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: 10442440
• 负责人: Sean Edward Lawler
• 金额: $ 51.64万
• 依托单位: BROWN UNIVERSITY
• 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 2024-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10442440
• 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; mouse model; neurosurgery; novel; novel therapeutics; peptide drug; pre-clinical; prevent; protein protein interaction; small molecule therapeutics; standard of care; stapled peptide; 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.

项目总结/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）仍然是一种恶性肿瘤。 非常具有挑战性的疾病和新的治疗方法是迫切需要的。一个最大的 有效治疗GBM的障碍是血脑屏障（BBB）的存在， 阻止许多药物进入大脑GBM的高度侵袭性意味着 在手术后，在正常的脑组织中总会有细胞残留，这些细胞 被保护在血脑屏障后面，阻止许多药物到达它们。为了解决这个问题，我们 肖恩·劳勒的临床前GBM治疗小组与 BWH和麻省理工学院的布拉德彭特鲁特的肽化学小组开发方法， 特异性靶向胶质母细胞瘤细胞，和2）鉴定将穿过BBB的试剂。我们 一项合作已经确定了一种新的肽（M13），它被氟化连接体修饰， 体内的BBB。在此基础上，我们的目标如下：具体目标1。调查影响 通过用氟化接头修饰的肽改变对BBB渗透的化学性质。 具体目标2。检查BBB渗透剂p53/MDM 2抑制剂的治疗效果。具体 目标3.血脑屏障渗透性大环肽药物偶联物在胶质母细胞瘤小鼠中的递送 模型我们的目标是利用我们的研究结果为进一步开发改进的 治疗并为胶质母细胞瘤和潜在的其他疾病的临床试验提供平台。 中枢神经系统肿瘤