Sensitizer Delivery for Focused Hyperthermia Cancer Treatment

描述(申请人提供)：图像引导射频消融，一种利用局部施加的能量来诱导肿瘤凝固性坏死的微创方法，已成为手术切除肿瘤不可行的病例的可靠替代治疗方案。尽管已经取得了成功，但尚未解决的问题，如肿瘤组织在大血管附近的周边冷却，能量沉积的大小受限，以及针状电极轨道周围种植残留肿瘤，都被证明是治疗不彻底导致局部肿瘤再生长的原因。我们建议探索一种独特的生物材料/药物方法来克服这些担忧，并确保可重复的、成功的消融治疗。通过结合肿瘤生物学、介入放射学和生物材料科学的研究，这项建议将研究聚环氧乙烷-聚环氧丙烷嵌段共聚物的局部输送，以加强图像引导的肿瘤射频消融。初步实验表明，这些非离子表面活性剂有可能增加癌细胞对热损伤的敏感性，同时使正常细胞不受伤害。因此，我们推测，消融与通过脂质纳米粒提供给作用部位的致敏预处理相结合将是一种比单独射频消融更好的治疗方法。在成功完成后，拟议的研究应该会改善局部肿瘤射频消融术的疗效。这项提议还可能进一步深入了解非离子表面活性物质分子在癌症治疗和热疗中的有趣作用，为未来对该领域的研究打开大门。 公共卫生相关性：我们的研究评估了一种改进图像引导射频(RF)肿瘤消融的新方法，该方法使用多功能递送载体中的无毒热敏剂来增加癌细胞对热相关应激的敏感性。这种技术可能会克服聚焦热疗的主要障碍之一--无法完全摧毁整个肿瘤体积--这一问题在一定程度上是由于癌细胞的恢复，这些癌细胞在肿瘤周围接受亚致命水平的热量。该项目解决了这一未得到满足的需求，将一种温和、无毒的制剂以脂质纳米颗粒的形式提供，攻击这些细胞并导致它们完全根除，并允许使用超声波进行非侵入性治疗跟踪。在这种应用中使用容易获得和安全的试剂可能会使这项工作迅速转化为临床研究，从而产生更有效的患者护理。

DESCRIPTION (provided by applicant): Image guided radiofrequency (RF) ablation, a minimally-invasive approach which utilizes locally applied energy to induce coagulative necrosis in tumors, has become a reliable alternative treatment of cases where surgical resection of the tumor is not a feasible option. Despite the demonstrated successes, unresolved issues such as peripheral cooling of tumor tissue near major blood vessels, restricted size of the energy deposition, and seeding of residual tumor around needle electrode track, have all been shown to be causes of incomplete treatments leading to local tumor re-growth. We propose to explore a unique biomaterial / pharmaceutical approach to overcome these concerns and ensure a reproducible, successful ablation treatment. Through research uniting cancer biology, interventional radiology, and biomaterials science, this proposal will investigate local delivery of poly (ethylene oxide)-poly (propylene oxide) block copolymers for the enhancement of image guided RF ablation of tumors. Preliminary experiments have demonstrated that these nonionic surfactants have the potential to increase the susceptibility of cancer cells to heat-related injury, while leaving normal cells unharmed. We thus hypothesize that ablation combined with this a sensitizing pretreatment delivered via lipid nanoparticles to the site of action will be a superior treatment to radiofrequency ablation alone. Upon successful completion, the proposed research should result in improved efficacy of local tumor radiofrequency ablation. The proposal may also lead to further insight into the interesting effects of nonionic surfactant molecules on cancer treatment and hyperthermia, opening doors to future investigations into the field. Public Health Relevance: Our study evaluates a new approach for the improvement of image-guided radiofrequency (RF) ablation of tumors which uses a nontoxic thermosensitizer entrapped in a multifunctional delivery vehicle to increase the susceptibility of cancer cells to heat-related stress. This technique may overcome one of the primary hurdles of focused hyperthermia treatment - the inability to completely destroy the entire tumor volume -- a problem due, in part, to the recovery of cancerous cells which receive sub-lethal levels of heat at the tumor periphery. This project addresses this unmet need with a mild, nontoxic agent delivered in a lipid nanoparticle that attacks these cells and leads to their total eradication and which permits noninvasive therapy tracking using ultrasound. The use of readily-available and safe agents for this application may allow rapid translation of this work to clinical studies, resulting in more effective patient care.