醇与 1V209 结合是靶向淋巴结和减少不良反应的有效方法。这项工作为潜在临床使用的 TLR 激动剂的分布优化提供了合理的基础。

更新日期：2021-10-13

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