Circumvent PEGylation dilemma by implementing matrix metalloproteinase-responsive chemistry for promoted tumor gene therapy
Circumvent PEGylation dilemma by implementing matrix metalloproteinase-responsive chemistry for promoted tumor gene therapy
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通过实施基质金属蛋白酶响应化学来促进肿瘤基因治疗，规避聚乙二醇化困境
DOI：
10.1016/j.cclet.2020.07.027
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发表时间：
2020-07
影响因子：
9.1
通讯作者：
Chen Qixian
中科院分区：
文献类型：
--
作者：
Wang Jingyun;Wang Hao;Cui Hongyan;Sun Peng;Yang Xi;Chen Qixian
聚乙二醇（PEGylation）表面修饰已被认为是减少生物医学设备非特异性反应的有力策略。一旦应用于药物/基因传递系统的制造，聚乙二醇化已被证明可以显著改善其在生理环境中的生物相容性和隐蔽性。尽管如此，由于聚乙二醇化，不情愿的细胞膜亲和性因此细胞摄取效率带来了进一步的问题，这些问题必须得到解决。针对这种聚乙二醇化的困境，我们尝试在聚乙二醇-聚{N'-[N-（2-氨基乙基）-2-氨基乙基]阿斯巴胺}PAsp（DET）嵌段共聚物之间引入肽链（GPLGVRG），其中阳离子PAsp（DET）可以与pDNA自组装成纳米级的复合物核。值得注意的是肽链，其氨基酸序列可以被基质金属蛋白酶（MMPs）特异性识别和降解（在肿瘤细胞外环境中过表达）。因此，我们随后的研究证实，在MMPs处理后，PEGylation从上述多聚胶束上容易分离，从而提高了细胞膜亲和性和细胞摄取效率。此外，通过PAsp（DET）直接破坏核内体膜的稳定性，也证实了促进了核内体的逃逸，进一步阐明了这是由于酸性核内体中PAsp（DET）的去聚乙二醇化和电荷密度升高所致。去聚乙二醇化的这些好处最终促进了受影响细胞的基因表达和基于抗血管生成方法的有效肿瘤生长抑制。因此，我们开发的策略为克服PEGylation的困境提供了一种简单的方法，可以为药物/基因传递系统的设计提供信息。
Surface modification by poly(ethylene glycol) (PEGylation) has been acknowledged as a powerful strategy in minimizing non-specific reactions for biomedical devices. Once applied into manufacture of drug/gene delivery systems, PEGylation has demonstrated to significantly improve their biocompatibility and stealthiness in physiological environment. Nonetheless, reluctant cell membrane affinities thus cellular uptake efficiencies owing to PEGylation brought up further issues that are imperative to be resolved. Pertain to this PEGylation dilemma, we attempted to introduce peptide (GPLGVRG) linkage between block copolymer of PEG-poly{N'-[N-(2-aminoethyl)-2-aminoethyl]aspartamide} PAsp(DET), wherein the cationic PAsp(DET) could self-assemble with pDNA into nanoscaled complex core. Noteworthy was the peptide linkage whose amino acids sequence could be specifically recognized and degraded by matrix metalloproteinases (MMPs) (overexpressed in extracellular milieu of tumors). Therefore, our subsequent studies validated facile detachment of PEGylation from the aforementioned polyplex micelles upon treatment of MMPs, which elicited improved cytomembrane affinities and cellular uptake efficiencies. In addition, promoted escape from endosome entrapment was also confirmed through direct endosome membrane destabilization by PAsp(DET), which was further elucidated to be attributable to dePEGylation as well as elevated charged density of PAsp(DET) in acidic endosomes. These benefits from dePEGylation eventually contributed to promoted gene expression at the affected cells and potent tumor growth suppression based on anti-angiogenic approach. Therefore, our developed strategy has provided a facile approach in overcoming the dilemma of PEGylation, which could be informative in design of drug/gene delivery systems.
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影响因子：
46.2
作者：
Karimi M;Ghasemi A;Sahandi Zangabad P;Rahighi R;Moosavi Basri SM;Mirshekari H;Amiri M;Shafaei Pishabad Z;Aslani A;Bozorgomid M;Ghosh D;Beyzavi A;Vaseghi A;Aref AR;Haghani L;Bahrami S;Hamblin MR
通讯作者：
Hamblin MR
影响因子：
18.3
作者：
Guo, Xia;Huang, Leaf
通讯作者：
Huang, Leaf
DOI：
10.1016/b978-0-12-814031-4.00011-8
发表时间：
2019
期刊：
Characterization and Biology of Nanomaterials for Drug Delivery
影响因子：
--
作者：
Y. Bal
通讯作者：
Y. Bal
影响因子：
16.1
作者：
Kopecek, Jindrich
通讯作者：
Kopecek, Jindrich
影响因子：
--
作者：
M. Sioud
通讯作者：
M. Sioud