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提供对mNPs在所有主要器官组织以及特定环境下的单个细胞中的移动和沉积的定性和定量评估。TPB核心还将提供专门和全面的药代动力学(Lewis)、人类和动物病理学/病理生理学(Memoli和Hoope)以及透射电子显微镜/扫描电子显微镜(Daghlian)的专业知识，以研究MNPs(铁、涂层、靶标多肽、荧光探针等)和/或交变磁场(AMF)暴露引起的潜在细胞和/或组织变化。由于整个DCCNE应用的主要目标是优化mNP/lron的观察方法，并选择性地将mNP/lron输送到癌细胞以用于随后的细胞毒激发，因此评估和量化细胞和FIss中的铁水平(普鲁士蓝组织形态计量学和电感耦合等离子体质谱(ICPMS))以及由此产生的肿瘤和正常FIss的病理效应是至关重要的。 TPB核心将在确定各种NP的重新启动能力方面发挥中心作用 物理参数、涂层、内化与非内化单链抗体多肽，以选择性地在体外和体内将mNP/铁靶向癌细胞(项目1)。此外，在有效激发和细胞毒性方面，透射电子显微镜将允许准确地评估各种NPs的体积和解剖位置。 TPB评估将确定哪些多肽在未来临床前、体内卵巢和乳腺肿瘤模型中具有最具靶向性的前景(项目2和3)。在项目2中，TPB将在决定mNP活体成像技术的准确性和灵敏度方面发挥重要作用。光学光谱学和磁共振成像等非侵入性成像技术观察到的变化的病理联合配准和验证仍然是确定新成像技术的敏感性和可靠性的金标准。在项目3中，使用电感耦合等离子体质谱和普鲁士蓝组织形态计量学mNP/铁定量技术将使研究人员能够确定mNP/铁含量在肿瘤治疗疗效研究中的绝对作用。在项目4中，TPB核心将在确定暴露于IP递送的mNPs的卵巢癌树突状细胞、癌细胞和其他腹部组织中的铁水平方面发挥重要作用。由于在该癌症模型中，靶向NP暴露范围很大，因此存在正常组织损伤的风险。对这些小鼠的病理评估对于安全性和了解毒性/疗效将是极其重要的。