Novel Strategy Development for Neuroprotective Therapeutics Delivery in Stroke

描述(申请人提供)：在缺血性中风的早期阶段，rt-PA与神经保护剂的联合治疗是一种很有前途的治疗策略。有证据表明，氙气等生物活性气体具有较强的神经保护作用，具有易于通过血脑屏障、扩散迅速、无已知副作用等优点。然而，由于缺乏合适的输送方法，这些气体的使用一直受到限制。我们之前的研究已经在开发适合生物活性气体包埋、rt-PA结合、凝块靶向、溶栓和超声控制生物活性气体释放的脂质体配方方面取得了许多里程碑。本研究旨在开发、优化和测试一种新型多功能回声脂质体(Elip)，包括溶栓剂和神经保护性生物活性气体共包裹、凝块靶向、超声和血栓溶解调制神经保护气体的释放，用于溶栓相关神经保护治疗。其具体目的是：(1)优化包埋氙气和其他神经保护气体的包裹体，以延长循环时间和释放足够的生物活性气体；(2)评估引发拟议Elip制剂释放生物活性气体的各种超声参数，以及(3)优化并鉴定在溶栓过程中由rt-PA与血栓相互作用引发的气体以及气体/环糊精复合体的释放，一旦完成目标1，2和3，以测试该策略在恢复脑循环和防止神经元损伤方面的有效性。在缺血性中风动物模型中，含有神经保护气体和rt-PA的多功能Elip将与颈动脉超声释放生物活性气体一起静脉注射。我们预计，这一策略将增加rt-PA的治疗窗口，防止神经元损伤，从而加强脑保护。开发的技术将为生物活性气体胶囊提供独特的多功能载体，这种载体易于管理、部位特定输送和US/溶栓控制释放。这可能有助于克服目前可用的策略中出现的不完全溶栓和脑缺血损伤的问题。本研究中开发的气体包裹和输送技术可以转化为生物活性气体输送可能有益的实体。 公共卫生相关性：这项建议的目标是开发和评价一种重组组织型纤溶酶原激活剂(rt-PA)包衣的回声脂质体配方，用于超声和溶栓控制的神经保护性气体输送到脑循环，用于治疗与血栓性中风相关的缺血性脑损伤。这可能有助于克服目前可用的策略中出现的不完全溶栓和脑缺血损伤的问题。本研究中开发的气体包裹和输送技术可以转化为生物活性气体输送可能有益的实体。

DESCRIPTION (provided by applicant): Combination therapeutic of rt-PA with a neuroprotective agent in the early phase of ischemic stroke is a promising therapeutic strategy. Evidences suggests that bioactive gases such as xenon have profound neuroprotective effects with advantages of ready passage through blood-brain barrier, rapid diffusion and no known side effects. However, use of these gases has been limited by lack of suitable delivery methods. Our previous research has achieved a number of milestones in developing liposomal formulations that are suitable for bioactive gas encapsulation, rt-PA association, clot targeting, thrombolysis and ultrasound-controlled bioactive gas release. The propose of this research is to develop, optimize and test a novel multifunctional echogenic liposomal (ELIP) formulation with thrombolytic agent and neuroprotective bioactive gas co-encapsulation, clot targeting, ultrasound and clot lysis modulated-release of neuroprotective gases for thrombolytic associated neuroprotective therapy. The specific aims are: (1) to optimize the encapsulation of xenon and other neuroprotective gases into ELIP for prolonged circulation time and sufficient bioactive gas release; (2) to evaluate various ultrasound parameters to trigger bioactive gases release from the proposed ELIP formulation, and (3) to optimal and identify gas and gas/cyclodextrin complexes release triggered by the interaction of rt-PA with clot during thrombolysis and once finished aims 1,2 and 3, to test the efficacy of this strategy in restoring cerebral circulation and preventing neuronal damage in an in vivo rat model of ischemic stroke. Multifunctional ELIP containing neuroprotective gases and rt-PA will be administered intravenously with carotid artery ultrasound release bioactive gas in an animal model of ischemia stroke. We anticipate that this strategy will enhance rt-PA therapeutic window and prevent neuronal damage, resulting in strengthened cerebral protection. Techniques developed will provide unique multifunctional vectors for bioactive gas encapsulation that can be easily administered, site-specific delivery and US/thrombolysis-controlled release. This may help overcome problems of incomplete thrombolysis and cerebral ischemia injury seen with current available strategies. Gas encapsulation and delivery technique developed in this research can be translated into entities in which bioactive gas delivery may be beneficial. PUBLIC HEALTH RELEVANCE: The objectives of this proposal are to develop and evaluate a recombinant tissue plasminogen activator (rt- PA) coated echogenic liposomal formulation for both ultrasound and thrombolysis controlled neuroprotective gas delivery to the cerebral circulation for the treatment of ischemic brain injury in association with thrombotic stroke. This may help overcome problems of incomplete thrombolysis and cerebral ischemia injury seen with current available strategies. Gas encapsulation and delivery technique developed in this research can be translated into entities in which bioactive gas delivery may be beneficial.