Therapeutic miRNA Modulation of Hepatocellular Carcinoma Using Ultrasound Guided Drug Delivery

使用超声引导药物输送对肝细胞癌进行治疗性 miRNA 调节

• 批准号: 9299022
• 负责人: Jeremy Dahl
• 金额: $ 61.79万
• 依托单位: STANFORD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-04-01 至 2022-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9299022
• 关键词: Acoustics; Adverse effects; Aftercare; Algorithms; Anatomy; Animals; Antineoplastic Agents; Apoptosis; Blood Circulation; Catheters; Clinical; Clinical Treatment; Control Groups; Development; Dimensions; Dose; Doxorubicin; Drug Delivery Systems; Ensure; FDA approved; Feedback; Gene Expression; Genes; Genetic; Glycolates; Goals; Gold; Growth; Hepatic; Histology; Human; Image; Immunocompetent; Immunofluorescence Microscopy; Incidence; Inhibition of Apoptosis; Interventional radiology; Liver; Location; Malignant Epithelial Cell; Malignant Neoplasms; Malignant neoplasm of liver; Mediating; MicroRNAs; Microbubbles; Modeling; Molecular Target; Monitor; Motion; Mus; Neoplasm Metastasis; Oligonucleotides; Oncogenic; Oryctolagus cuniculus; Pathogenesis; Patients; Pattern; Pharmaceutical Preparations; Play; Primary carcinoma of the liver cells; Recurrence; Regimen; Resistance; Role; System; Testing; Therapeutic; Therapeutic Effect; Time; Translating; Treatment Efficacy; Treatment outcome; Tumor Volume; Ultrasonography; United States; Vascular Permeabilities; Xenograft procedure; base; cancer type; chemotherapy; clinical application; clinical translation; conventional therapy; cytotoxic; experimental study; image guided; imaging biomarker; immunoregulation; improved; in vivo; mouse model; nanocarrier; nanoparticle; neoplastic cell; non-invasive imaging; novel; novel therapeutic intervention; novel therapeutics; nuclease; overexpression; restoration; treatment effect; treatment response; treatment strategy; tumor; tumor growth

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.

肝细胞癌（HCC）是肝脏的常见且致命的癌症，发生率增加 曼联说。由于当前的治疗选择有限，因此需要新的治疗策略， 特别是对于那些对阿霉素和其他化学疗法具有抗性的人。 microRNA（mirnas）是 有效的基因表达调节剂在异常表达时，在癌症发展中起着强烈的作用 和进展。已经确定了两个miRNA miRNA-122和miRNA-21，在肿瘤中起主要作用 HCC中的生长，转移和化学抗性。两种miRNA功能的治疗恢复 补充内源miRNA-122的寡核苷酸模仿，并抑制过表达的miRNA-21 反义-MIR-21（Antimir-21）不仅有可能减慢HCC的生长和转移，而且还具有敏感性 这些肿瘤为阿霉素。但是，一个关键的挑战是能够同质交付这些代理的能力 在体内具有高效率进入肿瘤细胞。使用超声（US）和微泡（MB）介导的药物 交付平台，我们最近首次证明了治疗性miRNA可以成功 当将miRNA加载到FDA批准的聚乳糖甘氨酸中时，在体内的小鼠中递送到HCC中 酸） - 纳米颗粒（PLGA-NP）。推定的关键机制和MB介导的交付是增强的 由声气水引起的血管通透性。但是，为了实现高效的癌症药物递送治疗 由于未经处理的区域的复发率最小，在空间上均匀的递送模式 肿瘤至关重要。我们假设miRNA-122和Antimir-21的均匀递送模式可以是 当整个肿瘤体积成功诱导气蚀时，可实现，导致强大的直接抗癌 对阿霉素化学疗法的效果和敏感性细胞。我们将开发和测试新的动议 - 用实时的被动式空化成像定量的补偿美国指导的药物输送平台 反馈算法在肿瘤体积上实施了美国系统。在此成像路线图的指导下， 在治疗期间，将实时调整几个治疗参数，以确保 均匀，有效的治疗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中的任何免疫调节作用 免疫能力小鼠中的模型。另外，作为临床翻译的下一步，我们将移动这种治疗性 从小动物到大动物（兔子）接近，并将其与经导管肝动脉结合 给药以近似于当前的临床肝导向疗法。成功完成将铺平 一种新型的遗传重编程方法，用于治疗抗焦霉素的HCC 表示miRNA，并暗示了常规化学疗法（例如阿霉素）的协同作用。 治疗性miRNA调节可能会满足HCC患者的当前治疗空隙。而且，这种治疗方法 策略可以很容易地适应为HCC和其他癌症提供其他治疗剂。