Therapeutic miRNA Modulation of Hepatocellular Carcinoma Using Ultrasound Guided Drug Delivery

肝细胞癌是一种常见的致命性肝癌，其发病率在世界范围内呈上升趋势。 美联航。由于目前的治疗选择有限，迫切需要新的治疗策略， 尤其是那些对阿霉素和其他化疗药物有抗药性的人。微RNA(MiRNAs)是 强大的基因表达调节剂，当异常表达时，在癌症的发展中发挥着深远的作用 和进步。已发现两种miRNA，miRNA-122和miRNA-21在肿瘤中起主要作用。 肝细胞癌的生长、转移和化疗耐药两种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抑制过表达的miRNA-21 反义miR-21(antimiR-21)不仅有可能减缓肝癌的生长和转移，而且还具有增敏作用 这些肿瘤对阿霉素的抗药性。然而，一个关键的挑战是能否均匀地和 在体内高效地进入肿瘤细胞。使用超声(US)和微泡(MB)介导的药物 最近，我们首次证明了治疗性miRNAs可以成功地 当miRNAs被FDA批准的聚乳酸-乙醇酸负载到小鼠体内的肝癌中 酸)-纳米粒(PLGA-NP)。US和MB介导的传递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，要实现高效的癌症药物输送治疗 在治疗不充分的区域复发率最低的情况下， 肿瘤是至关重要的。我们假设miRNA-122和AntimiR-21的同质递送模式可以是 当在整个肿瘤体积内成功地诱导空化时实现，从而产生强大的直接抗癌 阿霉素化疗对肝癌细胞的影响及增敏作用。我们将开发和测试一项新的动议- 基于实时被动空化成像的补偿式超声引导定量给药平台 反馈算法在US系统中实现的肿瘤体积。在这个成像路线图的指引下， 在治疗过程中可以实时调整多个治疗参数，以确保 均匀有效的治疗性miRNA输送，对肝癌具有良好的长期治疗效果。 此外，我们将评估我们的治疗方法在同基因肝癌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，我们将把这个治疗性的 从小动物到大动物(兔)的方法，并将其与经导管肝动脉结合 给药接近于目前的临床肝脏导向疗法。这项工程的成功竣工将为 一种新的基因重编程方法治疗靶点异常的阿霉素耐药肝细胞癌 表达miRNA，并暗示与阿霉素等传统化疗的协同作用。 治疗性miRNA调节可能填补目前对肝癌患者的治疗空白。而且，这种治疗， 该策略可能很容易被调整，以向肝癌和其他癌症提供其他治疗方法。

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.