Therapeutic miRNA Modulation of Hepatocellular Carcinoma Using Ultrasound Guided Drug Delivery

肝细胞癌（HCC）是一种常见的致命性肝癌， 美国。由于目前的治疗选择有限，迫切需要新的治疗策略， 特别是对于那些对阿霉素和其它化疗有抗性的患者。microRNAs（miRNAs） 一种有效的基因表达调节剂，当异常表达时，在癌症发展中起着重要作用 和进步。两种miRNA，miRNA-122和miRNA-21，已被鉴定在肿瘤中起主要作用。 肝癌的生长、转移和化疗耐药性。两种miRNAs功能的治疗性恢复， 补充内源性miRNA-122的寡核苷酸模拟物并用 反义miR-21（antimiR-21）不仅具有减缓HCC生长和转移的潜力， 阿霉素治疗肿瘤然而，一个关键的挑战是均匀地递送这些药剂的能力， 在体内高效地转化为肿瘤细胞。使用超声（US）和微泡（MB）介导的药物 我们最近首次证明，治疗性miRNAs可以成功地 当将miRNA装载在FDA批准的聚（乳酸-共-乙醇酸）中时， 酸）-纳米颗粒（PLGA-NP）。US和MB介导的递送的假定关键机制是增强的 由声空化引起的血管渗透性。然而，为了实现有效的癌症药物递送治疗， 由于未充分治疗区域的复发率最低， 肿瘤是关键。我们假设miRNA-122和antimiR-21的均匀传递模式可以是 当在整个肿瘤体积中成功诱导空化时实现，导致强的直接抗癌作用。 影响和敏感性肝癌细胞阿霉素化疗。我们会研发并测试一种新的运动- 具有基于实时被动空化成像的定量测量的补偿US引导的药物递送平台 在肿瘤体积中的US系统上实施的反馈算法。在此成像路线图的指导下， 在治疗期间可以实时调整几个治疗参数 均匀和有效的治疗性miRNA递送，在HCC中具有有利的长期治疗效果。 此外，我们将评估我们的治疗方法在同基因HCC中的任何免疫调节作用 免疫活性小鼠模型。此外，作为临床翻译的下一步，我们将把这种治疗方法 从小动物到大动物（兔），将其与经导管肝动脉联合联合收割机 给药以接近目前的临床肝脏定向疗法。成功完成将为 一种新的基因重编程方法治疗异常靶向的阿霉素耐药HCC的方法 表达的miRNA，并暗示与常规化疗如阿霉素的协同作用。 治疗性miRNA调节可以满足HCC患者目前的治疗空白。此外，这种治疗 可以容易地调整策略以将其它治疗剂递送至HCC和其它癌症。

Hepatocellular carcinoma (HCC) is a common and deadly cancer of the liver with increasing incidence in the United Stated. New therapeutic strategies are critically needed as current treatment options are limited, particularly for those who are resistant to doxorubicin and other chemotherapies. MicroRNAs (miRNAs) are potent gene expression regulators that when aberrantly expressed, play a profound role in cancer development and progression. Two miRNAs, miRNA-122 and miRNA-21, have been identified to play a major role in tumor growth, metastasis and chemoresistance in HCC. Therapeutic restoration of both miRNAs functions by supplementing oligonucleotide mimics of endogenous miRNA-122 and inhibiting overexpressed miRNA-21 with antisense-miR-21 (antimiR-21) has the potential to not only slow HCC growth and metastasis, but also sensitize these tumors to doxorubicin. A key challenge, however, is the ability to deliver these agents homogenously and with high efficiency into tumor cells in vivo. Using an ultrasound (US) and microbubble (MB) mediated drug delivery platform, we have recently demonstrated for the first time that therapeutic miRNAs can be successfully delivered into HCC in mice in vivo when the miRNAs were loaded in an FDA-approved poly(lactic-co-glycolic acid)-nanoparticle (PLGA-NP). The putative key mechanism to US and MB mediated delivery is the enhanced vascular permeability caused by acoustic cavitation. However, to achieve efficient cancer drug delivery therapy with minimal recurrence rates from insufficiently treated regions, a spatially homogeneous delivery pattern in the tumors is critical. We hypothesize that a homogeneous delivery pattern of miRNA-122 and antimiR-21 can be achieved when cavitation is successfully induced in the entire tumor volume, resulting in strong direct anticancer effects and sensitizing HCC cells to doxorubicin chemotherapy. We will develop and test a new motion- compensated US-guided drug delivery platform with a real-time passive cavitation-imaging-based quantitative feedback algorithm implemented on the US system in the tumor volume. Guided by this imaging roadmap, adjustment of several treatment parameters will be possible in real-time during the treatment to ensure homogeneous and efficient therapeutic miRNA delivery with favorable long-term treatment effects in HCC. Furthermore, we will assess any immunomodulatory effects of our treatment approach in a syngeneic HCC model in immunocompetent mice. Also, as a next step towards clinical translation, we will move this therapeutic approach from small to a larger animals (rabbits) and will combine it with transcatheter hepatic arterial administration to approximate current clinical liver-directed therapies. The successful completion will pave the way for a novel genetic reprogramming approach for treating doxorubicin-resistant HCC that targets aberrantly expressed miRNA and implies synergistic effects with conventional chemotherapy such as doxorubicin. Therapeutic miRNA modulation may fulfill the current therapeutic void for HCC patients. Moreover, this treatment strategy may be readily adapted to deliver other therapeutics to HCC and to other cancers.