<br>使用封装在 PLGA 纳米粒子中的短抗种子 PNA 抑制下一代 miRNA,Journal of Controlled Release

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使用封装在 PLGA 纳米粒子中的短抗种子 PNA 抑制下一代 miRNA
Journal of Controlled Release ( IF 10.5 ) Pub Date : 2020-08-21 , DOI: 10.1016/j.jconrel.2020.08.026
Shipra Malik ₁ , Jihoon Lim ₂ , Frank J Slack ₂ , Demetrios T Braddock ₃ , Raman Bahal ₁

Affiliation

选择性抑制 microRNA (miRNA) 为癌症治疗提供了新途径。虽然目前大多数抗 miRNA (antimiR) 试剂都靶向全长 miRNA，但在这里，我们研究了新型纳米颗粒递送的短 PNA 探针，其中包含靶向 miRNA 种子区域的阳离子结构域，以实现有效的抗 miR 治疗。为了验证概念，我们测试了靶向 miRNA-155 的 PNA，并采用基于聚乳酸-乙醇酸 (PLGA) 的纳米颗粒制剂进行递送。对包含短 PNA 探针的 PLGA 纳米粒子 (NP) 的综合评估显示，与传统的非阳离子 PNA 探针相比，其负载量、释放曲线和均匀的尺寸分布显着优越。共聚焦显微镜和流式细胞术分析显示，含有短 PNA 探针的 PLGA NP 在细胞质中具有高效的转染效率和均匀分布。功能分析还证实了有效的 miRNA-155 抑制，包括对其下游靶蛋白的影响。此外，在抑制 miR-155 后，在异种移植小鼠模型中全身递送含有短 PNA 探针的 PLGA 纳米颗粒后，观察到肿瘤生长减少。没有证据表明与小鼠体内全身递送含有短 PNA 探针的 PLGA NP 相关的急性或慢性毒性。总的来说，在本文中，我们提出了一种基于 PLGA 纳米颗粒的新型 antimiR 策略，该策略可传递短 PNA 探针，用于潜在的癌症治疗。

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Next generation miRNA inhibition using short anti-seed PNAs encapsulated in PLGA nanoparticles

Selective inhibition of microRNAs (miRNAs) offers a new avenue for cancer therapeutics. While most of the current anti-miRNA (antimiR) reagents target full length miRNAs, here we investigate novel nanoparticle-delivered short PNA probes containing cationic domains targeting the seed region of the miRNA for effective antimiR therapy. For proof of concept, we tested PNAs targeting miRNA-155 and employed poly(lactic--glycolic acid) (PLGA)-based nanoparticle formulation for delivery. A comprehensive evaluation of PLGA nanoparticles (NPs) containing short PNA probes showed significantly superior loading, release profile, and uniform size distribution, compared to conventional non-cationic PNA probes. Confocal microscopy and flow cytometry analyses showed efficient transfection efficiency and uniform distribution of PLGA NPs containing short PNA probes in the cytoplasm. Functional analysis also confirmed efficient miRNA-155 inhibition including an effect on its downstream target proteins. Further, reduced tumor growth was observed after systemic delivery of PLGA nanoparticles containing short PNA probes in a xenograft mouse model following inhibition of miR-155. There was no evidence of acute or chronic toxicity associated with systemic delivery of PLGA NPs containing short PNA probes in the mice. Overall, in this paper we present a novel antimiR strategy based on PLGA nanoparticle delivered short PNA probes for potential cancer therapy.

更新日期：2020-08-21

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