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 在所有主要器官组织以及特定环境中的单个细胞中的运动和沉积进行定性和定量评估。 TPB 核心还将提供专门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) 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）引起的潜在细胞和/或组织变化。 整个 DCCNE 应用的主要目标是优化观察方法并选择性地将 mNP/Iron 递送至癌细胞以进行随后的细胞毒性激发，评估和定量细胞和组织中的铁水平（普鲁士蓝组织形态测定法和 ICP-MS）以及由此产生的肿瘤和正常组织中的病理效应，这是至关重要的。 TPB 核心将成为确定各个 NP 相对能力的核心参与者 物理参数、涂层、内化与非内化 ScFv 肽，以在体外和体内选择性地将 mNP /铁靶向癌细胞（项目 1）。此外，TEM 将能够准确评估各种 NP 的体积和解剖位置，以及有效激发和细胞毒性。 TPB 评估将确定哪些肽在未来临床前体内卵巢和乳腺肿瘤模型中最具有靶向性（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。通过光谱学和 MRI 等非侵入性成像技术观察到的变化的病理联合注册和验证仍然是确定新成像技术的灵敏度和可靠性的黄金标准。在项目 3 中，使用 ICP-MS 和普鲁士蓝组织形态计量 mNP/铁定量技术将使研究人员能够确定 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吸收的铁水平非常重要。由于该癌症模型中的靶向纳米粒子暴露场很大，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毒性/功效的理解极其重要。