Submicron ultrasound contrast agents as diagnostic agents and therapeutic vehicles in type 1 diabetes

亚微米超声造影剂作为 1 型糖尿病的诊断剂和治疗载体

• 批准号: 10676667
• 负责人: Mark Ciccaglione
• 金额: $ 4.77万
• 依托单位: UNIVERSITY OF COLORADO DENVER
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-07-01 至 2025-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10676667
• 关键词: Ablation; Affect; Age; American; Anti-Inflammatory Agents; Antigen Targeting; Antigen-Presenting Cells; Antigens; Autoantibodies; Autoimmune Diseases; Autoimmunity; Beta Cell; Blood Vessels; CD3 Antigens; Clinical; Clinical Trials; Cohort Studies; Complications of Diabetes Mellitus; Continuous Infusion; Contrast Media; Data; Development; Diabetes Mellitus; Diabetes prevention; Diabetic Ketoacidosis; Diagnosis; Diagnostic; Disease; Disease Progression; Dose; Extravasation; Gases; Glucose; Goals; Hyperglycemia; Hypoglycemia; Image; Immune Tolerance; Immune mediated destruction; Immunologics; Immunotherapy; Implantable Pump; Infiltration; Inflammation; Infusion Pumps; Insulin; Insulin-Dependent Diabetes Mellitus; Investigation; Islets of Langerhans; Life; Measures; Microvascular Permeability; Monitor; Mus; Operative Surgical Procedures; Pancreas; Patients; Peptides; Phase; Prediabetes syndrome; Predictive Factor; Quality of life; Regulatory T-Lymphocyte; Research; Risk; Route; Signal Transduction; Site; Symptoms; T cell infiltration; T-Cell Activation; T-Lymphocyte; Testing; Therapeutic; Therapeutic Agents; Therapeutic Effect; Therapeutic Intervention; Tissues; Traction; Treatment Efficacy; Ultrasonography; Visualization; Work; autoimmune pathogenesis; autoreactive T cell; contrast enhanced; delivery vehicle; design; diagnostic strategy; disorder prevention; immunoregulation; implantation; improved; innovation; insulin dependent diabetes mellitus onset; insulitis; islet; nanobubble; novel; novel diagnostics; peptide drug; preclinical study; prevent; response; submicron; success; targeted delivery; targeted treatment; tool; treatment response; ultrasound; uptake; vascular factor; Ablation; Affect; Age; American; Anti-Inflammatory Agents; Antigen Targeting; Antigen-Presenting Cells; Antigens; Autoantibodies; Autoimmune Diseases; Autoimmunity; Beta Cell; Blood Vessels; CD3 Antigens; Clinical; Clinical Trials; Cohort Studies; Complications of Diabetes Mellitus; Continuous Infusion; Contrast Media; Data; Development; Diabetes Mellitus; Diabetes prevention; Diabetic Ketoacidosis; Diagnosis; Diagnostic; Disease; Disease Progression; Dose; Extravasation; Gases; Glucose; Goals; Hyperglycemia; Hypoglycemia; Image; Immune Tolerance; Immune mediated destruction; Immunologics; Immunotherapy; Implantable Pump; Infiltration; Inflammation; Infusion Pumps; Insulin; Insulin-Dependent Diabetes Mellitus; Investigation; Islets of Langerhans; Life; Measures; Microvascular Permeability; Monitor; Mus; Operative Surgical Procedures; Pancreas; Patients; Peptides; Phase; Prediabetes syndrome; Predictive Factor; Quality of life; Regulatory T-Lymphocyte; Research; Risk; Route; Signal Transduction; Site; Symptoms; T cell infiltration; T-Cell Activation; T-Lymphocyte; Testing; Therapeutic; Therapeutic Agents; Therapeutic Effect; Therapeutic Intervention; Tissues; Traction; Treatment Efficacy; Ultrasonography; Visualization; Work; autoimmune pathogenesis; autoreactive T cell; contrast enhanced; delivery vehicle; design; diagnostic strategy; disorder prevention; immunoregulation; implantation; improved; innovation; insulin dependent diabetes mellitus onset; insulitis; islet; nanobubble; novel; novel diagnostics; peptide drug; preclinical study; prevent; response; submicron; success; targeted delivery; targeted treatment; tool; treatment response; ultrasound; uptake; vascular factor

