Enhanced RF Tumor Ablation with Liposomal Chemotherapy

描述(申请人提供)：影像引导射频(RF)肿瘤消融术正在用于治疗肝脏、肾脏和其他肿瘤。然而，完全消融往往很难实现，尤其是在肿瘤边缘，这给临床疗效带来了很大的障碍。我们的初步研究利用了射频消融和脂质体阿霉素之间的互补作用，并证明与单独使用射频或射频与游离阿霉素联合治疗相比，这种联合治疗可以显著增加动物和患者的肿瘤破坏力，并显著增加动物存活率。与对照组相比，射频消融术还使肿瘤内脂质体中的阿霉素增加了7倍，尤其是在射频诱导的凝固区附近的外围区域。因此，这种联合治疗模式具有独特的潜力，既可以加强细胞毒剂在脂质体中的优先递送，又可以最大限度地提高人类已治疗肿瘤的消融完整性。 我们的近期目标是解决在启动第二阶段或更大规模的多中心临床试验之前需要进一步了解的几个关键问题。1)我们的数据表明，通过系统地优化相关的治疗参数，可以进一步增加药物摄取和肿瘤破坏的收益。2)需要更好地了解驱动这种相互作用的机制，特别是组织破坏增加的热剂量学，以及当给予空脂质体而不使用阿霉素时肿瘤破坏增加的原因，因为这可能导致开发出具有更好疗效的临床策略。3)局部和全身毒性需要更好地定义。 这将通过三个目标来实现。1)提高单纯形优化综合治疗犬性肉瘤的肿瘤杀伤率。肿瘤内热剂量学与阿霉素摄取增加和肿瘤破坏增加之间的关系将被用来阐明热疗的作用、阈值热剂量以及联合治疗最有效的条件。2)我们将测试关于脂质体载体组分可能作用的具体假设。将对RF和空脂质体进行研究，以确定脂类和阿霉素对细胞杀伤机制的相对贡献。我们将进一步确定肿瘤破坏的增加是否可以归因于氧化应激和脂质过氧化的增强，以及对发生脂质过氧化的底物的操纵是否可以进一步增强热消融的抗肿瘤效果。3)我们将确定潜在的局部和全身治疗毒性，包括确定在正常犬肝和肾中观察到组织效应的热剂量学，以及在肾脏肿瘤一个月的生存研究中。

DESCRIPTION (provided by applicant): Image-guided radiofrequency (RF) tumor ablation is being used to treat focal liver, renal, and other tumors. Yet, complete ablation is often difficult to achieve, particularly at tumor margins, presenting substantial barriers toward clinical efficacy. Our preliminary studies take advantage of complementary interactions between RF ablation and liposomal doxorubicin, and demonstrate that this combination may markedly increases tumor destruction in animals and patients, and animal survival compared to RF alone or RF combined with free doxorubicin. RF ablation also increased intratumoral liposomal doxorubicin 7 fold compared to controls, particularly in a peripheral region immediately adjacent to the zone of RF induced coagulation. Thus, this combined treatment paradigm has the unique potential both to potentiate preferential delivery of cytotoxic agents in liposomal vehicles, and to maximize the completeness of ablation of a treated tumor, in humans. Our immediate goals are to address several key issues that require further knowledge prior to initiation of Phase II or larger multicenter clinical trials. 1) Our data indicate that gains in both drug uptake and tumor destruction can be further increased through the systematic optimization of the relevant treatment parameters. 2) The mechanisms driving this interaction particularly the hyperthermic dosimetry of increased tissue destruction and the causes for increased tumor destruction seen when empty liposomes are given without doxorubicin need to be better understood, as this could lead to developing clinical strategies having even greater efficacy. 3) Local and systemic toxicities need to be better defined. This will be accomplished over 3 aims. 1) We will improve tumor destruction of combined therapy using simplex optimization in canine venereal sarcoma. The relationship between intratumoral thermal dosimetry to increased doxorubicin uptake and increased tumor destruction will be characterized to elucidate the role of hyperthermia, threshold thermal dosage, and the conditions under which combined therapy is most effective. 2) We will test specific hypotheses about the possible role of the liposome carrier components. RF and empty liposomes will be studied to define the relative contributions of the lipids and of the doxorubicin to the mechanisms of cell killing. We will further determine whether increased tumor destruction can be ascribed to enhanced oxidative stress and lipid peroxidation and whether manipulation of the substrate upon which lipid peroxidation occurs can further potentiate the antitumor effect of thermal ablation. 3) We will characterize potential local and systemic treatment toxicity including determining the thermal dosimetry at which tissue effects are seen in normal canine liver and kidney and in a one-month survival study in renal tumors.