High intensity focused ultrasound enhanced drug delivery for local therapy of hep

高强度聚焦超声增强药物输送用于肝癌局部治疗

• 批准号: 7873039
• 负责人: JOO HA HWANG
• 金额: $ 7.76万
• 依托单位: UNIVERSITY OF WASHINGTON
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-07-01 至 2011-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7873039
• 关键词: Ablation; Acoustics; Albumins; Applications Grants; Area; Blood Vessels; Blood capillaries; Capillary Permeability; Cells; Chemoembolization; Collaborations; Complex; Data; Diffusion; Doxorubicin; Drug Delivery Systems; Drug vehicle; Evans blue stain; Focused Ultrasound Therapy; Future; Goals; Grant; Hemostatic function; Image; Label; Local Therapy; Mechanics; Medical; Modeling; Multi-Drug Resistance; Penetration; Permeability; Pharmaceutical Preparations; Physiologic pulse; Primary carcinoma of the liver cells; Recurrence; Research; Research Design; Research Personnel; Role; Stream; Therapeutic; Tissues; Toxic effect; Ultrasonography; Vascular Permeabilities; capillary; chemotherapeutic agent; effective therapy; improved; in vivo; insight; interest; nanoparticle; neoplastic cell; novel; public health relevance; response; small molecule; tumor

DESCRIPTION (provided by applicant): The proposed research is intended to investigate the potential for pulsed HIFU to enhance drug penetration into the interstitium of tumors. This has particular applications to hepatocellular carcinoma (HCC), where localized therapy has demonstrated benefit; however, local recurrence is common. Ultrasound enhanced drug delivery can potentially be used in conjunction with TACE to improve local response and control. These studies are designed to provide additional insight into the acoustic mechanisms involved in ultrasound enhanced (cavitation, microstreaming, streaming). The concept of ultrasound enhanced drug delivery is extremely complex. It is highly likely that several mechanisms are involved and different ultrasound parameters will be needed to harness these effects. For example, it has been demonstrated that intravascular cavitation will increase capillary permeability in normal capillaries. Intravascular cavitation also appears to enhance permeability in capillaries of tumors permitting larger molecules, such as nanoparticles, to traverse the vascular barrier in greater concentrations. However, once these drug-loaded nanoparticles enter the interstitium, their penetration is limited by their size and diffusion. What has yet to be demonstrated is whether ultrasound can enhance the penetration of these molecules into the interstitum to exert effect on viable tumor cells that are not located adjacent to a vessel and the mechanisms involved. In addition, there is the possibility of ultrasound enhancing penetration of drug directly into the cell. The intent of this R03 grant is to obtain additional supporting data that could be used to support an R01 application to further investigate the role of ultrasound in enhancing the delivery of drug. In future studies, I intend to investigate the use of pulsed HIFU to enhance vascular permeability, followed by enhanced penetration. In addition, I have developed collaborations with other investigators who are developing novel nanoparticle vehicles for drugs that could be used in conjunction with ultrasound for targeted drug delivery. PUBLIC HEALTH RELEVANCE: The overall aim of this study is to investigate the use of pulsed HIFU for enhancing the penetration of a chemotherapeutic agent into the interstitium of tumors and to investigate the potential mechanisms involved. If effective, pulsed HIFU potentially could be used in conjunction with novel drug delivery vehicles (e.g., drug eluting beads or nanoparticles) to deliver newer chemotherapeutic agents for more effective treatment of localized HCC while limiting systemic toxicity. The overall hypothesis of this research is that pulsed HIFU can enhance penetration of small molecules into the interstitium of tumors such as hepatocellular carcinoma.

描述（由申请人提供）： 拟议的研究旨在研究脉冲HIFU增强药物渗透到肿瘤间质中的潜力。这在肝细胞癌（HCC）中具有特殊的应用，在该局部治疗已显示出好处。但是，局部复发很常见。超声增强的药物输送可能与TACE结合使用以改善局部反应和控制。这些研究旨在提供对超声增强（空化，微流，流媒体）涉及的声学机制的更多见解。超声增强药物输送的概念非常复杂。很可能涉及几种机制，并且需要不同的超声参数来利用这些效果。例如，已经证明血管内气蚀会增加正常毛细血管中的毛细血管渗透性。血管内气蚀似乎还提高了允许较大分子（例如纳米颗粒）的毛细血管中的渗透性，以较高的浓度横穿血管屏障。但是，一旦这些负载的纳米颗粒进入了间质，它们的穿透力就受其大小和扩散的限制。尚未证明的是，超声是否可以增强这些分子在星座中的渗透，从而对不在容器附近的可行肿瘤细胞和所涉及的机制中发挥作用。另外，有可能直接增强药物的渗透到细胞中。该R03赠款的目的是获得其他支持数据，这些数据可用于支持R01应用程序，以进一步研究超声在增强药物递送中的作用。在未来的研究中，我打算研究使用脉冲HIFU来增强血管通透性的使用，然后提高穿透性。此外，我还与其他正在开发新型纳米颗粒的药物的研究人员进行了合作，这些纳米颗粒车辆可与超声一起用于靶向药物递送。 公共卫生相关性：这项研究的总体目的是研究使用脉冲HIFU来增强化学治疗剂进入肿瘤间质的渗透，并研究所涉及的潜在机制。如果有效，则可能与新型药物输送车（例如药物洗脱珠或纳米颗粒）结合使用脉冲HIFU，以提供更新的化学治疗剂，以更有效地治疗局部HCC，同时限制全身毒性。这项研究的总体假设是，脉冲HIFU可以增强小分子在肿瘤中的渗透，例如肝细胞癌。

项目成果

Enhancement of Small Molecule Delivery by Pulsed High-Intensity Focused Ultrasound: A Parameter Exploration.

通过脉冲高强度聚焦超声增强小分子输送：参数探索。

• DOI: 10.1016/j.ultrasmedbio.2015.12.009
• 发表时间: 2016
• 期刊: Ultrasound in medicine & biology
• 影响因子: 2.9
• 作者: Zhou,Yufeng;Wang,Yak-Nam;Farr,Navid;Zia,Jasmine;Chen,Hong;Ko,BongMin;Khokhlova,Tatiana;Li,Tong;Hwang,JooHa
• 通讯作者: Hwang,JooHa