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

项目摘要 磁热疗是治疗各种癌症的一种非常有前途的治疗方法。它是基于 关于运送到癌症肿瘤的磁性纳米颗粒在暴露于 无创外交变磁场(AMF)。许多临床前和临床研究已经证实了 纳米颗粒介导的热疗在直接杀死癌细胞或增强其功能方面的巨大潜力 对放射和化疗的敏感性。尽管磁热疗法有很大的潜力，但目前 仅限于局部和相对容易接近的肿瘤的治疗，因为所需的治疗温度 超过42摄氏度只能通过直接在肿瘤内注射传统的氧化铁纳米颗粒来实现。至 认识到磁热疗作为治疗深层原发和转移肿瘤的真正潜力， 有必要开发能够有效地在肿瘤部位积聚的纳米颗粒 给药并在暴露于AMF时产生所需的肿瘤内温度。 一个由多学科研究人员组成的团队，在纳米医学、磁热疗法、 癌症研究将开发具有高加热能力的新型纳米颗粒，这些纳米颗粒可以有效地积累在 一次全身注射后的原发和转移肿瘤，并产生理想的肿瘤内 暴露在AMF中时的温度。研究小组将利用其最近发明的磁铁 由包裹在聚合物纳米颗粒中的六角形纳米加热器组成的纳米簇。初步 研究证实，这些纳米簇是安全的，有效地积聚在皮下癌症肿瘤后 静脉注射，在AMF存在的情况下将肿瘤内温度提高到440摄氏度，并显著 抑制肿瘤生长。为了推进这项技术，本项目的第一个主要目标是优化已开发的 纳米团簇通过修饰卵巢癌和胰腺癌肿瘤的表面来靶向传递 LHRH多肽。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类动物中 癌症，纳米簇在提高深层原发和转移的温度方面是有效的 肿瘤。第三个目标是验证纳米簇介导的热疗单独和在 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.优化已开发纳米簇的翻译潜力和肿瘤靶向递送。2. 在人类转移性卵巢癌小鼠中评估优化的磁性纳米簇。3.考核优化 胰腺癌原位模型中的磁性纳米簇。在这个项目完成时，团队 预计将产生强有力的证据，证明优化的纳米团簇将在转移的和 深层肿瘤在血管内注射后，产生所需的肿瘤内温度，以及 显著缩小卵巢和胰腺肿瘤的大小。长期目标是开发一种新型的磁体 基于热疗的测试肿瘤的治疗。

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.