Acid-transforming polypeptide micelles for targeted nonviral gene delivery
Acid-transforming polypeptide micelles for targeted nonviral gene delivery
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DOI：
10.1016/j.biomaterials.2010.01.019
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发表时间：
2010-04-01
期刊：
影响因子：
14
通讯作者：
Kwon, Young Jik
中科院分区：
文献类型：
--
作者：
Shim, Min Suk;Kwon, Young Jik
治疗性基因的有效传递需要克服关键的细胞外和细胞内障碍。这些包括循环期间的稳定性，靶细胞的内化，促进内体逃逸，以及基因在预定的细胞内隔间(如细胞核)中的定位。通过将DNA与聚乙二醇化的聚酮化丝氨酸[PEG-Poly(KSer)]自组装，合成了在中等酸性的内体中转化结构并将其货运基因释放到细胞质中的胶束。研究证实，缩酮键酸解后，聚(KSer)转变为中性的、天然存在的聚(丝氨酸)，破坏聚乙二醇聚(KSer)/DNA胶束的稳定性。体外研究表明，聚乙二醇聚赖氨酸/脱氧核糖核酸胶束通过有效地解离胞浆中的脱氧核糖核酸，比聚乙二醇聚赖氨酸/脱氧核糖核酸胶束和聚L赖氨酸/脱氧核糖核酸多聚体更能有效地转染NIH313细胞。此外，聚乙二醇聚(KSer)/DNA胶束的核心通过可酸裂解的含胺支链进行了交联化，得到的交联型聚乙二醇聚(KSer)/DNA胶束在有血清存在的情况下表现出更好的转染性。叶酸(FA)在酸转化胶束的聚乙二醇端的偶联导致表达FA受体的HeLa细胞在NIH313细胞上选择性地增加了细胞内化和转染率，这意味着使用FA-聚乙二醇聚(KSer)/DNA胶束进行肿瘤靶向基因传递的可能性。本研究表明，酸转化聚乙二醇聚(KSer)/DNA胶束是一种很有前途的非病毒载体，可用于刺激响应性、高效、生物相容性和靶向性的基因传递。(C)2010爱思唯尔有限公司。保留所有权利。
Efficient delivery of therapeutic genes requires overcoming key extracellular and intracellular barriers. These include stability during circulation, internalization by target cells, facilitated endosomal escape, and localization of genes in destined intracellular compartments (e.g., nucleus). Micelles that transform their structure in the mildly acidic endosome and release their cargo genes into the cytoplasm were synthesized by self-assembling DNA with PEG-conjugated poly(ketalized serine) [PEG-poly(kSer)]. It was confirmed that, upon acid-hydrolysis of ketal linkages, poly(kSer) converts to neutral and naturally occurring poly(serine), destabilizing PEG-poly(kSer)/DNA micelles. In vitro studies demonstrated that PEG-poly(kSer) micelles were able to transfect NIH 313 cells more efficiently than both PEG-poly(Lys)/DNA micelles and poly-L-lysine/DNA polyplexes through efficient DNA dissociation in the cytoplasm. In addition, the core of PEG-poly(kSer)/DNA micelles were cross-linked via acid-cleavable amine-bearing branches, and the resulting cross-linked PEG-poly(kSer)/DNA micelles showed improved transfection capability in the presence of serum. Conjugation of folic acids (FAs) at the PEG termini of the acid-transforming micelles resulted in selectively increased cellular internalization and transfection of FA receptor-expressing HeLa cells over NIH 313 cells, implicating the possibility of cancer-targeted gene delivery using FA-PEG-poly(kSer)/DNA micelles. This study demonstrates that the acid-transforming PEG-poly(kSer)/DNA micelles are promising nonviral vectors for stimuli-responsive, efficient, biocompatible, and targeted gene delivery. (C) 2010 Elsevier Ltd. All rights reserved.