Hayward Stephen L, Francis David M, Kholmatov Parviz, Kidambi Srivatsan
J Biomed Nanotechnol. 2016 Mar;12(3):554-68. doi: 10.1166/jbn.2016.2194.
MicroRNAs (miRNAs) are endogenous regulators of gene expression that play a pivotal role in biological processes spanning from global homeostasis to disease onset and progression. The ability to manipulate and induce cellular reequilibrium of deregulated miRNA expression profiles by inhibition of oncogenic miRNA or overexpression of tumor suppressor miRNA is a promising cancer strategy, but is currently hindered in application by the lack of nonviral delivery systems. Here we present a lipid nanoparticle (LNP) platform surface coated with Hyaluronic Acid (HA) for the delivery of mature tumor suppressor MicroRNA125a-5p to treat HER2 positive metastatic breast cancer. The delivery platform actively targets patient-derived metastatic breast cancer cells (21MT-1) isolated from the metastatic pleural effusion over normal breast tissue via an intrinsic HA-CD44 mediated endocytosis event, and has the ability to escape from the intracellular endolysosomal pathway for potent gene silencing. Knockdown of the HER2 proto-oncogene at the level of transcription and translation was achieved following HA-LNP mediated transfection with MicroRNA125a-5p. In addition, the PI3K/AKT and MAPK hyperactivated signaling pathways, cellular proliferation, and migration potential were also potently suppressed. Furthermore, the therapeutic efficacy of MicroRNA125a-5p by the HA-LNP platform was demonstrated to be significantly improved as compared to a commercial transfection reagent. This study highlights the therapeutic potential of MicroRNA125a-5p as a standalone treatment of HER2+ metastatic breast cancer via a translational nonviral delivery platform. These findings have major implications on future gene therapy regimens for breast cancer.
微小RNA（miRNA）是基因表达的内源性调节因子，在从整体稳态到疾病发生和发展的生物过程中起着关键作用。通过抑制致癌miRNA或过表达肿瘤抑制miRNA来操纵和诱导失调的miRNA表达谱的细胞再平衡的能力是一种很有前景的癌症治疗策略，但目前由于缺乏非病毒递送系统而在应用中受到阻碍。在此，我们展示了一种表面涂覆有透明质酸（HA）的脂质纳米颗粒（LNP）平台，用于递送成熟的肿瘤抑制性微小RNA125a - 5p以治疗HER2阳性转移性乳腺癌。该递送平台通过内在的HA - CD44介导的内吞作用事件，主动靶向从转移性胸腔积液中分离出的患者来源的转移性乳腺癌细胞（21MT - 1），而不是正常乳腺组织，并具有从细胞内溶酶体途径逃逸以实现有效基因沉默的能力。在用微小RNA125a - 5p进行HA - LNP介导的转染后，HER2原癌基因在转录和翻译水平上被敲低。此外，PI3K/AKT和MAPK过度激活的信号通路、细胞增殖和迁移潜能也受到有效抑制。此外，与市售转染试剂相比，HA - LNP平台对微小RNA125a - 5p的治疗效果有显著提高。本研究强调了微小RNA125a - 5p通过转化性非病毒递送平台作为HER2 +转移性乳腺癌单一治疗方法的治疗潜力。这些发现对未来乳腺癌的基因治疗方案具有重要意义。
