Dual imaging and therapeutic targeting agents for glioblastoma

胶质母细胞瘤的双重成像和治疗靶向剂

• 批准号: 7646415
• 负责人: RUIWU LIU
• 金额: $ 20.52万
• 依托单位: UNIVERSITY OF CALIFORNIA AT DAVIS
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-07-01 至 2011-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7646415
• 关键词: Affinity; Age; B-Lymphocytes; Binding; Biodistribution; Biology; Brain; Cancer cell line; Cause of Death; Cell Line; Cells; Chelating Agents; Chemicals; Child; Combined Modality Therapy; Cyclic Peptides; Cysteine; Development; Diagnosis; Diagnostic; Disease; Early Diagnosis; Excision; Fluorescence; Fluorescent Dyes; Fluorescent Probes; Glioblastoma; Glioma; Goals; Human; Hydroxyproline; Image; Inhibitory Concentration 50; Integrins; Kidney; Label; Lead; Libraries; Ligand Binding; Ligands; Liver; Lymphoma; Malignant - descriptor; Malignant Glioma; Malignant Neoplasms; Malignant neoplasm of brain; Malignant neoplasm of ovary; Methods; Modification; Mus; Nature; Neoplastic Astrocyte; Neuroglia; Neurons; Nude Mice; Operative Surgical Procedures; Optics; Pattern; Peptide Library; Peptides; Positron-Emission Tomography; Primary Brain Neoplasms; RGD (sequence); Radiation therapy; Radioisotopes; Radiolabeled; Relative (related person); Reporting; Research; Scanning; Screening procedure; Series; Small Intestines; Specificity; Surface; Surrogate Markers; Testing; Therapeutic Effect; Therapeutic Studies; Therapy Clinical Trials; Tumor Tissue; Xenograft Model; Xenograft procedure; cell type; chemotherapy; combinatorial; design; experience; homocitrulline; in vitro Assay; in vivo; irradiation; metal chelator; mouse model; novel therapeutics; optical imaging; preclinical evaluation; public health relevance; radiochemical; radiotracer; response; subcutaneous; therapeutic target; tumor; uptake; young adult

DESCRIPTION (provided by applicant): Brain cancer is the second leading cause of death in children under age 15 and in young adults up to age 34. Malignant glioma, the most common type of the primary brain tumors, remains largely incurable despite intensive multimodality treatments including surgical resection, irradiation and chemotherapy. There is a definite need for the development of novel therapeutic (e.g., targeted therapy) and diagnostic agents for this dreadful disease. The long-term goal of this proposed research is to develop clinically useful dual imaging and therapeutic targeting agents for glioblastoma. Integrins are potential targets for tumor imaging and therapy. Integrin 1321 is the major intergrin isotype expressed on the surface of glioma cells. Through screening "one-bead one- compound" (OBOC) combinatorial peptide libraries with a whole cell binding approach, we recently identified several cyclic peptide ligands against 1321 integrin. Modification of these peptides led to identification of a more potent peptide ligand, LXY1 (cyclic cdGLG- Hyp-Nc, Hyp=hydroxyproline), against malignant human glioblastoma A-172 and U- 87MG cell lines. In vivo optical imaging showed high tumor uptake in both subcutaneous and orthotopic U-87MG xenografts in mice. In this proposed research, we plan to use OBOC combinatorial library approaches to further optimize the lead compound LXY1. Highly potent and specific ligands will be selected to evaluate for in vivo tumor targeting and biodistribution studies in both subcutaneous and orthotopic U-87MG xenografts in mice, first using optical imaging and later microPET imaging. Because 64Cu is suitable for both PET imaging and radiotherapy, we hypothesize that fully optimized LXY1 derivatives for glioblastoma binding, when conjugated to a metal chelator CB-TE2A and labeled with 64Cu can be developed into new cancer-targeted PET imaging and radiotherapeutic agents for glioblastoma. Therapeutic effects of 64Cu-CB-TE2A-peptide are beyond the scope of this current R21 proposal. If successful, efficient and sensitive PET imaging agents can be used for early detection and diagnosis of glioblastoma, as well as a surrogate marker or end point for tumor response in therapeutic trials. PUBLIC HEALTH RELEVANCE: In this proposed research, highly potent and specific glioblastoma cell binding-peptides will be identified by focused one-bead one-compound library approaches. Such peptides, when radiolabeled with 64Cu, can be developed into clinically useful dual PET imaging and radiotherapeutic targeting agents for glioblastoma. MicroPET will be used to evaluate the cancer targeting potential of the peptides for glioblastoma in an orthotopic and subcutaneous xenograft mice model.

描述(申请人提供)：脑癌是15岁以下儿童和34岁以下年轻人的第二大死因。恶性胶质瘤是脑原发肿瘤中最常见的一种，尽管进行了手术切除、放疗和化疗等多种手段的强化治疗，但大多数情况下仍无法治愈。对于这种可怕的疾病，确实需要开发新的治疗方法(例如，靶向治疗)和诊断试剂。这项拟议研究的长期目标是开发临床上有用的胶质母细胞瘤双重成像和治疗靶向药物。整合素是肿瘤成像和治疗的潜在靶点。整合素1321是表达于胶质瘤细胞表面的主要整合素亚型。通过用全细胞结合的方法筛选“一珠一化合物”(OBOC)组合多肽文库，我们最近发现了几个针对1321整合素的环肽配体。对这些多肽的修饰导致了一种更有效的多肽配体LXY1的鉴定，LXY1(环状cdGLG-Hyp-NC，Hyp=羟脯氨酸)，对人恶性胶质母细胞瘤A-172和U-87 mg细胞系具有抑制作用。体内光学成像显示小鼠皮下和原位U-87 mg异种移植瘤均有高摄取率。在这项拟议的研究中，我们计划使用OBOC组合库方法来进一步优化先导化合物LXY1。将选择高效和特定的配体来评估在小鼠皮下和原位U-87 mg异种移植中的体内肿瘤靶向和生物分布研究，首先使用光学成像，然后使用microPET成像。由于64Cu既适合于PET成像，也适用于放射治疗，我们假设，当完全优化的用于胶质母细胞瘤结合的LXY1衍生物与金属螯合剂CB-TE2A结合并标记64Cu时，可以开发成新的肿瘤靶向PET成像和放射治疗胶质母细胞瘤的药物。64Cu-CB-TE2A多肽的治疗效果超出了当前R21提案的范围。如果成功，有效和灵敏的PET显像剂可以用于胶质母细胞瘤的早期检测和诊断，以及在治疗试验中作为肿瘤反应的替代标记物或终点。公共卫生相关性：在这项拟议的研究中，将通过聚焦一珠一化合物文库的方法鉴定高度有效和特定的胶质母细胞瘤细胞结合肽。当这种多肽被放射性标记为64Cu时，可以开发成临床上有用的胶质母细胞瘤的双重PET成像和放射治疗靶向药物。在原位和皮下移植的小鼠模型中，microPET将被用于评估多肽对胶质母细胞瘤的肿瘤靶向性。