Fluorinated macrocyclic peptides as BBB penetrating agent for improved GBM treatment

氟化大环肽作为 BBB 渗透剂，改善 GBM 治疗

• 批准号: 10189534
• 负责人: Sean Edward Lawler
• 金额: $ 27.61万
• 依托单位: BRIGHAM AND WOMEN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-07-04 至 2021-09-01
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10189534
• 关键词: 3-Dimensional; Address; Antineoplastic Agents; Binding; Biodistribution; Biological; Blood - brain barrier anatomy; Brain; Brain Diseases; Brain Neoplasms; Cell Line; Cell Survival; Cells; Cellular Structures; Central Nervous System Diseases; Central Nervous System Neoplasms; Chemical Structure; Chemicals; Chemistry; Cisplatin; Clinical; Clinical Trials; Collaborations; Data; Development; Disease; Drug Delivery Systems; Drug Kinetics; Engineering; Excision; Exposure to; Fluorine; Glioblastoma; Goals; Human; In Vitro; Investigation; MDM2 gene; Malignant - descriptor; Medicine; Modeling; Modification; Mus; Nature; Operative Surgical Procedures; Outcome; Patients; Penetration; Peptide Transport; Peptides; Pharmaceutical Preparations; Positioning Attribute; Prodrugs; Prognosis; Recurrence; Resistance; Structure-Activity Relationship; TP53 gene; Therapeutic; Therapeutic Agents; Therapeutic Effect; Toxic effect; Treatment Efficacy; Variant; Work; base; blood-brain barrier crossing; blood-brain barrier penetration; brain tissue; cancer therapy; chemical property; design; dosage; effective therapy; experience; improved; improved outcome; in vivo; inhibitor/antagonist; mouse model; neurosurgery; novel; novel therapeutics; peptide drug; pre-clinical; prevent; protein protein interaction; small molecule therapeutics; standard of care; temozolomide; therapeutically effective; three-dimensional modeling; tumor

Project Summary/Abstract Despite recent progress in cancer therapy, the brain tumor glioblastoma (GBM) remains an extremely challenging disease and new therapies are badly needed. One of the biggest obstacles to effective treatment of GBM is the presence of the blood-brain barrier (BBB), which prevents the passage of many drugs into the brain. The highly invasive nature of GBM means there are always cells that remain after surgery in otherwise normal brain tissue, and these cells are protected behind the BBB, preventing many drugs from reaching them. To address this we have formed a collaboration between Sean Lawler’s pre-clinical GBM therapeutics group at BWH, and Brad Pentelute’s peptide chemistry group at MIT to develop approaches to 1) specifically target glioblastoma cells, and 2) to identify agents which will cross the BBB. Our collaboration has identified a novel peptide (M13) modified with fluorinated linkers that penetrate the BBB in vivo. To build on this our aims are as follows: Specific Aim 1. Investigate effects of altered chemical properties on BBB penetration by peptides modified with fluorinated linkers. Specific Aim 2. Examine therapeutic effects of a BBB penetrant p53/MDM2 inhibitor. Specific Aim 3. Delivery of BBB-penetrant macrocyclic peptide-drug conjugates in glioblastoma mouse models. Our goal is to use our findings to provide the basis for further development of improved therapeutics and provide a platform for clinical trials for glioblastoma and potentially other tumors of the central nervous system.

项目摘要/摘要 尽管最近在癌症治疗方面取得了进展，但脑肿瘤胶质母细胞瘤(GBM)仍然是一种 迫切需要极具挑战性的疾病和新的治疗方法。世界上最大的 有效治疗基底膜的障碍是血脑屏障(BBB)的存在，这是 阻止许多药物进入大脑。GBM手段的高度侵入性 手术后，在其他正常的脑组织中总是有细胞残留，这些细胞 被保护在血脑屏障后面，防止许多药物到达他们手中。为了解决这个问题，我们 已经由肖恩·劳勒的临床前GBM治疗小组在 BWH和麻省理工学院布拉德·潘特鲁特的多肽化学小组共同开发方法，以实现1) 专门针对胶质母细胞瘤细胞，以及2)识别将穿越血脑屏障的药物。我们的 合作伙伴发现了一种新型多肽(M13)，该多肽由氟化连接物修饰，可穿透 体内的血脑屏障。在此基础上，我们的目标如下：具体目标1.调查影响 氟化连接物修饰的多肽对血脑屏障渗透的化学性质改变。 具体目的2.检测血脑屏障穿透性P53/MDM2抑制剂的治疗效果。特定的 目的3.血脑屏障穿透性大环肽-药物结合物在胶质母细胞瘤小鼠体内的传递 模特们。我们的目标是利用我们的发现为改进的进一步发展提供基础 治疗并为胶质母细胞瘤和其他潜在的临床试验提供平台 中枢神经系统的肿瘤。