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

描述(由申请人提供)： 这项拟议的研究旨在研究脉冲HIFU增强药物对肿瘤间质的渗透的潜力。这对肝细胞癌有特殊的应用，局部治疗显示了好处；然而，局部复发很常见。超声增强的药物输送可潜在地与TACE联合使用，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)涉及的声学机制提供更多的洞察力。超声增强药物输送的概念极其复杂。这很可能涉及到几种机制，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会增加正常毛细血管的毛细血管通透性。血管内空化似乎也增强了肿瘤毛细血管的渗透性，允许更大的分子，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间质，它们的渗透就受到它们的大小和扩散的限制。目前尚不清楚的是，超声是否能增强这些分子对间质的穿透作用，从而对不在血管附近的存活肿瘤细胞发挥作用，以及相关的机制。此外，超声波有可能促进药物直接渗透到细胞内。这笔R03拨款的目的是获得额外的支持数据，这些数据可以用来支持R01申请，以进一步研究超声波在增强药物输送方面的作用。在未来的研究中，我打算研究使用脉冲HIFU来增强血管的渗透性，然后再增强穿透性。此外，我还与其他研究人员开展了合作，他们正在开发用于药物的新型纳米颗粒载体，这种载体可以与超声波一起用于靶向药物输送。 公共卫生相关性：这项研究的总体目标是调查脉冲HIFU用于增强化疗药物对肿瘤间质的渗透，并探讨相关的潜在机制。如果有效，脉冲HIFU有可能与新型药物输送载体(例如药物洗脱微珠或纳米颗粒)联合使用，以输送更新的化疗药物，以更有效地治疗局限性肝癌，同时限制全身毒性。这项研究的总体假设是，脉冲HIFU可以增强小分子对肝细胞癌等肿瘤间质的渗透。

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.