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MNP在AIL主要器官组织中的运动和沉积以及在特定环境中的单个细胞中的运动和沉积提供定性和Quant性评估。 TPB核心还将提供专用且全面的药代动力学（LEWIS），人类和动物病理学/病理生理学（Memoli和Hoopes）以及TEM/SEM（Daghlian）的专业知识，以从MNPS（Iron，Coaffing piptides，Fuorsecties，fluores Extife and Fimefe and Itfecsion and Itfefe and）（或/或或或或或或或或或或或或以上），以恢复潜在的细胞和/或组织变化。整个DCCNE应用的主要目标是为了观察和选择性地传递MNP/LRON向癌细胞的观察方法，以随后的细胞毒性激发，对细胞和fissues（Prussian Blue Histormorphormetry和ICP-MS）中铁的评估和定量的评估和定量，以及在Tumor和Tumor中产生的病理学效应，并具有正常的Fissuntions。 TPB核心将是确定各种NP的Relafive能力的核心部分 物理参数，涂料，内部化与非内在化SCFV肽，可在体外和体内选择性地靶向MNP /铁对癌细胞（项目1）。此外，TEM将允许对有效激发和细胞毒性的各种NP的体积和解剖位置进行准确评估。 TPB评估将确定哪些肽在体内卵巢肿瘤和乳腺肿瘤模型中的未来使用最有目标（项目2和3）。在项目2中，TPB将发挥重要作用，以确定MNP在体内成像技术中的准确性和敏感性。通过非侵入成像技术（如光谱和MRI）观察到的变化的病理共同注册和验证仍然是确定新成像技术灵敏度和可靠性的黄金标准。在项目3中，使用ICP-MS和Prussian Blue Histormormormothomentry MNP /铁量化技术将使研究人员确定MNP /LRON含量在肿瘤治疗功效研究中的绝对作用。在项目4中，TPB核心对于确定卵巢癌树突状细胞，癌细胞和其他暴露于IP输送的MNP的铁的铁水平很重要。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。这些小鼠的病理评估对于安全性和对毒性/功效的理解将非常重要。