Toxicology, Pathology and Biodistribution Core (TPB Core)

毒理学、病理学和生物分布核心（TPB 核心）

• 批准号: 7982610
• 负责人: LIONEL David LEWIS
• 金额: $ 9.59万
• 依托单位: DARTMOUTH COLLEGE
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-09-01 至 2015-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7982610
• 关键词: Abdomen; Algorithms; Anatomy; Animals; Biodistribution; Biostatistics Core; CCNE1 gene; Cancer Model; Cells; Data Analyses; Dendritic Cells; Deposition; Development; Drug Kinetics; Feedback; Fluorescent Probes; Functional disorder; Future; Goals; Gold; Human; Imaging Techniques; In Vitro; Individual; Injury; Iron; Location; Magnetic Resonance Imaging; Malignant neoplasm of ovary; Mammary Neoplasms; Methods; Modeling; Movement; Mus; Normal tissue morphology; Optics; Organ; Ovarian; Participant; Pathologic; Pathology; Peptides; Plasma; Play; Production; Prussian blue; Relative (related person); Research Personnel; Research Project Grants; Risk; Role; Safety; Spectrum Analysis; Techniques; Time; Tissues; Toxic effect; Toxicology; Treatment Efficacy; Validation; Work; cancer cell; cytotoxic; cytotoxicity; design; in vivo; iron oxide; magnetic field; nanoparticle; pre-clinical; tumor

The Toxicology, Pathology, and Biodistribution Core will provide qualitative and quanfitative assessment of the movement and deposition of mNPs in ail major organ tissues as well as individual cells in specific settings. The TPB core will also provide dedicated and comprehensive pharmacokinetic (Lewis), human and animal pathology/pathophysiology (Memoli and Hoopes) and TEM/SEM (Daghlian) expertise for potential cellular and/or tissue change resulfing from the mNPs (iron, coafings, targefing peptides, fluorescent probes etc and/or the alternafing magnetic field (AMF) exposure. Since it is the primary goal of the entire DCCNE application to opfimize methods for the observation and selectively delivery of mNP/lron to cancer cells for subsequent cytotoxic excitation, the assessment and quantification of iron levels in cells and fissues (Prussian Blue histomorphometry and ICP-MS) and the resultant pathologic effects in the tumor and normal fissues, is of paramount importance. The TPB Core will be a central partcipant in the determination ofthe relafive ability ofthe various NP physical parameters, coatings, internalizing vs noninternalizing ScFv peptides to selectively target mNP /iron to cancer cells in vitro and in vivo (Project 1). In addition, TEM will allow an accurate assessment of the volume and anatomic location of the various NPs with respect to effective excitation and cytotoxicity. TPB assessments will determine which peptides have the most targeting promise for future use in preclinical in vivo ovarian and breast tumor models (Projects 2 and 3). In Project 2, the TPB will play an essential role determining the accuracy and sensitivity ofthe mNP in vivo imaging techniques. Pathologic co-registration and validation of changes observed by noninvasive imaging techniques such as optical spectroscopy and MRI remains the gold standard for determining the sensitivity and reliability of new imaging techniques. In Project 3, the use of ICP-MS and Prussian Blue histomorphometry mNP /iron quantificafion techniques will allow investigators to determine the absolute role of mNP/lron content in tumor treatment efficacy studies. In Project 4, the TPB Core will be important in determining the level of iron that is taken up by the ovarian cancer dendritic cells, cancer cells and other abdominal tissues that are exposed to the ip delivered mNPs. Since the targeted NP exposure field, in this cancer model, is large, there Is a risk of normal tissue injury. Pathologic assessment of these mice will be extremely important for safety and the understanding of toxicity/efficacy.

毒理学、病理学和生物分布核心将对所有主要器官组织以及特定环境中的单个细胞中mNP的移动和沉积进行定性和定量评估。TPB核心还将提供专门和全面的药代动力学（刘易斯）、人类和动物病理学/病理生理学（Memoli和Hoopes）和TEM/SEM（Daghlian）专业知识，用于mNP（铁、涂层、靶向肽、荧光探针等）和/或交变磁场（AMF）暴露导致的潜在细胞和/或组织变化。由于整个DCCNE应用的主要目标是优化用于观察和选择性地将mNP/铁递送至癌细胞以用于随后的细胞毒性激发的方法，因此细胞和裂隙中的铁水平的评估和定量（普鲁士蓝组织形态计量学和ICP-MS）以及在肿瘤和正常裂隙中产生的病理效应是至关重要的。 TPB核心将是确定各种NP相关能力的核心参与者 物理参数、包被、内化与非内化ScFv肽在体外和体内选择性靶向mNP /铁至癌细胞（项目1）。此外，TEM将允许关于有效激发和细胞毒性准确评估各种NP的体积和解剖位置。 TPB评估将确定哪些肽具有最大的靶向前景，可用于临床前体内卵巢和乳腺肿瘤模型（项目2和3）。在项目2中，TPB将在确定mNP体内成像技术的准确性和灵敏度方面发挥重要作用。通过非侵入性成像技术（如光谱学和MRI）观察到的变化的病理学共配准和验证仍然是确定新成像技术灵敏度和可靠性的金标准。在项目3中，ICP-MS和普鲁士蓝组织形态计量学mNP /铁定量技术的使用将允许研究者确定mNP/铁含量在肿瘤治疗功效研究中的绝对作用。在项目4中，TPB核心在确定暴露于ip递送的mNP的卵巢癌树突状细胞、癌细胞和其他腹部组织摄取的铁水平方面将是重要的。由于在该癌症模型中靶向的NP暴露场很大，因此存在正常组织损伤的风险。这些小鼠的病理学评估对于安全性和毒性/疗效的理解极为重要。