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

基本信息

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
项目类别：
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

项目摘要

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.

项目概要 1 型糖尿病 (T1D) 的特点是胰岛中自身反应性 T 细胞浸润，导致产生胰岛素的β细胞的自身免疫破坏和自身免疫的启动以及大量糖尿病。 β细胞损失可能在症状出现前几年就开始，因此，迫切需要开发。针对 T1D 这一通常漫长的症状前阶段进行诊断和治疗干预。针对症状前 T1D 的治疗方法的临床试验已证明取得的成功有限。虽然抗 CD3 药物已显示出希望，但抗 CD3 药物仅能预防一部分研究队列中的糖尿病发作，并且不是专门针对对 β 细胞抗原（例如胰岛素）有反应的 T 细胞的方法。在临床前研究中获得广泛关注的是使用肽疗法来提供耐受性已证明在小鼠体内施用胰岛素肽治疗剂可靶向自身反应性 T 细胞的抗原。通过扩大胰岛素反应性调节 T 细胞来预防糖尿病发作，这些细胞具有抗炎作用尽管胰岛素肽具有治疗潜力，但它对于适当的免疫耐受和调节至关重要。不同组之间显示出不同的结果，并且只能通过外科手术有效施用因此，通过靶向输送和输液泵的植入来优化治疗效果。与诊断相结合是必要的，这可以通过超声造影剂（UCA）来实现，它们是充满气体的小气泡，可以使用超声造影 (CEUS) 进行可视化，并且是一种安全、易于配制且经过临床批准的新型亚微米“纳米气泡”超声造影剂。已经开发出来，之前的工作已经证明纳米气泡在小鼠胰岛中的积累增强由炎症相关的微血管通透性导致的症状前 T1D 我的总体目标是开发并应用亚微米 UCA 来专门针对疾病部位和目标治疗药物跟踪治疗方法对 T1D 进展的影响，我发现亚微米 UCA 可应用于两者都预测治疗诱导的疾病预防，并作为靶向肽递送的载体。这是通过两个具体目标实现的：我的目标 1，我将使用亚微米 UCA 预测治疗引起的疾病预防，使用 CEUS 检测治疗干预后胰岛中亚微米 UCA 积累的变化。目标2，我将应用UCAs作为治疗性肽递送载体。初步数据表明肽可以是。掺入纳米气泡中并且纳米气泡可以将肽靶向胰岛。纳米气泡消融对肽细胞摄取的影响，表征肽纳米气泡胰岛外渗的动力学，并评估肽纳米泡治疗的免疫学和疾病缓解效果。允许治疗肽在胰岛中积累，增强治疗效果，并预防疾病- 逆转预测诊断可以作为 T1D 预防的重大进步。