Optimization of Magnetic Nanoparticle Breast Cancer Treatment

项目摘要（参见说明）： 磁性纳米颗粒疗法的使用有望成为一种细胞特异性/高治疗率、低毒性的癌症疗法。 mNP-AMF 癌症治疗最吸引人的特点是能够通过肽靶向将 mNP 递送至单个癌细胞，并通过用无创/安全的交变磁场 (AMF) 激发 mNP 来选择性杀死这些细胞。 项目 3 将进行各种所需的基础研究，以支持计划在达特茅斯使用 mNP-AMF 疗法进行乳腺癌临床试验。我们的初步数据表明，mNP-AMF 疗法能够完全控制小鼠乳腺肿瘤。目标 1 研究各种 mNP 变量（包括大小、递送途径和抗体靶向）对性能的影响，无论是体外乳腺癌细胞系还是体内同系或异种移植小鼠中的相同细胞。目标 2 利用我们的初步数据，表明间质肿瘤压力的降低可以改善纳米颗粒在肿瘤中的递送和生物分布，并研究这种降低的体内影响。除其他潜在作用外，mNP-AMF 还可以产生局部热疗，而轻度热疗在体外、动物和患者体内已得到充分证明，可以显着提高传统癌症治疗方式（例如放疗和化疗）的有效性。目标 3 研究 mNP-AMF 与放疗或化疗之间的协同作用。目标 4 旨在直接支持达特茅斯计划的 mNP-AMF 治疗乳腺癌临床试验。 我们的初步实验使我们能够确定 mNP-AMF 小鼠治疗的适当参数。虽然这些信息非常有用，但不会直接转化为人类患者。目标 4 将使用人类乳房和肿瘤模型以及体内猪乳房模型（我们有适当的发生器和线圈）来确定人类乳腺癌患者的最佳 mNP 和 AMF 输送技术。 项目 3 将与所有其他项目和核心进行交互。纳米粒子核心将提供粒子，项目 1 也将如此。项目 1 和 2 将使用项目 3 生成的模型。项目 4 将使用项目 3 中的 AMF 设备，并与项目 3 进行智能交互，因为每个项目都使用 mNP-AMF 进行治疗。 病理学、毒理学和生物分布核心将分析 mNP 生物分布，生物信息学、统计和数据分析核心将执行数据分析并支持实验设计。

PROJECT SUMMARY (See instructions): The use of magnetic nanoparticle therapy has promise as a cell specific/high therapeutic ratio, low-toxicity cancer therapy. The most attractive feature of mNP-AMF cancer therapy is the ability to deliver mNP to individual cancer cells via peptide targeting and to selectively kill such cells by exciting the mNPs with a noninvasive/ safe alternating magnetic field (AMF). Project 3 will perform a variety of fundamental studies required to support planned clinical trials for breast cancer using mNP-AMF therapy at Dartmouth. Our preliminary data demonstrate the ability to completely control murine breast tumors with mNP-AMF therapy. Aim 1 investigates performance impact of a variety of mNP variables including, size, delivery route, and antibody targeting, both in vitro in breast cancer cell lines and in vivo with the same cells in syngeneic or xenogeneic grafts in mice. Aim 2 exploits our preliminary data suggesting a reduction of interstitial tumor pressure improves nanoparticle delivery and biodistribution in tumors and investigates the in vivo impact of such reduction. mNP-AMF can among other potential effects generate local hyperthermia and mild hyperthermia is well documented in vitro, in animals and patients to significantly increase the effectiveness of conventional cancer treatment modalities such as radiation and chemotherapy. Aim 3 investigates the synergy between mNP-AMF and radiation or chemotherapy. Aim 4 is designed to directly support the planned clinical trials of mNP-AMF therapy for breast cancer at Dartmouth. Our preliminary experiments have allowed us to define appropriate parameters for mNP-AMF treatment for mice. While extremely useful, this information will not translate directly to human patients. Aim 4 will use human breast and tumor phantoms and an in vivo porcine breast model (we have the appropriate generator and coils) to determine optimal mNP and AMF delivery techniques for the human breast cancer patient. Project 3 will interact with all other projects and cores. The nanoparticle core will supply particles, as will project 1. Projects 1 and 2 will use the models generated by project 3. Project 4 will use the AMF equipment housed in project 3 and interact intellectually with project 3 since each both are using mNP-AMF for therapy. Pathology, Toxicology and Biodistribution core will analyze mNP biodistribution and the Bioinformatics, Statistics and Data Analysis core will perform data analysis and support experimental design.