Vitamin-B12-conjugated PLGA-PEG nanoparticles incorporating miR-532-3p induce mitochondrial damage by targeting apoptosis repressor with caspase recruitment domain (ARC) on CD320-overexpressed gastric cancer
Vitamin-B12-conjugated PLGA-PEG nanoparticles incorporating miR-532-3p induce mitochondrial damage by targeting apoptosis repressor with caspase recruitment domain (ARC) on CD320-overexpressed gastric cancer
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DOI：
10.1016/j.msec.2020.111722
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发表时间：
2021-02-01
影响因子：
7.9
通讯作者：
Hu, Yanfeng
中科院分区：
文献类型：
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作者：
Chen, Zhian;Liang, Yanrui;Hu, Yanfeng
在多种方法中，靶向核酸治疗是一种很有前途的抑制胃癌细胞快速生长和转移能力的方法。本研究将维生素B12标记的聚(d，L-丙交酯-乙交酯共聚物)和聚乙二醇纳米粒(PLGA-PEGVB12NPs)引入microRNAs-532-3P模拟物作为靶向基因传递系统(miR-532-3P@PLGA-PEGVB12NPs)，以对抗反式钴胺II(CD320)过表达的GC细胞的进展。PLGA-PEG-VB12纳米粒具有合适的粒径和良好的生物相容性，可以选择性地导入CD320过表达的GC细胞，并显著降低带有半胱氨酸天冬氨酸酶招募结构域(ARC)的凋亡抑制因子的表达。随后，更多的促凋亡蛋白(Bax)从细胞质流入线粒体，形成Bax寡聚，从而导致线粒体损伤，包括线粒体膜电位(MMPs)丧失和线粒体活性氧(MitoROS)的过度产生。此后，线粒体通透性转换孔(MPTP)被打开，随后诱导更多的细胞色素C(Cyto C)从线粒体释放到胞浆中，最终激活了caspase依赖的细胞凋亡途径。因此，我们设计的miR-532-3p@PLGA-PEG-VB12纳米粒具有增强的GC靶向性，并通过激活ARC/Bax/线粒体介导的凋亡信号通路诱导细胞凋亡，最终在体内外显著抑制GC细胞的增殖，为GC的治疗提供了一种有前景的治疗方法。
Among various methods, the use of targeting nucleic acid therapy is a promising method for inhibiting gastric cancer (GC) cells' rapid growth and metastasis abilities. In this study, vitamin B12-labeled poly (d,L-lactide-co-glycolide) and polyethylene glycol nanoparticles (PLGA-PEG-VB12 NPs) were developed for microRNAs-532-3p mimics incorporating as targeting gene delivery systems (miR-532-3p@PLGA-PEG-VB12 NPs) to fight against transcobalamin II (CD320)-overexpressed GC cells' progression. The PLGA-PEG-VB12 NPs with appropriate particle sizes and good bio-compatibility could be selectively delivered into CD320-overexpressed GC cells, and significantly decrease the expression of apoptosis repressor with caspase recruitment domain (ARC). Following that, more pro-apoptotic protein (Bax) flowed from cytoplasm into mitochondria to form Bax oligomerization, thus induced mitochondrial damage, including mitochondrial membrane potentials (MMPs) loss and excessive production of mitochondrial reactive oxygen species (mitoROS). Since that, mitochondrial permeability transition pore (mPTP) was opened, followed by induced more cytochrome c (Cyto C) releasing from mitochondria into cytosol, and finally activated caspase-depended cell apoptosis pathway. Therefore, our designed miR-532-3p@PLGA-PEG-VB12 NPs showed enhanced GC targeting ability, and could induce apoptosis through activating ARC/Bax/mitochondria-mediated apoptosis signaling pathway, finally remarkably suppressed proliferation of GC cells both in vitro and in vivo, which presented a promising treatment for GC.