Sensitizer Delivery for Focused Hyperthermia Cancer Treatment

描述（由申请人提供）：图像引导射频消融（RF）是一种利用局部施加能量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法。尽管取得了成功，但尚未解决的问题，如主要血管附近肿瘤组织的外周冷却，能量沉积的大小限制，以及针电极轨道周围残余肿瘤的播散，都被证明是不完全治疗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问题，并确保可重复，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，我们假设消融结合这种通过脂质纳米颗粒递送到作用部位的增敏预处理将是比单独射频消融更好的治疗方法。一旦成功完成，本研究将提高局部肿瘤射频消融的疗效。该建议也可能导致进一步了解非离子表面活性剂分子对癌症治疗和热疗的有趣作用，为该领域的未来研究打开大门。

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.