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

描述（由申请人提供）： 该研究旨在探讨脉冲HIFU增强药物渗透到肿瘤组织中的潜力。这对肝细胞癌（HCC）有特殊的应用，局部治疗已证明是有益的;然而，局部复发是常见的。超声增强药物递送可能与TACE结合使用，以改善局部反应和控制。这些研究旨在为超声增强（空化，微流，流）中涉及的声学机制提供额外的见解。超声增强药物递送的概念是极其复杂的。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应。例如，已经证明血管内空化将增加正常毛细血管中的毛细血管渗透性。血管内空化似乎还增强了肿瘤毛细血管的渗透性，从而允许较大的分子（如纳米颗粒）以更高的浓度穿过血管屏障。然而，一旦这些载药纳米颗粒进入氚，它们的渗透就受到它们的尺寸和扩散的限制。尚待证明的是，超声是否可以增强这些分子进入间质的渗透，以对不位于血管附近的活肿瘤细胞产生影响，以及所涉及的机制。此外，存在超声增强药物直接渗透到细胞中的可能性。该R 03资助的目的是获得额外的支持数据，这些数据可用于支持R 01申请，以进一步研究超声在增强药物输送中的作用。在未来的研究中，我打算调查使用脉冲HIFU，以提高血管通透性，其次是增强渗透。此外，我还与其他研究人员合作，他们正在开发新型纳米颗粒药物载体，这些药物可以与超声结合用于靶向药物递送。 公共卫生相关性：本研究的总体目的是研究使用脉冲HIFU来增强化疗剂渗透到肿瘤的结缔组织中，并研究所涉及的潜在机制。如果有效，脉冲HIFU可能与新型药物递送载体（例如，药物洗脱珠粒或纳米颗粒）来递送更新的化疗剂，以更有效地治疗局部HCC，同时限制全身毒性。本研究的总体假设是，脉冲HIFU可以增强小分子渗透到肿瘤（如肝细胞癌）的结缔组织中。

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.