Optimization of Magnetic Nanoparticle Breast Cancer Treatment

项目总结(见说明)： 磁性纳米颗粒治疗有望成为一种细胞特异性/高治疗率、低毒的肿瘤治疗方法。MNP-AMF癌症治疗最吸引人的特点是能够通过多肽靶向将mNP输送到单个癌细胞，并通过无创/安全的交变磁场(AMF)刺激mNP选择性地杀死这些细胞。 项目3将进行各种基础研究，以支持达特茅斯使用mNP-AMF治疗乳腺癌的计划中的临床试验。我们的初步数据表明，用mNP-AMF治疗完全控制小鼠乳腺肿瘤的能力。目的1研究不同的mNP变量，包括mNP的大小、传递途径和抗体靶向性，在体外和体内对小鼠同基因或异种移植物中相同细胞的影响。目的2利用我们的初步数据，表明肿瘤间质压力的降低改善了纳米颗粒在肿瘤中的传递和生物分布，并研究了这种降低对体内的影响。除其他潜在作用外，MNP-AMF可产生局部热疗，而温和热疗在动物和患者的体外实验中得到了很好的证明，可以显著提高放射和化疗等传统癌症治疗方法的有效性。目的研究mNP-AMF与放化疗的协同作用。AIM 4旨在直接支持达特茅斯大学计划进行的乳腺癌mNP-AMF治疗临床试验。 我们的初步实验使我们能够为小鼠的mNP-AMF治疗确定合适的参数。虽然非常有用，但这些信息不会直接转化为人类患者。Aim 4将使用人类乳房和肿瘤模型以及活体猪乳房模型(我们有适当的发电机和线圈)来确定适用于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互动。纳米粒子核心将提供颗粒，项目1和项目2将使用项目3生成的模型。项目4将使用项目3中安装的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的生物分布，生物信息学、统计和数据分析核心将执行数据分析和支持实验设计。

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.