Quantitative optical dosimetry of magnetic nanoparticle cancer treatments

描述(申请人提供)：这项提案的目标是让PI成为一个多学科生物医学团队的领导成员，该团队开发基于光子学的系统来诊断和治疗癌症，重点是新兴纳米颗粒技术的临床翻译。这项提案概述了一项导师培训计划，将候选人置于NIH资助的研究人员群中，其中包括达特茅斯的NIH癌症纳米技术卓越中心(DCCNE)。该计划包括4个互补的重点领域：1)建立更坚实的癌症生物学知识基础；2)在标准生物医学成像系统方面开发卓越的理论和实验专业知识；3)领导实验性纳米抗癌治疗的临床前研究的经验；以及4)将开发的方法/装置转化为正在进行的临床试验的经验。为了实现这些目标，候选人将利用这笔资金专门用于参加学院和医学院的癌症、影像和转化医学研究生课程，并参加癌症研讨会、培训研讨会和大型讲座。这一知识库将应用于DCCNE正在进行的一个项目中，该项目正在进行磁性纳米颗粒(MNP)介导的交变磁场(AMF)治疗作为实体恶性肿瘤的靶向治疗的人体试验。DCCNE团队缺乏一种实用的方法来定量确定mNPs在选定的感兴趣组织中的分布 给药是一个关键的限制，因为在结构和血管方面 肿瘤类型。这项建议的研究项目部分将利用一种新颖的光学系统设计来探测吸收和荧光，以定量估计体内mNP的分布，返回与背景光学性质的扭曲无关的mNP浓度。本项目的4个研究目的是调查这样一个概念，即mNP-AMF治疗需要准确的mNP摄取剂量测定，以便定量解释并以最佳方式减少受试者之间预期的个体差异。目的(1)是设计一种新的光学装置，用于体内组织中mNP的定量光学测量。目的(2)研究mNP在肿瘤及其周围正常组织中的摄取和分布。目的(3)将使用定量剂量学来监测和优化临床前mNP-AMF治疗期间提供的治疗剂量。MNP摄取测量的预后价值将通过与肿瘤生长延迟的比较来评估。这些数据将被用来检验肿瘤特异性mNP-AMF剂量学可以通过减少治疗结果的变异性来优化给药剂量的假设。目的(4)是将这些获得观察性测量的光学技术集成到正在进行的mNP-AMF治疗乳腺癌的试验性临床研究中。在本试验中获得的数据将进行回顾分析，以 确定肿瘤反应与治疗时测得的mNP浓度之间的相关性。这项建议包括一个由多学科导师组成的小组，他们拥有癌症生物学、外科、放射肿瘤学、兽医、生物医学光学和成像、临床实践和临床翻译方面的专业知识，并在NIH资金方面拥有充足的专业知识。

DESCRIPTION (provided by applicant): The goal of this proposal is to allow the PI to become a leading member of a multidisciplinary biomedical team that develops photonics-based systems to diagnose and treat cancer, with a focus on clinical translation of emerging nanoparticle technologies. This proposal outlines a mentored-training program, which places the candidate within a cluster of NIH funded researchers, including an NIH Center of Cancer Nanotechnology Excellence at Dartmouth (DCCNE). The plan involves 4 complementary areas of focus: 1) building a firmer base of cancer biology knowledge; 2) developing superior theoretical and experimental expertise in standard biomedical imaging systems; 3) experience leading a pre-clinical investigating of an experimental nanoparticle anti-cancer treatment; and 4) experience in translation of a developed approach/device into an ongoing clinical trial. To achieve these goals the candidate will use the funding to dedicate time to participate in graduate cancer, imaging, and translational medicine courses at the College and Medical School, and to attend cancer workshops, training seminars and grand rounds lectures. This knowledge base will be applied within an ongoing program project conducted by DCCNE, which is carrying out human trials in magnetic-nanoparticle (mNP)-mediated alternating magnetic field (AMF) therapy as a targeted treatment for solid malignant tumors. The DCCNE teams lack a practical method to quantitatively determine the distribution of mNPs within a selected tissue of interest following administration, a critical limitation given the large variance in structure and vascularity between tumor types. The research project component of this proposal will utilize a novel optical system design to probe absorption and fluorescence to quantitatively estimate mNP distribution in vivo, returning mNP concentrations independent of distortions from background optical properties. The 4 research aims of this project investigate the concept that mNP-AMF therapy requires accurate dosimetry of mNP uptake in order to quantitatively interpret, and optimally reduce, the individual variation expected between subjects. Aim (1) is to design a novel optical device that will be validated for quantitative optical measurements of mNP in tissues in vivo. Aim (2) is to characterize the mNP uptake and distribution of mNPs in both tumor and surrounding normal tissues in vivo. Aim (3) will use quantitative dosimetry to monitor and optimize therapeutic dose delivered during preclinical mNP-AMF treatments. The prognostic value of mNP uptake measurements will be assessed by comparison with tumor growth delay. These data will be used to test the hypothesis that tumor- specific mNP-AMF dosimetry can optimize the delivered dose by reducing variability in treatment outcome. Aim (4) is to integrate these optical techniques to obtain observational measurements into an ongoing pilot clinical study of mNP-AMF for treatment of breast cancer. Data acquired in this trial will be retrospectively analyzed to determine correlation between tumor response and measured mNP concentrations at the time of treatment. This proposal includes a multi-disciplinary group of mentors that possess expertise in cancer biology, surgery, radiation oncology, veterinary medicine, biomedical optics and imaging, clinical practice, and clinical translation and have ample expertise in NIH funding.