Optimization of Magnetic Nanoparticle Breast Cancer Treatment

项目总结（见说明）： 磁性纳米粒子疗法的使用有望成为细胞特异性/高治疗率、低毒性的癌症疗法。mNP-AMF癌症治疗最吸引人的特征是能够通过肽靶向将mNP递送至个体癌细胞，并通过用非侵入性/安全的交变磁场（AMF）激发mNP来选择性地杀死这些细胞。 项目3将进行各种基础研究，以支持计划在达特茅斯进行的使用mNP-AMF治疗乳腺癌的临床试验。我们的初步数据证明了用mNP-AMF疗法完全控制鼠乳腺肿瘤的能力。目的1研究了各种mNP变量的性能影响，包括大小，递送途径和抗体靶向，在体外乳腺癌细胞系中和在体内小鼠中同基因或异种移植物中的相同细胞中。目的2利用我们的初步数据，表明间质肿瘤压力的降低改善了肿瘤中的纳米颗粒递送和生物分布，并研究了这种降低的体内影响。mNP-AMF在其他潜在作用中可以产生局部热疗，并且在体外、动物和患者中充分记录了轻度热疗，以显著增加常规癌症治疗方式如放疗和化疗的有效性。目的3研究mNP-AMF与放疗、化疗的协同作用。目的4旨在直接支持计划在达特茅斯进行的mNP-AMF治疗乳腺癌的临床试验。 我们的初步实验使我们能够定义用于小鼠的mNP-AMF治疗的适当参数。虽然非常有用，但这些信息不会直接转化为人类患者。目标4将使用人乳腺和肿瘤模型以及体内猪乳腺模型（我们有适当的发生器和线圈）来确定用于人乳腺癌患者的最佳mNP和AMF递送技术。 项目3将与所有其他项目和核心互动。纳米颗粒核心将提供颗粒，如项目1所示。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进行智力互动，因为两者都使用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、统计学和数据分析核心将进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.