Nanotherapeutics for acute kidney injury

急性肾损伤的纳米疗法

• 批准号: 8224076
• 负责人: ALEXANDER L KLIBANOV
• 金额: $ 19.67万
• 依托单位: UNIVERSITY OF VIRGINIA
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-04-26 至 2014-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8224076
• 关键词: Acoustics; Acute; Acute Renal Failure with Renal Papillary Necrosis; Address; Adverse drug effect; Adverse effects; Agonist; Area; Binding; Blood; Blood Circulation; Blood Vessels; Body Temperature; Caliber; Cell Culture System; Characteristics; Chronic; Clinical Treatment; Clinical Trials; Complex; Data; Development; Disadvantaged; Discipline; Drug Carriers; Drug Delivery Systems; Drug Kinetics; Drug effect disorder; Dyes; Educational workshop; Effectiveness; Encapsulated; Endothelium; Engineering; Epithelial; Exposure to; Extravasation; FDA approved; Fluorocarbons; Foundations; Frequencies; Future; Gases; Half-Life; Heart Rate; Immunosuppressive Agents; In Vitro; Injury; Kidney; Lipids; Liposomes; Liquid substance; Mediating; Membrane; Microbubbles; Modeling; Mus; Nanotechnology; Organ; Pharmaceutical Preparations; Phase; Physiologic pulse; Prevention; Property; Publishing; Reading; Relapsing-Remitting Multiple Sclerosis; Reperfusion Injury; Research Personnel; Rupture; Specificity; Sphingosine; Structure; Surface; System; Tamoxifen; Techniques; Testing; Therapeutic; Thick; Time; Tissues; Toxic effect; Tubular formation; Ultrasonic Therapy; Ultrasonography; United States National Institutes of Health; Vascular Endothelium; Wild Type Mouse; analog; aqueous; base; cancer therapy; cell determination; cell injury; edg-1 Protein; improved; in vivo; industry partner; injured; innovation; interest; intravenous administration; meetings; member; monolayer; nanometer; nanoparticle; nanotherapeutic; novel; novel strategies; particle; perfluoropentane; preclinical study; renal ischemia; response; success; symposium; vascular bed

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.

描述（由申请人提供）：这是一项探索性的多 PI 提案，它将融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未满足的需求，即目前尚无 FDA 批准的药物用于预防和治疗急性肾损伤 (AKI)。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。我们提出了一种在 AKI 领域的新方法，利用超声 (US) 刺激的载药纳米颗粒进行药物输送。尽管纳米粒子（脂质体）已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，该微泡由被壳（几纳米厚）封装的气体核心组成，药物嵌入膜内或附着在表面，或装饰微泡表面的载药脂质体。在声波作用过程中，微泡会振荡；较高的超声强度会破坏微泡，部分释放脂质体有效负载。这种药物载体系统的缺点是循环时间短（静脉给药后几分钟内气体通常从气泡中消失）和药物释放不完全。此外，复合物的大尺寸（微米）限制了颗粒外渗到血管床之外。我们建议开发一种新型药物载体系统（shiftosome），该系统基于两种载体方法的组合，即负载相移纳米颗粒剂的脂质体纳米颗粒。这些研究将使用过热液体全氟化碳（例如全氟戊烷和/或全氟丁烷）填充脂质体内核内的纳米颗粒以及包埋的药物。我们将测试以下假设：移位体具有改进的特性，并且可以特异性靶向肾内皮的新型鞘氨醇 1 受体 (S1P1) 类似物，以减少肾缺血再灌注损伤 (IRI)。具体目标 1 将检验以下假设：新型药物载体系统，shiftosome，改善了超声触发药物输送的特性，并且当装载 FTY720 时，可以在体外减少血管内皮或肾小管上皮损伤。具体目标2将测试以下假设：新型药物载体系统携带的S1P激动剂FTY720选择性地靶向肾脏以降低体内肾脏IRI。两年后，我们将确定：1）移位体是否安全、有效且选择性地靶向肾脏，2）FTY720（AKI 临床试验的主要候选药物）是否可以选择性地递送至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 的临床前研究奠定基础。 公共健康相关性：我们提议开发一种治疗急性或慢性肾损伤的新型药物治疗方法，将药物直接输送到受伤的肾脏。将治疗药物装载在充气微泡（直径约 1 微米）或脂质体（膜结合小颗粒；直径 100-200 纳米）内，并通过低能超声将其释放到肾脏中，可以对所需区域进行靶向治疗，同时最大限度地减少全身给药可能产生的药物潜在副作用。我们将开发一种新型纳米颗粒，并比较其与使用免疫抑制药物 (FTY720) 的经过验证的微泡脂质体系统的药物输送效果，该药物正在进行治疗复发缓解型多发性硬化症的临床试验，并已在小鼠身上显示，全身给药时可保护肾脏免受急性缺血性损伤；因此，通过这种技术可以避免该药物已知的副作用（心率降低）。