文献：Ultrasound-triggered release of miR-199a-3p from liposome nanobubbles for enhanced hepatocellular carcinoma treatment

文献链接：https://www.tandfonline.com/doi/full/10.1080/21691401.2023.2268137#abstract

作者：Xinmin GuoORCID Icon,Jianru LinORCID Icon,Liwen Pan,Kun He,Zhihui Huang,Jialin Chen

摘要：

This study was aimed to develop an efficient tumour-targeted liposome nanobubbles (LNBs) system using ultrasound-targeted nanobubble destruction for enhanced release and transfection of miRNA-199a-3p in hepatocellular carcinoma (HCC) therapy. The prepared LNBs comprised a polyethylene glycol-modified liposome shell and a perfluoropentane (PFP) core. MiRNA-199a-3p was attached to the nanocomposite surface via electrostatic adsorption, while RGD peptide functionalized the LNBs surface for enhanced HCC cell targeting, namely PFP@miR-RGD-LNBs. The LNBs were spherical with a narrow size distribution. The gene-loaded LNBs effectively condensed miR-199a-3p and protected it from enzymatic degradation. Low-intensity focused ultrasound (LIFU) promoted a fast release of miR-199a-3p from the prepared LNBs, thereby enhancing therapeutic effects. The combined application of PFP@miR-RGD-LNBs and LIFU exhibited a more potent inhibitory effect on HepG2 cells than the other groups, potentially due to LIFU promoting rapid and efficient gene release at the target site and increasing cell membrane permeability. Quantitative reverse transcription-polymerase chain reaction analysis revealed significantly increased mRNA expression levels of key apoptosis markers (Bad, Bax, Caspase-9 and Caspase-3) in the PFP@miR-RGD-LNBs + LIFU group compared to other groups. These findings suggest that the prepared LNBs are highly likely to be promising candidates for further exploration of HCC gene delivery and therapy.

结果与讨论

LNBs的制备与表征

在这项研究中，开发了一种高效的肿瘤靶向超声响应LNBs系统，用于靶向递送和释放miRNA。首先，将DSPE-PEG-COOH接枝到PEI上，得到带正电的脂质体（DSPE-PEG-PEI）。

DSPE-PEG-PEI与DSPE-PEG2000-Mal结合，允许在LNB表面引入马来酰亚胺官能团，同时将PFP封装在LNB内。随后，RGD（精氨酸-甘氨酸-天冬氨酸）肽通过马来酰亚胺官能团共价连接到LNBs表面。RGD在这些LNB中的主要作用是靶向HCC。RGD因其特定的结构和电荷分布而对αvβ3整合素具有独特的亲和力。RGD中的精氨酸和天冬氨酸残基与αvβ3整合素建立了盐桥。

同时，甘氨酸的紧凑结构使肽具有精确结合的最佳构象[引用29]。这使得RGD对αvβ3整合素特别特异，这是一种已知在肿瘤细胞中过表达的整合素。

我们之前的工作也证实了RGD肽在引导载体特异性靶向HepG2细胞方面的功效。通过静电吸附将MiRNA-199a-3p负载到LNBs上，形成PFP@miR-RGD-LNBs.ζ电位分析结果表明PFP@RGD-LNBs为36.2 ± 0.4 mV，而PFP@miR-RGD-LNBs是21.6 ± 0.9 ζ电位的变化表明基因负载LNBs的成功制备。

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DSPE-PEG-CHO

DSPE-PEG-CHEMS

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DSPE-PEG-β-cyclodextrin

DSPE-PEG-DBCO

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DSPE-PEG-PEI

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