Optimization of ultrasound-mediated drug delivery to the brain under clinically relevant conditions

在临床相关条件下优化超声介导的药物递送至大脑

• 批准号: 10701788
• 负责人: Nathan J. McDannold
• 金额: $ 49.45万
• 依托单位: BRIGHAM AND WOMEN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-12 至 2026-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10701788
• 关键词: Acoustics; Adverse event; Animal Experiments; Animals; Back; Blood - brain barrier anatomy; Blood Vessels; Brain; Brain Neoplasms; Calibration; Carboplatin; Cell Line; Central Nervous System; Central Nervous System Diseases; Cephalic; Clinic; Clinical; Clinical Treatment; Clinical Trials; Contrast Media; Disease; Disease model; Dose; Drug Delivery Systems; Electronics; Focused Ultrasound; Future; Glioblastoma; Glioma; Goals; Growth; Human; Infiltration; Learning; Long-Term Effects; Mediating; Methods; Microbubbles; Modeling; Monitor; Motivation; Mus; Neurodegenerative Disorders; Noise; Nude Rats; Patients; Pharmaceutical Preparations; Pre-Clinical Model; Procedures; Property; Protocols documentation; Rattus; Research; Safety; Sampling; Series; Signal Transduction; Sonication; Structure; System; Technology; Therapeutic; Therapeutic Agents; Tissues; Tumor Burden; Validation; Variant; Visit; Work; attenuation; bench to bedside; blood-brain barrier disruption; clinically relevant; cranium; detector; early experience; effective therapy; experience; experimental study; histological studies; improved; improved outcome; nonhuman primate; patient derived xenograft model; pre-clinical; preclinical study; prevent; simulation; success; tool; treatment planning; tumor; ultrasound; white matter

Summary The blood-brain barrier prevents most drugs from reaching the central nervous system and is one of the biggest problems in developing new effective therapies for patients with brain tumors, neurodegenerative diseases, and other disorders. The use of ultrasound in combination with injected microbubble agents has emerged as a prom- ising method to temporarily disrupt the barrier. After over a decade of preclinical studies in animals, multiple commercial systems have been developed and clinical trials have begun. Early experience with these trials have shown several problems that were predicted by the preclinical work. The clinical treatments use lower doses of microbubbles, have to overcome the variable attenuation of the human skull, and are often in white matter. As a result, treatments have been suboptimal. The purpose of this proposal is to provide a roadmap to clinical success for ultrasound-mediated blood-brain barrier opening. We will develop new treatment planning methods that ac- count for the human skull, electronic steering of the focused ultrasound beam, and variations in microbubble concentrations in different tissue structures. These methods will be employed to improve safety and control of the procedure. Next, we will investigate whether we can improve our ability to control the procedure in white matter targets and evaluate the safety of repeated blood-brain barrier disruption in white matter targets. Finally, using what we have learned, we will investigate whether we can deliver sufficient drugs to treat a highly infiltrating tumor model. If successful, this work could have a significant impact on future use of this exciting technology.

概括 血脑屏障可以阻止大多数药物进入中枢神经系统，并且是最大的药物之一 针对患有脑肿瘤患者，神经退行性疾病和 其他疾病。超声使用与注入的微泡剂的结合已成为一种舞会 临时破坏障碍的方法。在动物中进行了十多年的临床前研究之后，多个 已经开发了商业系统，并开始临床试验。这些试验的早期经验有 显示了临床前工作预测的几个问题。临床治疗使用较低剂量 微泡，必须克服人颅骨的可变衰减，并且通常在白质中。作为 结果，治疗次优。该建议的目的是为临床成功提供路线图 用于超声介导的血脑屏障开口。我们将开发新的治疗计划方法 计数人头骨，聚焦超声梁的电子转向以及微泡中的变化 不同组织结构中的浓度。这些方法将用于提高安全性和控制 过程。接下来，我们将调查我们是否可以提高控制白色程序的能力 物质目标并评估白质目标中反复的血脑屏障破坏的安全性。最后， 使用我们学到的知识，我们将调查是否可以提供足够的药物来治疗高度浸润 肿瘤模型。如果成功，这项工作可能会对这种令人兴奋的技术的未来使用产生重大影响。

项目成果

Nonspherical ultrasound microbubbles.

• DOI: 10.1073/pnas.2218847120
• 发表时间: 2023-03-28
• 期刊: PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
• 影响因子: 11.1
• 作者: Dasgupta, Anshuman;Sun, Tao;Palomba, Roberto;Rama, Elena;Zhang, Yongzhi;Power, Chanikarn;Moeckel, Diana;Liu, Mengjiao;Sarode, Apoorva;Weiler, Marek;Motta, Alessandro;Porte, Celine;Magnuska, Zuzanna;Elshafei, Asmaa Said;Barmin, Roman;Graham, Adam;McClelland, Arthur;Rommel, Dirk;Stickeler, Elmar;Kiessling, Fabian;Pallares, Roger M.;De Laporte, Laura;Decuzzi, Paolo;McDannold, Nathan;Mitragotri, Samir;Lammers, Twan
• 通讯作者: Lammers, Twan

Transferrin Receptor-Targeted Nonspherical Microbubbles for Blood-Brain Barrier Sonopermeation.

用于血脑屏障超声渗透的转铁蛋白受体靶向非球形微泡。

• DOI: 10.1002/adma.202308150
• 发表时间: 2023
• 期刊: Advanced materials (Deerfield Beach, Fla.)
• 作者: Dasgupta,Anshuman;Sun,Tao;Rama,Elena;Motta,Alessandro;Zhang,Yongzhi;Power,Chanikarn;Moeckel,Diana;Fletcher,Stecia-Marie;Moosavifar,Mirjavad;Barmin,Roman;Porte,Céline;Buhl,EvaMiriam;Bastard,Céline;Pallares,RogerM;Kiessling,Fa
• 通讯作者: Kiessling,Fa