Sustained delivery of carfilzomib by tannic acid-based nanocapsules helps develop antitumor immunity.
Sustained delivery of carfilzomib by tannic acid-based nanocapsules helps develop antitumor immunity.
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DOI：
10.1021/acs.nanolett.9b04147
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发表时间：
2019-10
期刊：
影响因子：
10.8
通讯作者：
Maie S. Taha;Gregory M. Cresswell;Joonyoung Park;Wooin Lee;T. Ratliff;Y. Yeo
中科院分区：
文献类型：
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作者：
Maie S. Taha;Gregory M. Cresswell;Joonyoung Park;Wooin Lee;T. Ratliff;Y. Yeo
由于有可能诱导免疫原性细胞死亡（ICD），一组化疗药物在癌症免疫治疗中引起了越来越多的兴趣。在癌症免疫治疗中使用ICD诱导剂的一个关键挑战是伴随其抗增殖作用的免疫毒性。为了缓解这一问题，利用单宁酸（TA）和铁的界面超分子组装，并辅以白蛋白涂层，开发了一种诱导icd的蛋白酶体抑制剂卡非佐米（CFZ）的纳米胶囊配方。白蛋白包被的CFZ纳米胶囊（CFZ- pta -alb）减少了CFZ的释放，降低了对免疫细胞的毒性。此外，由于TA组装的粘附性，CFZ-pTA-alb充当了从垂死肿瘤细胞释放的损伤相关分子模式的储存库，以激活树突状细胞。在B16F10和CT26肿瘤模型中，经瘤内给药后，CFZ- pta -alb延长了CFZ的肿瘤滞留时间，并表现出比环糊精溶解CFZ （CFZ- cd）更强的抗肿瘤作用。与CFZ-CD不同，局部注射CFZ-pTA-alb保护或增强肿瘤中的CD8+ T细胞群，帮助产生具有肿瘤特异性干扰素-应答的脾细胞，并延迟免疫功能正常小鼠（胸腺裸小鼠）对侧肿瘤的发展，这支持CFZ-pTA-alb有助于激活抗肿瘤免疫。该研究表明，通过基于ta的纳米胶囊持续递送ICD诱导剂是将局部ICD诱导转化为全身抗肿瘤免疫的有效途径。
A group of chemotherapeutic drugs has gained increasing interest in cancer immunotherapy due to the potential to induce immunogenic cell death (ICD). A critical challenge in using the ICD inducers in cancer immunotherapy is the immunotoxicity accompanying their antiproliferative effects. To alleviate this, a nanocapsule formulation of carfilzomib (CFZ), an ICD-inducing proteasome inhibitor, was developed using interfacial supramolecular assembly of tannic acid (TA) and iron, supplemented with albumin coating. The albumin-coated CFZ nanocapsules (CFZ-pTA-alb) attenuated CFZ release, reducing toxicity to immune cells. Moreover, due to the adhesive nature of TA assembly, CFZ-pTA-alb served as a reservoir of damage-associated molecular patterns released from dying tumor cells to activate dendritic cells. Upon intratumoral administration, CFZ-pTA-alb prolonged tumor retention of CFZ and showed consistently greater antitumor effects than cyclodextrin-solubilized CFZ (CFZ-CD) in B16F10 and CT26 tumor models. Unlike CFZ-CD, the locally injected CFZ-pTA-alb protected or enhanced CD8+ T cell population in tumors, helped develop splenocytes with tumor-specific interferon- response, and delayed tumor development on the contralateral side in immunocompetent mice (but not in athymic nude mice), which support that CFZ-pTA-alb contributed to activating antitumor immunity. This study demonstrates that sustained delivery of ICD inducers by TA-based nanocapsules is an effective way of translating local ICD induction to systemic antitumor immunity.