Improved glyburide therapy via acid- triggered release functional nanoparticles and therapeutic imaging

通过酸触发释放功能纳米颗粒和治疗成像改进格列本脲治疗

• 批准号: 10017332
• 负责人: Kevin Navin Sheth
• 金额: $ 37.1万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-09-15 至 2024-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10017332
• 关键词: AMD3100; Acidity; Acids; Amines; Antiinflammatory Effect; Antioxidants; Astrocytes; Betulinic Acid; Brain; Brain Edema; Brain Infarction; Cessation of life; Chemistry; Clinical; Clinical Management; Collection; Disease; Dose; Drug Delivery Systems; Drug Kinetics; Edema; Endothelial Cells; Engineering; FDA approved; Formulation; Glyburide; Goals; Hospitals; Hour; Image; Infarction; Inflammatory; Ischemia; Ischemic Stroke; Malignant - descriptor; Measures; Mediating; Medical; Molecular; Morbidity - disease rate; Mus; Natural Products; Necrosis; Neurons; Oligodendroglia; Outcome; Pathway interactions; Patients; Penetration; Pharmaceutical Preparations; Pharmacotherapy; Phase; Phase III Clinical Trials; Physiology; Positron-Emission Tomography; Pre-Clinical Model; Prevention; Public Health; Rattus; Recovery of Function; Regulation; Research Project Grants; Stroke; Surface; Swelling; Symptoms; Synapses; Testing; Therapeutic; Toxic effect; Translating; United States; Work; base; cell type; clinical application; clinically relevant; combinatorial; density; disability; effective therapy; imaging approach; improved; innovation; intravenous administration; mortality; nanocarrier; nanoformulation; nanomaterials; nanoparticle; neurovascular unit; non-invasive monitor; novel; novel strategies; post stroke; prevent; primary endpoint; stroke model; stroke recovery; stroke therapy; stroke victims; success; targeted delivery; trend

Stroke is the leading cause of disability and death in the U.S. Intravenous administration of tPA within 3 hours of symptom onset remains the only FDA-approved pharmacotherapy. Novel approaches to improving the treatment of stroke are in high demand. We recently discovered that the SUR1-TRPM4 channel is upregulated de novo in all cell types of the neurovascular unit following ischemia and channel blockade using glyburide achieved robust, clinically-relevant beneficial effects in multiple preclinical models. This finding has led to a phase II GAMES-RP trial. Clinical results revealed a trend toward improved survival and a significant reduction in edema but failed to meet the primary endpoint. The degree of swelling reduction was insufficient to prevent decompressive craniectomy or significantly increase clinical outcome. Further analysis showed that the unmet efficacy is due to the limitations associated with the current formulation. First, glyburide in the current formulation has limited penetration into the ischemic brain and thus does not allow fully capitalizing its anti- edema and neuron protective actives. Second, the current formulation does not accommodate the requirement for prompt drug administration. To overcome these limitations, we propose to develop a novel nanoformulation, acid responsive, stroke- targeting, antioxidant nanoparticles (ARSTA NPs), to enhance the delivery and efficacy of glyburide. As preliminary work, we developed an innovative approach for isolating natural nanomaterials from medicinal natural products (MNPs), and identified betulinic acid (BA) that forms NPs. We showed that BA NPs penetrated the ischemic brain, effectively reduced brain infarction through regulation of the antioxidant and pro-inflammatory pathways, and mediated efficient delivery of glyburide to the brain. We demonstrated that the ischemic microenvironment is acidic. We developed chemistry to convert BA to betulinic amine (BAM) and showed that BAM NPs released glyburide in a rate significantly greater than BA NPs in acidic pH. We screened a collection of MNPs and identified three new nanomaterials that have anti-stroke activity and drug delivery capacity comparable to BA. We demonstrated that targeted delivery of NPs to the ischemic brain can be achieved through surface conjugation of AMD3100. We developed a PET imaging approach for non-invasive monitoring stroke recovery by measuring synapse density. Building on these progress, we propose to synthesize and characterization of ARSTA NPs for targeted delivery of glyburide to the ischemic brain in Aim 1, and to evaluate glyburide-loaded ARSTA NPs for treating ischemic stroke and the PET imaging approach for non-invasively monitoring post-stroke functional recovery in Aim 2. The success of this project will result in a new paradigm for treating ischemic stroke and for non-invasively monitoring post- stroke functional recovery, which can be translated into clinical applications to improve clinical management of patients with the disease.

在美国，卒中是导致残疾和死亡的主要原因。 仍然是FDA唯一批准的药物治疗。改善环境的新方法 对中风的治疗有很高的需求。我们最近发现，SUR 1-TRPM 4通道被上调， 缺血和格列本脲通道阻断后，神经血管单位的所有细胞类型中重新发生 在多个临床前模型中实现了稳健的、临床相关的有益效果。这一发现导致了 II期GAMES-RP试验。临床结果显示生存率有提高的趋势， 水肿，但未能达到主要终点。肿胀减少的程度不足以防止 去骨瓣减压术或显著增加临床结果。进一步分析表明， 有效性是由于与当前制剂相关的局限性。首先，格列本脲在目前 制剂对缺血性脑的渗透有限，因此不允许充分利用其抗缺血性脑损伤的作用。 水肿和神经元保护活性。第二，现时的提法并不符合有关规定 以便及时给药。为了克服这些限制，我们提出开发一种新的纳米制剂， 酸响应性、中风靶向抗氧化纳米颗粒（ARSTA NPs），以增强递送和 格列本脲的疗效。作为初步工作，我们开发了一种创新的方法， 从药用天然产物（MNP）中提取纳米材料，并鉴定形成NP的桦木酸（BA）。我们 表明BA NPs穿透缺血性脑，通过调节 抗氧化剂和促炎途径，并介导格列本脲向大脑的有效递送。我们 表明缺血微环境是酸性的。我们发明了化学方法将BA转化为桦木酸 胺（BAM），并显示BAM NPs释放格列本脲的速率显著大于BA NPs。 我们筛选了一系列MNP，并确定了三种具有抗中风作用的新纳米材料。 活性和药物递送能力与BA相当。我们证明了将NP靶向递送至 缺血性脑可以通过AMD 3100的表面缀合来实现。我们开发了一种PET成像技术 通过测量突触密度来非侵入性监测中风恢复的方法。根据这些 进展，我们建议合成和表征的ARSTA纳米颗粒的格列本脲靶向输送， 目的1中的缺血性脑，并评估用于治疗缺血性中风的格列本脲负载的ARSTA NP和 Aim 2中用于无创监测卒中后功能恢复的PET成像方法。的成功 该项目将为治疗缺血性中风和非侵入性监测术后 中风功能恢复，这可以转化为临床应用，以改善临床管理， 患有这种疾病的患者。