Theranostic system for targeted, sustained-delivery with quantitative "hot spot" MPI of magnetic extracellular vesicles

通过磁性细胞外囊泡定量“热点”MPI 进行靶向、持续递送的治疗诊断系统

• 批准号: 10573855
• 负责人: Dian Respati Arifin
• 金额: $ 20.65万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-22 至 2025-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10573855
• 关键词: Address; Adjuvant; Adopted; Alginates; Beta Cell; Biodistribution; Blood; Cations; Cell Therapy; Cell Transplantation; Cells; Clinic; Clinical; Cosmetics; Custom; Dose; Drug Delivery Systems; Drug Kinetics; Engineering; Ensure; Excipients; FDA approved; Fatty acid glycerol esters; Food; GLP-I receptor; Gel; Heart Diseases; Hot Spot; Hour; Human; Hydrogels; Image; Immune system; Implant; In Vitro; Inflammation; Injectable; Injections; Insulin; Insulin-Dependent Diabetes Mellitus; Islets of Langerhans; Islets of Langerhans Transplantation; Japan; Kidney Failure; Kinetics; Label; Life; Ligands; Liposomes; Liver; Logistics; Luciferases; Magnetic Resonance Imaging; Magnetism; Medicine; Mesenchymal Stem Cells; Methods; Microcapsules drug delivery system; Modality; Molecular Weight; Monitor; Morphologic artifacts; Motion; Mus; Non-Insulin-Dependent Diabetes Mellitus; Outcome; Pathologic; Patients; Performance; Pharmacologic Substance; Physicians; Portal vein structure; Positron-Emission Tomography; Production; Property; Protocols documentation; Radioactive; Reporting; Route; Savings; Site; Spatial Behavior; Surface; System; Testing; Therapeutic; Tissues; Tracer; Translations; Transplantation; Vesicle; Visualization; X-Ray Computed Tomography; base; bench to bedside; bioluminescence imaging; capsule; cell type; clinical translation; clinically relevant; cost; design; detection sensitivity; exenatide; extracellular vesicles; ferumoxtran; ferumoxytol; follow-up; imaging detection; immunogenicity; implantation; improved; in vivo; individual patient; insulin secretion; interest; intraperitoneal; iron oxide nanoparticle; islet; particle; post-transplant; preservation; scaffold; single photon emission computed tomography; theranostics; therapy outcome; tool; uptake

Transplantation of therapeutic cells holds great potential to cure or provide relief to various ailments. In the clinic, cell grafts often perish or cease to function within a short period post-transplantation. An emerging strategy is the use of extracellular vesicles (EVs) derived from mesenchymal stem cells (MSCs) as an adjuvant to cell therapy. However, there remain challenges for effective EV delivery to and retention at the target sites, and the inability to elucidate the biodistribution and pharmacokinetic profiles of EVs using a clinically relevant tool. Moreover, a few new studies indicated that multiple deliveries of EVs are essential for therapeutic outcomes, which are hard to accomplish using the current clinical administration routes. We propose to develop theranostic, injectable microspheroid EV-delivery systems (EVDS) for local, targeted, and sustained-delivery of EVs while enabling EV tracking in vivo with magnetic particle imaging (MPI). The design of our EVDS is modular where each main component of the system can be independently modified to suit different purposes. Our interest lies in pancreatic islet transplantation to treat type 1 and advanced type 2 diabetes. Two designs of EVDS – LipoCap and MICap – are proposed. LipoCaps (500 μm) can be infused into the liver via the portal vein (a clinically tested islet transplantation protocol) for co-implantation with islets, or for follow-up doses post-transplantation. MICaps (900 µm) are appropriate for implant site with larger volumes, such as the intraperitoneal cavity. Both designs aim to obtain a local, sustained delivery of EVs to islets. LipoCaps and MICaps will be composed of ultrapurified alginate, an FDA-approved excipient of food, cosmetic and pharmaceutical products. In order to minimize non- specific uptake by nearby fat and tissues after the release from alginate matrix, EVs will be loaded inside islet- targeting liposomes prior to alginate encapsulation. This will be achieved by conjugating the liposomes to exendin-4, a ligand of glucagon-like peptide-1 receptors which are abundantly expressed on the surface of islet beta cells. In addition, EVs will be labeled with clinical-grade ultrasmall superparamagnetic iron oxide nanoparticles (USPIO) to facilitate imaging by MPI. MPI is an emerging modality that provides “hot spot” visualization as well as EV quantification, much alike to PET and SPECT without the use of radioactive agents. Unlike 1H MRI, background artifacts from blood pools and motion effects are not an issue with MPI. MPI is reported to be more sensitive than 19F MRI and CT, and therefore may reduce the quantity of labels introduced into the patients. MPI may inform physicians on the temporal and spatial behavior of EVs which, in turns, may afford EV therapy to be customized. To systemically investigate the feasibility of the project, three specific aims are proposed: 1) To synthesize and characterize LipoCaps and MICaps carrying MSC-EVs, and to test their effects on human islets’ survival and function in vitro; 2) To develop a USPIO-labeling method that will preserve EV properties while maximizing MPI detection sensitivity; 3) To test if the proposed EVDS can improve islet survival and function in immunodeficient NU/J mice while being tracked by MPI.

