Reduced Temperature Thermal Ablation for HCC and other Liver Tumors

描述(由申请人提供)：环十五内酯(CPDL)乳剂显著降低了热消融固体组织所需的阈值温度。这项拟议的研究将检验这样一种假设，即靶向向肝脏肿瘤输送CPDL将优先使它们对44-55oC的温度下的热消融敏感，并且这种CPDL介导的降温热消融(CPDL-RTTA)策略将导致更安全、更有效的肝肿瘤热消融，并改善对正常肝组织的保护。实验将使用大鼠Walker 256肝肿瘤模型进行。具体目的之一是确定将有效剂量的CPDL局部输送到肝脏肿瘤的最有效方法，并在开始热消融之前确认规定的CPDL剂量已被输送到肿瘤。第二个目的是证明CPDL-RTTA增加了肿瘤消融体积，可以克服血管热沉效应，并将提高建立局部肿瘤控制的能力。如果这项研究成功，开发的治疗策略可以用于治疗目前不符合肝肿瘤热消融治疗条件的患者。因此，热消融将在建立局部肿瘤控制、降低肝脏肿瘤分期以使切除或肝移植成为治疗选择、或缓解晚期疾病以提高生活质量方面具有更广泛的适用性和实用性。 公共卫生相关性：这项建议的目标是开发一种更好的程序，用于热消融人类肝细胞癌(HCC)和其他肝肿瘤，从而提高肿瘤杀伤率，同时保留更多正常组织并保持其功能。这将通过靶向输送化学乳剂(活性成分环十五内酯(CPDL))来实现，该乳剂可显著降低切除肿瘤所需的温度阈值。有效的肿瘤消融将在45-55oC之间进行，这不会损害正常的肝组织，因为他们不会接受热敏性CPDL。如果成功，CPDL手术将提高肿瘤消融效率，并应使肿瘤热消融适用于目前因肝脏肿瘤太多和/或太大而被排除在外的患者。

DESCRIPTION (provided by applicant): Cyclopentadecanolide (CPDL) emulsions markedly lower the threshold temperature required to thermally ablate solid tissues. The proposed study will test the hypothesis that targeted delivery of CPDL into liver tumors will preferentially sensitize them to thermal ablation at temperatures of 44-55oC and that this CPDL-mediated reduced temperature thermal ablation (CPDL-RTTA) strategy will result in safer and more effective thermal ablation of liver tumors with improved sparing of normal liver tissue. Experiments will be performed using the rat Walker 256 liver tumor model. Specific aim one is to identify the most effective means for localizing delivery of effective doses of CPDL to liver tumors and to confirm that the prescribed CPDL dose has been delivered to tumors before initiating thermal ablation. The second aim is to demonstrate that CPDL-RTTA increases tumor ablation volume, can overcome the vascular heat sink effect, and will improve the ability to establish local tumor control. If this study is successful the developed treatment strategies can be directed towards treating patients that are currently ineligible for thermal ablation therapy for their liver tumors. Thermal ablation will then have broader applicability and utility as a treatment for establishing local tumor control, downstaging liver tumors so that resection or liver transplant become treatment options, or palliating advanced disease to improve quality of life. PUBLIC HEALTH RELEVANCE: The objective of this proposal is to develop a better procedure for thermally ablating human hepatocellular carcinoma (HCC) and other liver tumors such that tumor killing is improved while more normal tissue is spared and remains functional. This will be accomplished by targeting delivery of a chemical emulsion (active ingredient cyclopentadecanolide (CPDL)) that markedly lowers the temperature threshold required to ablate the tumor. Effective tumor ablation will be performed using temperatures between 45-55oC, which will not harm normal liver tissues since they will not have received the thermal sensitizing CPDL. If successful, the CPDL procedure will improve tumor ablation efficacy and should make tumor thermal ablation available to patients that are currently excluded because their liver tumors are too numerous and/or massive.