Nanotherapeutics for acute kidney injury

描述（由申请人提供）：这是一个探索性的多PI提案，将合并来自两个不同学科的两位研究者的独特专业知识，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（AKI）。统计效力低、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AKI领域使用超声（US）刺激药物递送从载药纳米颗粒。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，尚未在靶向药物输送中进行测试。目前的递送系统使用微泡，微泡由包裹在膜内或附着在表面的药物外壳（几纳米厚）的气核或修饰微泡表面的载药脂质体组成。在超声波过程中，微气泡振荡；较高的美国强度破坏微泡，部分释放脂质体载荷。这种药物载体系统的缺点是其循环时间短（气体通常在静脉给药后几分钟内从气泡中消失）和药物释放不完全。此外，复合物的大尺寸（微米）限制了颗粒在血管床之外的外渗。我们建议开发一种新的药物载体系统（shiftosome），该系统基于两种载体方法的结合，即脂质体纳米颗粒装载相移纳米颗粒剂。这些研究将在脂质体内芯内与包裹的药物一起使用过热液体全氟碳（如全氟戊烷和/或全氟丁烷）填充纳米颗粒。我们将验证shiftosome具有改进的特性，并且可以特异性靶向一种新的鞘氨醇1受体（S1P1）类似物到肾内皮以减少肾缺血再灌注损伤（IRI）的假设。特异性目的1将验证一种假设，即新型药物载体系统shiftosome具有改进的超声触发药物递送特性，并且当装载FTY720时，可以减少体外血管内皮或小管上皮损伤。特异性目的2将验证由新型药物载体系统携带的S1P激动剂FTY720在体内选择性靶向肾脏以减少肾脏IRI的假设。两年后，我们将确定：1)shiftosome在靶向肾脏方面是否安全、有效和选择性；2)作为AKI临床试验的主要候选药物，FTY720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. PUBLIC HEALTH RELEVANCE: We are proposing the development of a novel form of drug treatment for acute or chronic kidney injury that delivers the drug directly to the injured kidney. Loading therapeutic drug within gas-filled microbubbles (~1 micron in diameter) or liposomes (small membrane-bound particles; 100-200 nanometer diameter) and releasing it in the kidney with low energy ultrasound allows for targeted treatment to the desired area while minimizing any potential side effects of a drug that would result from systemic administration. We will develop a novel nanoparticle and compare its effectiveness for drug delivery to a proven microbubble-liposome system using an immunosuppressive drug (FTY720) that is in clinical trials for the treatment of relapsing-remitting multiple sclerosis and has been shown in mice to protect the kidney from acute ischemic injury when given systemically; the known side effect of this drug (reduced heart rate) can thus be avoided with this technique.