治疗细胞的移植具有治愈或减轻各种疾病的巨大潜力。在 诊所，细胞移植物经常在移植后短期内灭亡或停止发挥作用。一个新兴 策略是使用源自间充质干细胞（MSC）的细胞外蔬菜（EV） 进行细胞疗法。但是，有效在目标部位有效交付EV和保留的挑战， 以及无法使用临床相关的电动汽车的生物分布和药代动力学特征 工具。此外，一些新的研究表明，多次交付电动汽车对于治疗结果至关重要， 使用当前的临床给药路线很难完成。我们建议发展疗法， 用于局部，有针对性和持续交付的电动汽车的可注射的微磷类电动汽车交付系统（EVD） 使用磁性颗粒成像（MPI）在体内启用EV跟踪。我们的EVD的设计是模块化的 可以独立修改系统的每个主要组件以适合不同的目的。我们的兴趣在于 在胰岛移植中，以治疗1型和晚期2型糖尿病。 EVD的两种设计 - 脂肪卡普 和MICAP - 提出。可以通过门静脉将脂肪胶囊（500μm）注入肝脏（经过临床测试） 胰岛移植方案）用于与胰岛共植入或转移后的随访剂量。麦克风 （900 µm）适用于具有较大体积的植入物位，例如腹膜内腔。两种设计 旨在获得电动汽车向胰岛的局部持续交付。脂肪胶囊和麦克风将由超抑制作用组成 Alginate是FDA批准的食品，化妆品和药品的赋形剂。为了最大程度地减少非 从算法基质释放后，附近脂肪和组织的特定摄取，EV将在胰岛内部加载 在藻酸盐封装之前靶向脂质体。这将通过将脂质体结合到 Exendin-4，一种绝对在胰岛表面表达的胰高血糖素样肽-1受体的配体 β细胞。此外，电动汽车将用临床级超级超磁铁标记 纳米颗粒（USPIO）促进MPI成像。 MPI是一种提供“热点”的新兴方式 可视化和EV量化，在不使用放射性剂的情况下与PET和SPECT相似。 与1H MRI不同，血液库中的背景伪像，运动效应不是MPI的问题。 MPI是 据报道，比19F MRI和CT更敏感，因此可能会减少引入的标签数量 进入患者。 MPI可能会将电动汽车的暂时和空间行为告知医生 提供自定义的电动汽车疗法。为了系统地调查项目的可行性，三个具体目标 提出：1）合成并表征携带MSC-EV的脂质胶囊和MICAPS，并测试其 对人类胰岛在体外生存和功能的影响； 2）开发一种将保留的USPIO标签方法 EV特性，同时最大化MPI检测灵敏度； 3）测试提议的EVD是否可以改善胰岛 由MPI跟踪时，在免疫缺陷型NU/J小鼠中的生存和功能。