Image-guided, ultrasound-enhanced long-term intracranial drug delivery

图像引导、超声增强的长期颅内药物输送

• 批准号: 9884240
• 负责人: Yevgeny Brudno
• 金额: $ 16.79万
• 依托单位: NORTH CAROLINA STATE UNIVERSITY RALEIGH
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-02-15 至 2022-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9884240
• 关键词: Acoustics; Biological Products; Blood - brain barrier anatomy; Blood Circulation; Bolus Infusion; Brain; Brain Diseases; Cephalic; Clinical; Combined Modality Therapy; Craniotomy; Degenerative Disorder; Development; Disease; Disease Progression; Dose; Drug Delivery Systems; Drug Implants; Drug Modelings; Erlotinib; Erythrocytes; Excision; Extracellular Fluid; Extravasation; Focused Ultrasound; Glioblastoma; Gold; Growth; Hour; Immunosuppressive Agents; Immunotherapeutic agent; Implant; Injectable; Life; Magnetic Resonance Imaging; Malignant neoplasm of brain; Mediating; Methods; Modeling; Nature; Neurons; Operative Surgical Procedures; Pathway interactions; Patient Care; Patients; Penetration; Pharmaceutical Preparations; Primary Brain Neoplasms; Prodrugs; Radio; Recurrence; Savings; Scheme; Side; Site; Stroke; Surgical margins; Symptoms; System; Techniques; Technology; Testing; Therapeutic; Therapeutic Agents; Time; Tissues; Tumor-Derived; Ultrasonography; Vision; blood-brain barrier disruption; blood-brain barrier permeabilization; cancer therapy; chemotherapeutic agent; chemotherapy; clinical application; clinical translation; controlled release; cranium; epidermal growth factor receptor VIII; flexibility; image guided; implantation; improved; innovation; new technology; novel; novel therapeutic intervention; post stroke; preclinical study; prevent; regenerative agent; side effect; standard of care; subcutaneous; treatment strategy; tumor; tumor growth

PROJECT SUMMARY The blood-brain barrier (BBB) serves as the major hindrance to efficient transport of life-saving therapeutics to the brain. Image-guided focused ultrasound can disrupt the BBB, but only temporarily and for a short period of time. Local implantation of drug-eluting depots is another option, but these are single-use systems that cannot be refilled or reused after implantation at inaccessible sites, limiting their clinical utility. Recently, we introduced click-modified refillable drug depots: injectable depots that capture prodrug refills from systemic circulation and release active drugs locally in a sustained manner. Capture of systemically-administered refills serves as an efficient and non-toxic method to repeatedly refill depots. Refillable depots in combination with prodrug refills achieve sustained release at tumor sites to improve cancer therapy while eliminating systemic side effects. Refillable depots have been successful in subcutaneous models of tumor recurrence, preventing tumor growth while eliminating systemic side effects. Unfortunately, the prodrug refills do not cross the BBB and thus refillable depots cannot be used alone in brain diseases such as stroke, degenerative disorders and brain cancers. We now propose refilling intracranial drug depots through the combination of non-toxic therapeutic prodrugs and image-guided transient disruption of the blood brain barrier. BBB disruption with focused- ultrasound provide a transient (~1 hour) window for the refilling of intracranial depots. The use of nontoxic prodrug refills allows us to administer large doses to maximally exploit the short window for drug delivery, allowing weeks and potentially months worth of therapeutic to be given in the short time window. After BBB reformation, the intracranial depots will release active drugs for a long period of time before being non-invasively refilled again. We further propose testing this innovative drug-delivery strategy in a patient-derived orthotopic GBM tumor model. This innovative combination of these two promising new technologies provides an approach to present therapeutic agents over a long period of time directly to the brain. Our efforts will further develop this promising approach, optimize parameters, and validate efficacy in preclinical studies. Clinical applications include the local release of chemotherapeutics, biologics and immunotherapy agents against GBM and other brain cancers, and administration of regenerative and immunosuppressive agents after stroke. If successful, the improvements made to this very innovative drug delivery strategy could open the pathway to clinical translation of refillable drug delivery technology.

项目概要 血脑屏障 (BBB) 是有效输送救生药物的主要障碍 到大脑。图像引导聚焦超声可以扰乱血脑屏障，但只是暂时的、短时间内的 的时间。局部植入药物洗脱库是另一种选择，但这些是一次性系统，不能 植入后难以到达的部位需要重新填充或重复使用，限制了其临床用途。最近，我们推出了 点击修改的可再填充药物储存库：可注射储存库，可从体循环中捕获前药再填充，并 以持续的方式局部释放活性药物。捕获系统管理的补充品可作为 重复填充仓库的高效且无毒的方法。可再填充的储库与前药再填充相结合 在肿瘤部位实现持续释放，以改善癌症治疗，同时消除全身副作用。 可再填充储库已在肿瘤复发的皮下模型中取得成功，可防止肿瘤生长 同时消除全身副作用。不幸的是，前药补充品不会穿过血脑屏障，因此可补充 长效制剂不能单独用于治疗中风、退行性疾病和脑癌等脑部疾病。 我们现在建议通过结合无毒治疗药物来补充颅内药物库 前药和图像引导的血脑屏障短暂破坏。 BBB 破坏与集中- 超声为颅内储库的再填充提供短暂（约 1 小时）的窗口。使用无毒 前药补充使我们能够施用大剂量，以最大限度地利用短窗口进行药物输送， 允许在短时间内给予数周甚至数月的治疗。 BBB之后 改造后，颅内储库会长时间释放活性药物，然后才能无创地释放 再次补充。我们进一步建议在源自患者的原位测试这种创新的药物输送策略 GBM肿瘤模型。 这两种有前途的新技术的创新组合提供了一种方法来呈现 治疗剂长期直接作用于大脑。我们的努力将进一步发展这个有前途的 在临床前研究中方法、优化参数并验证疗效。临床应用包括局部 释放针对 GBM 和其他脑癌的化疗药物、生物制剂和免疫治疗药物，以及 中风后给予再生剂和免疫抑制剂。如果成功的话，改进 这种非常创新的药物输送策略可以为可再填充药物的临床转化开辟途径 交付技术。