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H2O2-responsive and plaque-penetrating nanoplatform for mTOR gene silencing with robust anti-atherosclerosis efficacy.

ABSTRACT: The mammalian target of rapamycin (mTOR) that controls autophagy and lipid metabolism is pivotal for atherosclerosis initiation and progression. Although blocking the mTOR function with rapamycin and its analogs may stimulate autophagy and consequently attenuate lipid storage and atherosclerotic lesions, only limited success has been achieved in clinical applications due to the unsatisfactory efficacy and safety profiles. In this study, we engineered a cerium oxide nanowire (CeO2 NW)-based RNA interference (RNAi) oligonucleotide delivery nanoplatform for the effective silencing of mTOR and treatment of atherosclerosis. This nanoplatform is composed of the following three key components: (i) a stabilin-2-specific peptide ligand (S2P) to improve plaque targeting and penetration; (ii) polyethylene glycosylation (PEGylation) to extend in vivo circulation time; and (iii) a high aspect ratio CeO2 core to facilitate endosome escape and ensure "on-demand" release of the RNAi payloads through competitive coordination of cytosolic hydrogen peroxide (H2O2). Systemic administration of the nanoplatforms efficiently targeted stabilin-2-expressing plaque and suppressed mTOR expression, which significantly rescued the impaired autophagy and inhibited the atherosclerotic lesion progression in apolipoprotein E-deficient (ApoE-/-) mice fed with a high-fat diet. These results demonstrated that this H2O2-responsive and plaque-penetrating nanoplatform can be a potent and safe tool for gene therapy of atherosclerosis.

SUBMITTER: Gao W

PROVIDER: S-EPMC5868311 | biostudies-literature | 2018 Jan

REPOSITORIES: biostudies-literature

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H2O2-responsive and plaque-penetrating nanoplatform for mTOR gene silencing with robust anti-atherosclerosis efficacy.

Gao Wen W Zhao Yujie Y Li Xiang X Sun Yuhui Y Cai Michelle M Cao Wenhua W Liu Zhenhua Z Tong Lili L Cui Guanwei G Tang Bo B

Chemical science 20171027 2

The mammalian target of rapamycin (mTOR) that controls autophagy and lipid metabolism is pivotal for atherosclerosis initiation and progression. Although blocking the mTOR function with rapamycin and its analogs may stimulate autophagy and consequently attenuate lipid storage and atherosclerotic lesions, only limited success has been achieved in clinical applications due to the unsatisfactory efficacy and safety profiles. In this study, we engineered a cerium oxide nanowire (CeO2 NW)- ...[more]

PMID: 29629115

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Project description:BackgroundRupture of atherosclerotic plaque can cause acute malignant heart and cerebrovascular events, such as acute coronary heart disease, stroke and so on, which seriously threaten the safety of human life and property. Therefore, the early diagnosis and inhibition of atherosclerotic plaque progress still be a vital task.ResultsIn this study, we presented the development of composite mesoporous silica nanoparticle (Ru(bpy)3@SiO2-mSiO2, CMSN)-based nanomedicines (NMs) (Ru(bpy)3@SiO2-mSiO2@SRT1720@AntiCD36, CMSN@SRT@Anti) for accurate diagnosis and treatment of atherosclerosis (AS). In vitro cell experiments showed that both RAW264.7 and oxidized low density lipoprotein (ox-LDL)-stimulated RAW264.7 cells could significantly uptake CMSN@SRT@Anti. Conversely, little fluorescence signal could be observed in CMSN@SRT group, showing the excellent targeting ability of CMSN@SRT@Anti to Class II scavenger receptor, CD36 on macrophage. Additionally, such fluorescence signal was significantly stronger in ox-LDL-stimulated RAW264.7 cells, which might benefit from the upregulated expression of CD36 on macrophages after ox-LDL treatment. For another, compared with free SRT1720, CMSN@SRT@Anti had a better and more significant effect on the inhibition of macrophage foaming process, which indicated that drug-carrying mesoporous silicon with targeting ability could enhance the efficacy of SRT1720. Animal experimental results showed that after the abdominal injection of CMSN@SRT@Anti, the aortic lesions of ApoE-/-mice could be observed with obvious and persistent fluorescence signals. After 4 weeks post-treatment, the serum total cholesterol, aortic plaque status and area were significantly improved in the mouse, and the effect was better than that in the free SRT1720 group or the CMSN@SRT group.ConclusionsThe designed CMSN@SRT@Anti with excellent biocompatibility, high-performance and superior atherosclerosis-targeting ability has great potential for accurate identification and targeted therapy of atherosclerotic diseases.

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H2O2-responsive and plaque-penetrating nanoplatform for mTOR gene silencing with robust anti-atherosclerosis efficacy.

Publications

H<sub>2</sub>O<sub>2</sub>-responsive and plaque-penetrating nanoplatform for mTOR gene silencing with robust anti-atherosclerosis efficacy.

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