Development of magnetic hyperthermia for the systemic treatment of endometriosis

摘要/摘要(30行) 热疗是一种通过提高肿瘤组织的温度来根除癌症组织的临床干预方法。 肿瘤。纳米颗粒介导的磁热疗是一种热疗形式，其中 运送到癌症部位的纳米颗粒暴露在外部交变磁场中后会产生热量 (AMF)。该项目的目标是将纳米颗粒介导的磁热疗法作为一种非侵入性的 治疗子宫内膜异位症。子宫内膜异位症是一种子宫内膜样组织出现在“异位”处的疾病。 子宫以外的部位。异位子宫内膜形成病变，导致盆腔疼痛和不孕。 尽管治疗子宫内膜异位症相关的盆腔疼痛取得了进展，但目前仍没有药物治疗 对于许多女性来说，手术切除病变仍然是一种治疗方法。不幸的是， 疾病复发率超过50%，许多患者需要三次或更多手术。这样做的前提是 建议磁热疗可以提供一种非手术的选择来移除子宫内膜异位病变。 磁热治疗目前仅限于治疗肿瘤的局部性和通用性 肿瘤，因为所需的治疗温度(≥42 0C)只能通过直接肿瘤内实现 注入常规磁性纳米颗粒。为了解决这一局限，这个研究小组发明了小说 具有高加热能力的磁性纳米团簇。纳米团簇由六角形磁体组成 包裹在聚合物载体中的纳米颗粒。动物研究证实，这些纳米簇是安全的， 静脉注射(IV)后有效地在肿瘤内蓄积，并提高肿瘤内 在AMF存在的情况下，温度为440℃。初步研究表明，在静脉注射后，这些 纳米团簇也有效地积聚在猕猴异位内膜病变中，移植成重度联合 免疫缺陷(SCID)小鼠及其在纳米簇传递后对外部AMF的暴露 将移植物内部的温度提高到430摄氏度。为了推进这种新的治疗方法，这种多学科的 在纳米医学、磁热疗法和临床领域拥有互补专业知识的研究团队 子宫内膜异位症研究在特定目标1中提出，优化这些纳米簇的靶向效率，以 人类和猕猴子宫内膜异位症。靶向将通过改变纳米团簇的表面来优化 具有与受体(例如，血管内皮生长因子(VEGF)受体2)特异性结合的多肽 (KDR)在灵长类子宫内膜异位间质细胞中过表达。结合特异度和治疗效果 这些新的纳米簇将在原发性子宫内膜和子宫内膜异位症(人类和猕猴)中进行评估。 体外培养间充质细胞。在具体目标2中，靶向与非靶向纳米团簇对 将在植入人和猕猴的SCID小鼠身上评估根除子宫内膜异位症病变的情况 子宫内膜异位移植物。在特定目标3中，介导性磁热的安全性和疗效 优化后的纳米簇将在出现子宫内膜异位症病变的猕猴身上进行评估。

Summary/Abstract (30 lines) Thermal therapy is a clinical intervention to eradicate cancerous tissue by increasing the temperature of the tumors. Nanoparticle-mediated magnetic hyperthermia is a form of thermal therapy where magnetic nanoparticles delivered to cancer sites generate heat after exposure to an external alternating magnetic field (AMF). The goal of this project is to advance nanoparticle-mediated magnetic hyperthermia as a non-invasive treatment for endometriosis. Endometriosis is a disorder where endometrium-like tissue is present at “ectopic” sites outside of the uterus. The ectopic endometrium forms lesions that cause pelvic pain and infertility. Despite advances in therapies for endometriosis-related pelvic pain, there remains no medical cure for the disorder, and surgical removal of the lesions remains a treatment for many women. Unfortunately, the rate of disease recurrence exceeds 50% with many patients requiring three or more surgeries. The premise of this proposal is that magnetic hyperthermia can provide a non-surgical option to remove endometriotic lesions. Magnetic hyperthermia for cancer is currently restricted to the treatment of localized and accessible tumors because the required therapeutic temperatures (≥42 0C) can only be achieved by direct intratumoral injection of conventional magnetic nanoparticles. To address this limitation, this research team invented novel magnetic nanoclusters with high heating capacity. The nanoclusters consist of hexagonal-shaped magnetic nanoparticles encapsulated in polymeric vehicles. Animal studies validated that these nanoclusters are safe, efficiently accumulate in cancer tumors after intravenous (IV) injection, and elevate the intratumoral temperature to 44 0C in the presence of AMF. Preliminary studies revealed that following IV injection these nanoclusters also efficiently accumulated in the macaque endometriotic lesions grafted into severe combined immunodeficient (SCID) mice and exposure of these mice to external AMF after nanoclusters delivery increased the temperature inside of the grafts up to 43 0C. To advance this new therapy this multidisciplinary team of investigators with complementary expertise in nanomedicine, magnetic hyperthermia, and clinical endometriosis research proposes in Specific Aim 1, to optimize targeting efficiency of these nanoclusters to human and macaque endometriosis. Targeting will be optimized by modifying the surface of the nanoclusters with peptides that specifically bind to receptors (e.g., vascular endothelial growth factor (VEGF) receptor 2 (KDR)) overexpressed in primate endometriotic stromal cells. Binding specificity and therapeutic efficacy of these new nanoclusters will be assessed in primary endometrial and endometriosis (human and macaque) stromal cells in vitro. In Specific Aim 2, the effect of targeted versus non-targeted nanoclusters on the eradication of endometriosis lesions will be evaluated in SCID mice engrafted with human and macaque endometriotic grafts. In Specific Aim 3, safety and therapeutic efficacy of magnetic hyperthermia mediated by the optimized nanoclusters will be evaluated in macaques with induced endometriotic lesions.