Nanotherapeutics for acute kidney injury

描述（由申请人提供）：这是一项探索性多PI提案，将融合来自两个不同学科的两名研究者的独特专业知识，以应用创新方法来解决未满足的需求，即没有FDA批准的药物用于预防和治疗急性肾损伤（阿基）。统计功效低、给药时机不佳以及不良反应阻碍了临床试验的成功。我们提出了一种新的方法，在该领域的阿基使用超声（US）刺激的药物从载药纳米粒子的交付。虽然纳米颗粒（脂质体）已经被批准并用于癌症治疗，但我们的研究结合了纳米技术领域的最新进展，尚未在靶向药物递送中进行测试。目前的递送系统使用微泡，所述微泡由被壳（几nm厚）包封的气体核组成，其中药物嵌入膜内或附着于表面，或者使用装饰微泡表面的载药脂质体。在超声作用期间，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其循环时间短（通常在静脉内给药后几分钟内气体从气泡中损失）和药物释放不完全。此外，复合物的大尺寸（微米）限制了颗粒外渗超出血管床。我们建议开发一种新的药物载体系统（shiftosome），它是基于两种载体方法的组合，即脂质体纳米颗粒加载相转移纳米颗粒剂。这些研究将使用脂质体内核内的过热液体全氟化碳（例如，全氟戊烷和/或全氟丁烷）填充的纳米颗粒以及包埋的药物沿着。我们将测试的假设，shiftosomes具有改善的特性，可以特异性地针对一种新的鞘氨醇1受体（S1 P1）类似物的肾内皮细胞，以减少肾缺血再灌注损伤（IRI）。具体目标1将测试以下假设：新型药物载体系统shiftosome具有改进的超声触发药物递送特性，并且当负载FTY 720时，可以减少体外血管内皮或肾小管上皮损伤。具体目标2将检验由新型药物载体系统携带的S1 P激动剂FTY 720选择性靶向肾脏以减少体内肾脏IRI的假设。在两年后，我们将确定：1）移位体是否安全，有效和选择性地靶向肾脏，2）FTY 720，阿基临床试验的主要候选药物，是否可以选择性地递送到肾脏，以避免潜在的全身副作用。这些研究将为未来使用新型载体方法治疗阿基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.