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

血管内输送纳米簇用于磁热疗治疗深部癌症

• 批准号: 9887348
• 负责人: Oleh Taratula
• 金额: $ 59.66万
• 依托单位: OREGON STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-03-01 至 2025-02-28
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/9887348
• 关键词: Address; Animal Model; Animals; Biodistribution; Cell Death; Chemotherapy and/or radiation; Clinical; Clinical Research; Cobalt; Data; Desmoplastic; Disseminated Malignant Neoplasm; Dose; Encapsulated; Exposure to; Goals; Heating; Human; Hyperthermia; Implant; In Situ; Injections; Intravenous; Ions; Magnetic nanoparticles; Magnetism; Malignant Neoplasms; Malignant neoplasm of ovary; Malignant neoplasm of pancreas; Manganese; Mediating; Metals; Modality; Modeling; Mus; Neoplasm Metastasis; Pancreatic Ductal Adenocarcinoma; Peptides; Polymers; Predisposition; Primary Neoplasm; Rattus; Reproducibility; Research; Research Personnel; Rodent; Site; Surface; Technology; Temperature; Testing; Therapeutic; Tissues; Toxic effect; Treatment Efficacy; Xenograft procedure; Zinc; anticancer research; base; biomaterial compatibility; cancer cell; cancer therapy; chemotherapy; clinically relevant; intraperitoneal; intravenous administration; intravenous injection; invention; iron oxide; iron oxide nanoparticle; magnetic field; multidisciplinary; nanocluster; nanomedicine; nanoparticle; nanoparticle delivery; novel; ovarian neoplasm; pancreatic cancer cells; pancreatic cancer model; pancreatic neoplasm; preclinical study; preservation; subcutaneous; targeted delivery; tumor; tumor growth; tumor specificity

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.

项目摘要 磁性高温是一种非常有前途的治疗方式，用于治疗各种癌症。它是基于的 关于磁性纳米颗粒输送到癌症肿瘤的概念可以在暴露于A后产生热量 非侵入性外部交替磁场（AMF）。许多临床前研究和临床研究验证了 纳米颗粒介导的高温直接杀死癌细胞或增强其巨大潜力 对放射和化学疗法的敏感性。尽管具有有希望的潜力，但目前磁性高温是 由于所需的治疗温度，仅限于局部且相对可访问的肿瘤的治疗 仅通过直接肿瘤内注入常规的氧化铁纳米颗粒才能实现42 0C。到 实现磁性高温作为对深处原发性和转移性肿瘤的疗法的真正潜力， 有必要开发可以在全身后在肿瘤部位有效积聚的纳米颗粒 暴露于AMF时，给药并产生理想的肿瘤内温度。 一个多学科的研究人员团队，具有纳米医学的互补专业知识，磁性高温， 癌症研究将开发具有高加热能力的新型纳米颗粒，可有效地积累 单个全身注射后的原发性和转移性肿瘤并产生理想的肿瘤内 暴露于AMF时的温度。研究小组将利用其最近的磁性发明 纳米簇组成的六角形纳米甲基蛋白包装在聚合物纳米颗粒中。初步的 研究证实了这些纳米簇是安全的，有效地在皮下癌症中积累的研究 静脉注射，在AMF存在下将肿瘤内温度升至44 0c，并显着 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 通过对卵巢和胰腺癌肿瘤的有针对性递送的纳米簇来修饰其表面 LHRH肽。第二个目标是在转移性卵巢癌和原位胰腺的啮齿动物中确认 癌症，纳米群体在升高的原发性和转移性的温度升高方面有效 肿瘤。第三个目标是验证单独和纳米簇介导的高温的治疗功效 这些动物模型中的化疗结合。这些目标将通过以下来解决 具体目的：1。优化已发达纳米簇的转化潜力和以肿瘤为目标的递送。 2。 评估患有人体转移性卵巢癌小鼠中优化的磁性纳米簇​​。 3。评估优化 胰腺癌原位模型中的磁纳米簇。该项目完成时，团队 希望产生有力的证据，表明优化的纳米簇将有效地积累在转移性和 血管内注射后深层肿瘤，产生所需的肿瘤内温度，并 显着减少卵巢和胰腺肿瘤的大小。长期目标是开发一种新颖的磁性 基于高温的测试肿瘤治疗。