Nat Commun:上海药物所合成可用于肿瘤特异性蛋白降解和乳腺癌治疗的高分子蛋白降解剂

2022-07-29 中科院上海药物所 网络

该研究成果提出了一种特异性递送PROTAC分子至肿瘤部位的通用型纳米平台,并证实了其抗肿瘤潜能。

蛋白质降解靶向嵌合体( proteolysis targeting chimeras,PROTACs)可高效降解蛋白质从而实现多种疾病治疗,受到了科研人员广泛关注。尽管前景看好,传统PROTAC小分子的药代动力学行为并不理想,并且缺乏肿瘤特异性。其持续保持的高效催化降解特性会不可控降解正常组织部位POI蛋白,从而导致严重毒副作用,极大限制了其临床应用。因此,精准递送PROTAC分子至肿瘤部位并有效降解瘤内目标蛋白对开发PROTAC抗肿瘤药物至关重要。

针对上述挑战,于海军课题组2022年7月26日在Nature Communications发表了题为“Engineered bioorthogonal POLY-PROTAC nanoparticles for tumour-specific protein degradation and precise cancer therapy”的研究论文。

该研究在于海军课题组前期发展多种肿瘤微环境响应的智能递药系统基础上(Adv Mater, 2020. 1907210; Adv Mater 2021, 2101155; Adv Mater, 2021, 2102668.),创新性提出了一种聚合物化PROTAC(POLY-PROTAC)纳米治疗策略,实现了肿瘤特异性PROTAC递送和蛋白降解。研究成果展示了POLY-PROTAC精准降解目标蛋白以及基于PROTAC的高效肿瘤治疗前景。

为实现PROTAC的精准肿瘤递送,研究人员首先合成了系列基于von Hipel-Lindau (VHL) 配体的小分子PROTACs,然后通过共价的可逆加成-断裂链转移聚合(RAFT)将含有二硫键修饰的前体PROTACs连接在两亲性的高分子聚合物上。该高分子聚合物可自组装形成均一稳定的纳米粒,且具有肿瘤细胞外酶环境,胞内酸环境和还原环境的响应性,从而该纳米粒可实现肿瘤组织的特异性聚集和高效渗透。

生物正交POLY-PROTAC纳米粒用于肿瘤特异性蛋白降解和精准治疗示意图

此外,研究人员对该纳米粒进行了叠氮化修饰以通过生物正交策略进一步增加纳米粒在肿瘤组织的蓄积滞留。为此,研究人员设计了载有DBCO基团的肿瘤细胞外微酸环境响应的预靶向纳米粒,该纳米粒可在肿瘤细胞外微酸环境下解离并暴露DBCO基团,从而通过点击化学反应捕获叠氮修饰的POLY-PROTAC纳米粒。

滞留的N3@POLY-PROTAC纳米粒在肿瘤微环境中过表达的MMP-2酶作用下实现PEG脱壳从而更易在肿瘤组织渗透和被肿瘤细胞摄取;进入细胞后,纳米粒的肿瘤细胞内微酸环境响应性使其解离并恢复其荷载的光敏剂焦脱镁叶绿素a(PPa)的荧光活性,与此同时过表达的谷胱甘肽(GSH)切断连接PROTAC分子的二硫键将其释放以降解目标蛋白。

研究人员证明了该生物正交的POLY-PROTAC纳米粒联合光动力治疗可有效激活凋亡蛋白caspase-3,从而实现高效抗肿瘤作用。

该研究成果提出了一种特异性递送PROTAC分子至肿瘤部位的通用型纳米平台,并证实了其抗肿瘤潜能。

同济大学联合培养博士生高晶为论文第一作者,上海药物所于海军研究员为本文通讯作者。复旦大学附属中山医院徐辉雄教授,华东师范大学徐志爱教授为共同通讯作者。华东师范大学联合培养博士生候博、上海药物所博士后祝奇文分别为本文的生物正交化学和PROTAC分子设计优化提供了支撑。上海药物所郑明月课题组、徐田锋课题组和武汉大学陈宜鸿教授给予了大力支持。上海药物所黄敏研究员在肿瘤模性构建方面给予了专业指导。

该研究得到了国家自然科学基金,上海市科委国家合作项目,上海市健康委员会等项目的资助。该研究中生物效应评价部分得到了张江实验室国家蛋白质科学研究(上海)设施的大力支持。

全文链接

https://doi.org/10.1038/s41467-022-32050-4

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    2022-08-16 liuli5079
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    2023-04-25 liye789132251
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肿瘤复发、化疗耐药和转移仍然是癌症治疗中未解决的问题。最近的一种方法是仔细检查临床上用于治疗其他疾病的药物,并修改它们的结构以增加对癌细胞的选择性。

百奥赛图与LiberoThera共同开发全人GPCR抗体药物取得里程碑式进展

机制上,这些克隆可通过增强的ADCC效应来耗竭肿瘤微环境中的Treg,也可通过抑制其配体CCL1介导的CCR8信号通路来抑制肿瘤微环境中的Treg活性,进而达到增强抗肿瘤免疫反应的目的