Sensitizer Delivery for Focused Hyperthermia Cancer Treatment

描述（由申请人提供）：图像引导射频（RF）消融是一种微创方法，利用局部施加的能量诱导肿瘤凝固性坏死，已成为手术切除肿瘤不可行的病例的可靠替代治疗。尽管取得了成功，但尚未解决的问题，如主血管附近肿瘤组织的外周冷却、能量沉积的尺寸受限以及针电极轨道周围残留肿瘤的接种，都被证明是导致局部肿瘤再生长的不完全治疗的原因。我们建议探索一种独特的生物材料/药物方法，以克服这些问题，并确保可重复的，成功的消融治疗。通过联合癌症生物学、介入放射学和生物材料科学的研究，本提案将研究聚（环氧乙烷）-聚（环氧丙烷）嵌段共聚物的局部递送，以增强肿瘤的图像引导射频消融。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相关损伤的易感性，同时使正常细胞不受伤害。因此，我们假设消融术与通过脂质纳米颗粒递送到作用部位的敏化预处理相结合将是比单独的射频消融术更上级的治疗。成功完成后，拟议的研究应导致局部肿瘤射频消融术的疗效提高。该提案还可能导致进一步深入了解非离子表面活性剂分子对癌症治疗和热疗的有趣影响，为该领域的未来研究打开大门。 公共卫生相关性：我们的研究评估了一种新的方法，用于改善肿瘤的图像引导射频（RF）消融术，该方法使用一种无毒的热敏剂包埋在多功能递送载体中，以增加癌细胞对热相关应激的易感性。这种技术可以克服集中热疗治疗的主要障碍之一-无法完全破坏整个肿瘤体积-这一问题部分是由于在肿瘤周边接受亚致死水平热量的癌细胞的恢复。该项目解决了这一未满足的需求，在脂质纳米颗粒中提供了一种温和的无毒药物，攻击这些细胞并导致其完全根除，并允许使用超声进行非侵入性治疗跟踪。使用易于获得且安全的试剂用于此应用可以将这项工作快速转化为临床研究，从而实现更有效的患者护理。

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.