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

文獻鏈接：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.

結果與討論

LNBs的制備與表征

在這項研究中，開發(fā)了一種高效的腫瘤靶向超聲響應LNBs系統(tǒng)，用于靶向遞送和釋放miRNA。首先，將DSPE-PEG-COOH接枝到PEI上，得到帶正電的脂質(zhì)體（DSPE-PEG-PEI）。

DSPE-PEG-PEI與DSPE-PEG2000-Mal結合，允許在LNB表面引入馬來酰亞胺官能團，同時將PFP封裝在LNB內(nèi)。隨后，RGD（精氨酸-甘氨酸-天冬氨酸）肽通過馬來酰亞胺官能團共價連接到LNBs表面。RGD在這些LNB中的主要作用是靶向HCC。RGD因其特定的結構和電荷分布而對αvβ3整合素具有獨特的親和力。RGD中的精氨酸和天冬氨酸殘基與αvβ3整合素建立了鹽橋。

同時，甘氨酸的緊湊結構使肽具有精確結合的最佳構象[引用29]。這使得RGD對αvβ3整合素特別特異，這是一種已知在腫瘤細胞中過表達的整合素。

我們之前的工作也證實了RGD肽在引導載體特異性靶向HepG2細胞方面的功效。通過靜電吸附將MiRNA-199a-3p負載到LNBs上，形成PFP@miR-RGD-LNBs.ζ電位分析結果表明PFP@RGD-LNBs為36.2?±?0.4?mV，而PFP@miR-RGD-LNBs是21.6?±?0.9?ζ電位的變化表明基因負載LNBs的成功制備。

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