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

项目总结 血脑屏障(BBB)是有效运输救命药物的主要障碍。 对大脑的影响。图像引导的聚焦超声可以破坏血脑屏障，但只是暂时的和短时间的。 时间的流逝。局部植入药物洗脱库是另一种选择，但这些是一次性使用的系统，不能 植入后在难以接触的部位重新灌装或重复使用，限制了其临床应用。最近，我们介绍了 点击修改的可再灌装药库：可注射的药库，可从体循环和 持续在当地释放活性药物。捕获系统管理的再灌装可以作为一种 高效、无毒的重复补给仓库的方法。可重新填充的仓库与前体药物重新填充相结合 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。 可再填充的储存库已经成功地用于皮下肿瘤复发模型，防止肿瘤生长 同时消除全身副作用。不幸的是，前药补充剂不能通过血脑屏障，因此可以重新灌装。 仓库不能单独用于中风、退行性疾病和脑癌等脑部疾病。 我们现在建议通过无毒疗法的组合来重新填充颅内药物仓库 前药和影像引导的血脑屏障的一过性破坏。BBB颠覆与聚焦- 超声提供了一个短暂的(~1小时)的时间窗，用于脑血管的再充盈。无毒食品的使用 前体药物再灌装使我们能够给予大剂量药物，以最大限度地利用药物输送的短窗口， 允许在短时间窗口内进行数周甚至数月的治疗。在BBB之后 改革，颅内仓库将长期释放活性药物，然后才是非侵入性的 又加了一杯。我们进一步建议在患者衍生的原位移植中测试这一创新的药物传递策略。 GBM肿瘤模型。 这两种前景看好的新技术的创新组合提供了一种呈现 治疗剂在很长一段时间内直接进入大脑。我们的努力将进一步发展这一前景 临床前研究中的方法、优化参数和有效性验证。临床应用包括局部应用 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 卒中后再生性和免疫抑制剂的应用。如果成功，改进措施 这一非常创新的药物传递策略可能会为可再填充药物的临床翻译开辟道路 交付技术。

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.