Enhanced RF Tumor Ablation with Liposomal Chemotherapy

描述（由申请人提供）：图像引导射频（RF）肿瘤消融术被用于治疗局灶性肝脏、肾脏和其他肿瘤。然而，完全消融通常很难实现，特别是在肿瘤边缘，这对临床疗效构成了很大的障碍。我们的初步研究利用了射频消融和阿霉素脂质体之间的互补相互作用，并证明与射频单独或射频联合游离阿霉素相比，这种组合可能显著增加动物和患者的肿瘤破坏和动物存活率。与对照组相比，射频消融也使肿瘤内脂质体多柔比星增加了7倍，特别是在射频诱导凝血区附近的外周区域。因此，这种联合治疗模式具有独特的潜力，既可以增强细胞毒性药物在脂质体载体中的优先递送，又可以最大限度地消除人类治疗肿瘤的完全性。

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.