Intravascular Delivery of Nanoclusters for Treatment of Deep-Seated Cancers with Magnetic Hyperthermia

项目摘要 磁热疗是一种非常有前途的治疗方式，用于治疗各种癌症。它是基于 这一概念是，递送到癌症肿瘤中的磁性纳米颗粒在暴露于一种 非侵入性外部交变磁场（AMF）。许多临床前和临床研究已经证实了 纳米粒子介导的热疗直接杀死癌细胞或增强其 对放疗和化疗敏感。尽管磁热疗具有很大的潜力，但目前 局限于治疗局部和相对可及的肿瘤，因为所需的治疗温度 高于42 ℃只能通过直接瘤内注射常规的氧化铁纳米颗粒来实现。到 实现磁热疗作为治疗深层原发性和转移性肿瘤的真正潜力， 有必要开发可以在全身给药后有效地在肿瘤部位积聚的纳米颗粒， 施用并在暴露于AMF时产生期望的肿瘤内温度。 一个多学科的研究小组，在纳米医学，磁热疗， 癌症研究将开发具有高发热能力的新型纳米粒子， 在单次全身注射后， 在暴露于AMF时的温度。该研究小组将利用其最近发明的磁 纳米团簇由封装在聚合物纳米颗粒中的六边形纳米加热器组成。初步 研究证实，这些纳米团簇是安全的，有效地积累在皮下癌肿瘤后， 静脉注射，在AMF存在的情况下将肿瘤内温度升高至44 ℃， 抑制肿瘤生长。为了推进这项技术，该项目的第一个主要目标是优化开发的 用于靶向递送至卵巢癌和胰腺癌肿瘤的纳米团簇， LHRH肽。第二个目标是证实，在患有转移性卵巢癌和原位胰腺的啮齿动物中， 癌症，纳米团簇是有效的，在提高温度的深层原发性和转移性 肿瘤的第三个目标是验证纳米团簇介导的热疗单独和联合应用的治疗效果。 在这些动物模型中联合化疗。这些目标将通过以下方式实现 具体目标：1。优化开发的纳米簇的翻译潜力和肿瘤靶向递送。2. 在患有人转移性卵巢癌的小鼠中评估优化的磁性纳米簇。3.评估优化 磁性纳米团簇在胰腺癌原位模型中的应用。在这个项目完成后，团队 期望产生强有力的证据表明，优化的纳米团簇将有效地积累在转移性和 血管内注射后的深部肿瘤，产生所需的肿瘤内温度， 显著减小卵巢和胰腺肿瘤的大小。长期目标是开发一种新的磁性 用于测试的肿瘤的基于高血压的治疗。

Project Summary Magnetic hyperthermia is a highly promising therapeutic modality for treatment of various cancers. It is based on the concept that magnetic nanoparticles delivered to cancer tumors can generate heat after exposure to a non-invasive external alternating magnetic field (AMF). Many preclinical and clinical studies have validated the significant potential of nanoparticle-mediated hyperthermia to either kill cancer cells directly or enhance their susceptibility to radiation and chemotherapy. Despite its promising potential, magnetic hyperthermia is currently limited to treatment of localized and relatively accessible tumors, because the required therapeutic temperatures above 42 0C can only be achieved by direct intratumoral injection of conventional iron oxide nanoparticles. To realize the true potential of magnetic hyperthermia as a therapy for deep-seated primary and metastatic tumors, it is necessary to develop nanoparticles that can efficiently accumulate at tumor sites following systemic administration and generate desirable intratumoral temperatures upon exposure to AMF. A multidisciplinary team of investigators with complementary expertise in nanomedicine, magnetic hyperthermia, and cancer research will develop novel nanoparticles with high heating capacity that efficiently accumulate in primary and metastatic tumors following a single systemic injection and generate desirable intratumoral temperatures upon exposure to AMF. The research team will capitalize on its recent invention of magnetic nanoclusters consisting of hexagonal-shaped nanoheaters encapsulated in polymeric nanoparticles. Preliminary studies validated that these nanoclusters are safe, efficiently accumulate in subcutaneous cancer tumors after intravenous injection, elevate the intratumoral temperature to 44 0C in the presence of AMF, and significantly inhibit tumor growth. To advance this technology, the first major goal of this project is to optimize the developed nanoclusters for targeted delivery to ovarian and pancreatic cancer tumors by modifying their surface with the LHRH peptide. The second goal is to confirm, in rodents with metastatic ovarian cancer and orthotopic pancreas cancer, that the nanoclusters are efficient in increasing temperature of deep-seated primary and metastatic tumors. The third goal is to validate therapeutic efficacy of the nanocluster-mediated hyperthermia alone and in combination with chemotherapy in these animal models. These goals will be addressed with the following Specific Aims: 1. Optimize translational potential and tumor-targeted delivery of the developed nanoclusters. 2. Evaluate optimized magnetic nanoclusters in mice with human metastatic ovarian cancer. 3. Assess optimized magnetic nanoclusters in an orthotopic model of pancreatic cancer. At the completion of this project, the team expects to produce strong evidence that the optimized nanoclusters will efficiently accumulate in metastatic and deep-seated tumors following intravascular injection, produce the required intratumoral temperature, and significantly reduce the size of ovarian and pancreatic tumors. The long term goal is to develop a novel magnetic hyperthermia-based treatment for the tested tumors.