PROJECT SUMMARY Type 1 diabetes (T1D) is characterized by infiltration of autoreactive T cells in pancreatic islets, leading to autoimmune destruction of insulin-producing beta cells and diabetes. Initiation of autoimmunity and substantial beta cell loss may begin years prior to symptomatic onset. Therefore, there is a crucial need to develop diagnostics and therapeutic interventions directed towards this often-lengthy presymptomatic phase of T1D. Limited success has been demonstrated in clinical trials for therapeutics directed towards presymptomatic T1D. While anti-CD3 has shown promise, anti-CD3 only prevented diabetes onset in a subset of the study cohort and is not directed specifically against T cells reactive to beta cell antigens, such as insulin. An approach that has gained substantial traction in preclinical studies is the usage of peptide therapeutics to provide tolerance towards antigens targeted by autoreactive T cells. Administration of insulin peptide therapeutics in mice has been shown to prevent diabetes onset by expanding insulin-reactive regulatory T cells, which are anti-inflammatory and are essential for proper immune tolerance and regulation. Despite their therapeutic potential, insulin peptides have shown mixed results amongst different groups and have only been effectively administered via surgical implantation of an infusion pump. Therefore, optimizing therapeutic efficacy through targeted delivery and incorporation with diagnostics is warranted. This could be accomplished with ultrasound contrast agents (UCAs), which are small gas-filled bubbles that can be visualized using contrast enhanced ultrasound (CEUS) and are safe, easy to formulate, and clinically approved. A novel, submicron, ‘nanobubble’ ultrasound contrast agent has been developed and prior work has demonstrated enhanced accumulation of nanobubbles in islets of mice with presymptomatic T1D as a result of inflammation-associated microvascular permeability. My overall goal is to develop and apply submicron UCAs to both target therapeutic agents specifically to the disease site and track the effect of therapeutics on T1D progression. I hypothesize that submicron UCAs can be applied to both predict therapeutic induced disease prevention and as vehicles for targeted peptide delivery. I will examine this via two specific aims: I aim 1, I will predict therapeutic-induced disease prevention using submicron UCAs, using CEUS to detect changes in islet accumulation of submicron UCAs following therapeutic intervention. In aim 2, I will apply UCAs as therapeutic peptide delivery vehicles. Preliminary data indicates that peptide can be incorporated into nanobubbles and nanobubbles can target peptide to islets. I will characterize effect of nanobubble ablation on peptide cellular uptake characterize dynamics of peptide-nanobubble islet extravasation, and assess immunological and disease-modifying effects of peptide-nanobubble treatment. Developing an agent that allows for accumulation of therapeutic peptides in islets, enhanced therapeutic efficacy, and disease- reversal-predicting diagnostics can serve as a major advancement in T1D prevention.

项目摘要 1型糖尿病（T1D）的特征是胰岛中自动反应性T细胞浸润，导致 产生胰岛素的β细胞和糖尿病的自身免疫性破坏。启动自身免疫和实质性 贝塔细胞损失可能在症状发作前几年开始。因此，有至关重要的需要发展 诊断和治疗干预措施针对T1D的这个经常长度的同情阶段。 在针对Presymptom T1D的临床试验中已证明了有限的成功。 尽管抗CD3已显示出希望，但抗CD3仅防止研究队列的一部分糖尿病发作 不是针对T细胞反应针对β细胞抗原的T细胞（例如胰岛素）。一种方法 在临床前研究中获得大量牵引是肽疗法的使用，以提供对 由自动反应性T细胞靶向的抗原。已经显示了小鼠胰岛素肽疗法的给药 通过扩展胰岛素反应性调节性T细胞，以防止糖尿病发作 适当的免疫耐受性和调节至关重要。尽管具有治疗性的潜力，但胰岛素petides还是 在不同组之间显示出混合的结果，并且仅通过手术有效地给药 输液泵的植入。因此，通过有针对性的交付优化治疗效率和 保证与诊断合并。这可以通过超声对比剂（UCA）来实现， 是小气泡的小气泡，可以使用对比度增强超声（CEU）可视化，并且是 安全，易于制定和临床批准。一种新颖的亚微米，“纳米泡”超声对比剂具有 已开发并先前的工作表明，纳米泡的积累增强了 炎症相关的微血管渗透性导致的肿瘤性T1D。我的总体目标是 开发并将亚ucas施加给两个针对疾病部位的靶向治疗剂，并 跟踪理论对T1D进展的影响。我假设可以将乌卡斯ucas应用于 两者都预测治疗性诱导疾病预防和作为靶向肽递送的车辆。我会检查的 这是通过两个具体目标：我瞄准1，我将使用亚微米UCAS预测治疗诱导的疾病预防， 使用CEU检测治疗干预后亚微米UCA的胰岛积累的变化。在 AIM 2，我将使用UCA作为治疗肽递送车。初步数据表明肽可以是 并入纳米泡和纳米泡中可以将肽靶向胰岛。我将表征 肽细胞摄取上的纳米泡消融表征了肽 - 纳米布布尔胰岛渗出的动力学， 并评估胡椒粉治疗的免疫学和疾病改良作用。开发代理 这允许在胰岛中积累热胡椒粉，治疗效率提高和疾病 - 逆转预测的诊断可以作为预防T1D的重大进步。