Dual imaging and therapeutic targeting agents for glioblastoma

描述（由申请人提供）：脑癌是15岁以下儿童和34岁以下年轻人死亡的第二大原因。恶性胶质瘤是最常见的原发性脑肿瘤类型，尽管进行了包括手术切除、放疗和化疗在内的多模式强化治疗，但在很大程度上仍无法治愈。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）和诊断方法。本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是胶质瘤细胞表面表达的主要间素同型。通过全细胞结合筛选“一头一化合物”（OBOC）组合肽文库，我们最近发现了几种针对1321整合素的环肽配体。对这些多肽进行修饰后，鉴定出一种更有效的肽配体LXY1 (cyclic cdGLG- Hyp- nc, Hyp=hydroxyproline)，可以对抗人类恶性胶质母细胞瘤a -172和U- 87MG细胞系。体内光学成像显示，小鼠皮下和原位U-87MG异种移植物均有较高的肿瘤摄取。在本研究中，我们计划使用OBOC组合文库方法进一步优化先导化合物LXY1。将选择高效和特异性的配体来评估小鼠皮下和原位U-87MG异种移植物的体内肿瘤靶向和生物分布研究，首先使用光学成像，然后使用微pet成像。由于64Cu既适用于PET显像，也适用于放疗，我们假设充分优化的LXY1衍生物结合成胶质母细胞瘤，当与金属螯合剂CB-TE2A结合并标记64Cu时，可以开发成新的肿瘤靶向的成胶质母细胞瘤PET显像和放疗药物。64cu - cb - te2a肽的治疗作用超出了本R21提案的范围。如果成功，高效灵敏的PET显像剂可用于胶质母细胞瘤的早期检测和诊断，也可作为治疗试验中肿瘤反应的替代标志物或终点。公共卫生相关性：在这项拟议的研究中，高效和特异性胶质母细胞瘤细胞结合肽将通过集中的单头单化合物文库方法鉴定。当用64Cu进行放射标记时，这些肽可以发展成为临床有用的胶质母细胞瘤双PET成像和放射治疗靶向药物。MicroPET将用于评估多肽在原位和皮下异种移植小鼠模型中对胶质母细胞瘤的靶向潜力。

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.