Nanotherapeutics for acute kidney injury

描述(由申请人提供)：这是一项探索性的多PI提案，将结合来自两个不同学科的两名研究人员的独特专业知识，应用创新方法来解决尚未得到满足的需求，即没有FDA批准的预防和治疗急性肾损伤(AKI)的药物。统计能力低，给药时机不当，以及不良反应，都阻碍了临床试验的成功。我们在AKI领域提出了一种新的方法，使用超声(US)刺激的载药纳米粒的药物传递。虽然纳米粒子(脂质体)已经被批准并用于癌症治疗，但我们的研究纳入了纳米技术领域的最新进展，这些进展尚未在靶向药物输送中进行测试。目前的给药系统使用微泡，包括由壳层(几纳米厚)包裹的气体核心，膜内或附着在膜内或附着在表面的药物，或装饰微泡表面的载药脂质体。在辐射过程中，微泡振荡；较高的US强度破坏微泡，部分释放脂质体有效载荷。这种药物载体系统的缺点是循环时间短(气体通常在静脉给药后几分钟内从气泡中流失)和药物不完全释放。此外，大尺寸的复合体(微米)限制了颗粒向血管床外渗。我们建议开发一种新型的药物载体系统(转移体)，该系统基于两种载体方法的组合，即载相移纳米粒制剂的脂质体纳米粒。这些研究将使用过热的液体全氟碳(例如，全氟戊烷和/或全氟丁烷)填充在脂质体内部核心内的纳米颗粒以及包裹的药物。我们将验证这样一种假设，即移位体具有改进的特征，并且可以特异性地靶向肾内皮细胞的新的鞘氨醇1受体(S1P1)类似物，以减少肾脏缺血再灌注损伤(IRI)。特定目标1将验证这样一个假设，即新型药物载体系统Shift osome具有改善超声触发药物传递的特性，并且当负载FTY720时，可以减少体外血管内皮细胞或肾小管上皮细胞损伤。特殊目的2将验证这样的假设，即由新型药物载体系统携带的S1P激动剂FTY720在体内选择性地靶向肾脏以减少肾脏IRI。在两年结束时，我们将确定：1)移位体在靶向肾脏方面是否安全、有效和有选择性，以及2)AKI临床试验的领先候选药物FTY720是否可以选择性地输送到肾脏，以避免潜在的全身副作用。这些研究将为未来使用新的载体方法治疗AKI的临床前研究提供基础。

DESCRIPTION (provided by applicant): This is an exploratory multi PI proposal that will merge the unique expertise of two investigators from two different disciplines to apply an innovative approach to address an unmet need, namely, that there are no FDA approved drugs for the prevention and treatment of acute kidney injury (AKI). Low statistical power, poorly timed administration of the drug, and adverse effects have hampered the success of clinical trials. We propose a new approach in the field of AKI using ultrasound (US)-stimulated drug delivery from drug-loaded nanoparticles. Although nanoparticles (liposomes) have already been approved and are in use for cancer therapy, our studies incorporate recent advances in the field of nanotechnology yet to be tested in targeted drug delivery. Current delivery systems use microbubbles that consist of a gas core encapsulated by a shell (several nm thick) with drugs embedded within the membrane or attached to the surface, or drug-loaded liposomes that decorate the surface of microbubbles. During insonation, microbubbles oscillate; higher US intensities destroy the microbubbles, partially releasing the liposome payload. The disadvantage of this drug carrier system is its short circulation time (gas is usually lost from the bubble within minutes following intravenous administration) and incomplete drug release. Furthermore, the large size of the complex (micrometers) limits extravasation of the particles beyond the vascular bed. We propose to develop a novel drug carrier system (shiftosome) that is based on the combination of two carrier approaches, i.e. liposome nanoparticles loaded with phase-shift nanoparticle agents. These studies will use a superheated liquid perfluorocarbon (e.g. perfluoropentane and/or perfluorobutane) filled nanoparticle inside the liposome internal core along with the entrapped drug. We will test the hypothesis that shiftosomes have improved characteristics and can specifically target a novel sphingosine 1 receptor (S1P1) analog to the kidney endothelium to reduce kidney ischemia-reperfusion injury (IRI). Specific Aim 1 will test the hypothesis that the novel drug carrier system, shiftosome, has improved characteristics for ultrasound-triggered drug delivery, and, when loaded with FTY720, can reduce vascular endothelial or tubular epithelial injury in vitro. Specific Aim 2 will test the hypothesis that the S1P agonist, FTY720, carried by the novel drug carrier system is targeted selectively to the kidney to reduce kidney IRI in vivo. At the end of two years, we will have identified: 1) if shiftosomes are safe, effective and selective in targeting to the kidney, and 2) if FTY720, a leading candidate for clinical trials in AKI, can be selectively delivered to the kidney to avoid potential systemic side effects. These studies will provide the foundation for future preclinical studies using a novel carrier approach to treat AKI.