Synthesis, characterization, and evaluation of poly (D,L-lactide-co-glycolide)-based nanoformulation of miRNA-150: potential implications for pancreatic cancer therapy.
Synthesis, characterization, and evaluation of poly (D,L-lactide-co-glycolide)-based nanoformulation of miRNA-150: potential implications for pancreatic cancer therapy.
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DOI：
10.2147/ijn.s61949
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发表时间：
2014
影响因子：
8
通讯作者：
Singh AP
中科院分区：
文献类型：
--
作者：
Arora S;Swaminathan SK;Kirtane A;Srivastava SK;Bhardwaj A;Singh S;Panyam J;Singh AP
MicroRNA 是小型（18-22 个核苷酸长）非编码 RNA，通过基因表达的转录后调控在生物过程中发挥重要作用。据报道，它们在包括胰腺癌在内的几种人类恶性肿瘤中存在异常表达和功能意义。最近，我们发现 miR-150 是胰腺癌中的一种新型抑癌 microRNA。此外，在大多数肿瘤病例中，miR-150 的表达下调，表明其恢复可以作为胰腺癌治疗的有效方法。在本研究中，我们开发了一种基于纳米颗粒的 miR-150 递送系统并测试了其体外治疗效果。采用双乳液溶剂蒸发法，我们开发了一种基于聚(D,L-丙交酯-共-乙交酯) (PLGA) 的 miR-150 纳米制剂 (miR-150-NF)。将聚乙烯亚胺（一种阳离子聚合物）掺入 PLGA 基质中以增加 miR-150 的封装。 miR-150-NF 的物理表征表明这些纳米颗粒具有高包封率 (~78%) 并表现出持续释放特性。用 miR-150-NF 处理胰腺癌细胞，可有效地在细胞内递送 miR-150 模拟物，并导致其靶基因 (MUC4) 表达显着下调。 MUC4 的抑制与其相互作用伙伴 HER2 的表达同时减少，并抑制其下游信号传导。此外，用 miR-150-NF 治疗胰腺癌细胞可抑制其生长、克隆形成、运动和侵袭。总之，这些发现表明基于 PLGA 的纳米制剂有可能作为安全有效的纳米载体平台，将 miR-150 递送至胰腺肿瘤细胞。
MicroRNAs are small (18–22 nucleotide long) noncoding RNAs that play important roles in biological processes through posttranscriptional regulation of gene expression. Their aberrant expression and functional significance are reported in several human malignancies, including pancreatic cancer. Recently, we identified miR-150 as a novel tumor suppressor microRNA in pancreatic cancer. Furthermore, expression of miR-150 was downregulated in the majority of tumor cases, suggesting that its restoration could serve as an effective approach for pancreatic cancer therapy. In the present study, we developed a nanoparticle-based miR-150 delivery system and tested its therapeutic efficacy in vitro. Using double emulsion solvent evaporation method, we developed a poly (D,L-lactide-co-glycolide) (PLGA)-based nanoformulation of miR-150 (miR-150-NF). Polyethyleneimine (a cationic polymer) was incorporated in PLGA matrix to increase the encapsulation of miR-150. Physical characterization of miR-150-NF demonstrated that these nanoparticles had high encapsulation efficiency (~78%) and exhibited sustained release profile. Treatment of pancreatic cancer cells with miR-150-NF led to efficient intracellular delivery of miR-150 mimics and caused significant downregulation of its target gene (MUC4) expression. Inhibition of MUC4 correlated with a concomitant decrease in the expression of its interacting partner, HER2, and repression of its downstream signaling. Furthermore, treatment of pancreatic cancer cells with miR-150-NF suppressed their growth, clonogenicity, motility, and invasion. Together, these findings suggest that PLGA-based nanoformulation could potentially serve as a safe and effective nanovector platform for miR-150 delivery to pancreatic tumor cells.