Tumor Ablation and Therapeutic Immunity Induction by an Injectable Peptide Hydrogel
Tumor Ablation and Therapeutic Immunity Induction by an Injectable Peptide Hydrogel
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可注射肽水凝胶的肿瘤消融和治疗性免疫诱导
DOI：
10.1021/acsnano.7b08148
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发表时间：
2018-04-01
期刊：
影响因子：
17.1
通讯作者：
Yang, Kunyu
中科院分区：
文献类型：
--
作者：
Jin, Honglin;Wan, Chao;Yang, Kunyu
免疫抑制性肿瘤微环境（TME）为有效的癌症治疗创造了巨大的障碍。在此，我们开发了一种装载有多柔比星（DOX）的蜂毒肽-RADA（32）杂合肽水凝胶，用于通过主动调节TME来针对黑色素瘤的有效化学免疫疗法。所形成的蜂毒肽-RADA（32）-DOX（MRD）水凝胶具有交织的网状结构，并表现出优异的生物相容性，在体外和体内均具有受控的药物释放特性，并且对黑色素瘤细胞具有增强的杀伤作用。MRD水凝胶的单剂量注射由于负载蜂毒素和DOX而使原发性黑素瘤肿瘤的生长延迟超过95%，同时在肿瘤中募集活化的自然杀伤细胞。此外，MRD水凝胶可以激活引流淋巴结的树突状细胞，特异性地消耗M2样肿瘤相关巨噬细胞（TAM），并产生活性细胞毒性T细胞，以进一步保护细胞免受剩余肿瘤的侵害，从而在体内提供针对皮下和转移性肿瘤的有效抗癌功效。多剂量注射MRD水凝胶消除了50%的原发性肿瘤，并在根除初始肿瘤后提供了针对肿瘤再激发的强烈免疫记忆效应。由于MRD水凝胶具有控制药物释放、调节先天免疫细胞、消耗M2样TAM、指导抗癌和免疫刺激能力以及重塑免疫抑制性TME的能力，因此MRD水凝胶可用作抗癌应用的有力工具。
Immunosuppressive tumor microenvironments (TMEs) create tremendous obstacles for an effective cancer therapy. Herein, we developed a melittin-RADA(32) hybrid peptide hydrogel loaded with doxorubicin (DOX) for a potent chemoimmunotherapy against melanoma through the active regulation of TMEs. The formed melittin-RADA(32)-DOX (MRD) hydrogel has an interweaving nanofiber structure and exhibits excellent biocompatibility, controlled drug release properties both in vitro and in vivo, and an enhanced killing effect to melanoma cells. A single-dose injection of MRD hydrogel retarded the growth of primary melanoma tumors by more than 95% due to loaded melittin and DOX, with concomitant recruitment of activated natural killer cells in the tumors. Furthermore, MRD hydrogel can activate dendritic cells of draining lymph nodes, specifically deplete M2-like tumor-associated macrophages (TAMs), and produce active, cytotoxic T cells to further defend the cells against remaining tumors, providing potent anticancer efficacy against subcutaneous and metastatic tumors in vivo. Multidose injection of MRD hydrogel eliminated 50% of the primary tumors and provided a strong immunological memory effect against tumor rechallenge after eradication of the initial tumors. Owing to its abilities to perform controlled drug release, regulate innate immune cells, deplete M2-like TAMs, direct anticancer and immune-stimulating capabilities, and reshape immunosuppressive TMEs, MRD hydrogel may serve as a powerful tool for anticancer applications.