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Nat Commun:发表肿瘤靶向新机制:助力癌症精准诊疗!

2019-11-05 佚名 BioArt

药物递送一直是人们关注的热点问题。传统的分子化疗药物和造影剂在体内会被快速代谢清除,所以生物利用度不到3%。纳米药物虽然具有被动靶向和主动靶向效应,但是在体内的滞留情况差强人意,很多情况下只有不到5%的注射剂量到达实体瘤。此外,大多数纳米药物通过非特异性摄入而沉积在肝脏和脾脏中,从而引起系统毒性。

药物递送一直是人们关注的热点问题。传统的分子化疗药物和造影剂在体内会被快速代谢清除,所以生物利用度不到3%。纳米药物虽然具有被动靶向和主动靶向效应,但是在体内的滞留情况差强人意,很多情况下只有不到5%的注射剂量到达实体瘤。此外,大多数纳米药物通过非特异性摄入而沉积在肝脏和脾脏中,从而引起系统毒性。

近日,国家纳米科学中心赵宇亮院士、王浩研究员与哈尔滨医科大学附属第四医院徐万海团队合作,在Nature Communications发表了题为:A tumour-selective cascade activatable self-detained system for drug delivery and cancer imaging的研究成果(第一作者安红维博士)。他们的团队构建了一种新型肿瘤选择性级联激活自滞留系统(TCASS),用于肿瘤的诊断和治疗。

为了解决药物高效递送问题,国家纳米科学中心王浩课题组基于活体自组装的策略,首次提出了一种全新的肿瘤靶向机制。那么什么是“活体自组装”呢?众所周知,生命体就是一个智能的“加工厂”,这个工厂每时每刻都在运转,根据“各个部门”的需求,将氨基酸、脱氧核苷酸等原料加工成具有生物功能的蛋白质和DNA等生物大分子,去维持生命活动的正常运转。受到这一过程的启发,他们提出了活体自组装的策略,外源提供小分子多肽原料,生命体会根据肿瘤部位的需求,将小分子多肽原料在肿瘤部位原位加工成具有“超能力”的纳米药物,一举消灭肿瘤君。然而,分布在其他器官的小分子多肽原料被代谢器官快速清除,降低了系统毒性。

该团队一直致力于发展体内原位自组装的新型生物纳米材料,系统研究了小分子药物在生命体中的自组装过程和机制,提出了聚集/组装滞留效应(aggregation/assemblyinduced retention (AIR) effect),该效应能够提高造影剂或药物在病灶部位的滞留时间,增强了疾病的诊断和治疗效果(Adv. Mater. 2015, 27, 6125,Adv. Mater. 2016, 2, 254,Nano Letters, 2018, 18, 6229,Angew. Chem.Int. Ed. Engl. 2019,131,15431,Adv. Mater. 2019, 31, 1807175)。

该团队构建了一种新型肿瘤选择性级联激活自滞留系统(a tumour-selective cascade activatable self-detained system , TCASS)作为肿瘤诊疗的一种新策略。在该系统中,小分子多肽经特异性识别肿瘤中过表达的X连锁凋亡抑制蛋白(X-linked inhibitor of apoptosis protein, XIAP),该识别引发肿瘤细胞的caspase-3激活从而引发分子剪切,自组装形成的纳米纤维结构增强在肿瘤组织中的富集和滞留。系统研究了药物靶向富集、肿瘤渗透和器官竞争行为,揭示其在肿瘤部位蓄积和滞留机制。TCASS与典型的纳米载体材料相比,能增强肿瘤穿透能力,表现出高效的分子蓄积和滞留效应。同时,TCASS的代谢行为类似于小分子,可以从肝脏和肾脏迅速排泄,降低系统毒性。最后,作为一种药物递送系统,既可以增强传统化疗药物(例如DOX)的治疗效果,又可以降低其毒副作用。另外一方面通过偶联造影剂,TCASS显着提高了造影剂的特异性和敏感性,并在动物和人离体膀胱癌模型表现出良好的诊断效果。这项研究提供了一种全新肿瘤靶向机制,加速了纳米药物的应用步伐,为纳米药物的基础研究和临床转化开辟了新思路。

原始出处:
An HW1,2, Li LL1, Wang Y1,3, et al.A tumour-selective cascade activatable self-detained system for drug delivery and cancer imaging.Nat Commun. 2019 Oct 24;10(1):4861. doi: 10.1038/s41467-019-12848-5.

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    2020-09-25 liye789132251
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    2020-10-19 liuli5079
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