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

基本信息

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
项目类别：
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

项目摘要

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.

治疗细胞移植具有治愈或缓解各种疾病的巨大潜力。在临床上，细胞移植物经常在移植后的短时间内死亡或停止功能。策略是使用源自间充质干细胞（MSC）的细胞外囊泡（EV）作为佐剂然而，将 EV 有效输送到目标部位并保留在目标部位仍然存在挑战。以及无法使用临床相关的方法阐明 EV 的生物分布和药代动力学特征此外，一些新的研究表明，多次递送 EV 对于治疗结果至关重要，使用当前的临床管理途径很难实现这一点，我们建议开发治疗诊断学，可注射微球 EV 输送系统 (EVDS)，用于局部、有针对性和持续输送 EV，同时通过磁粒子成像 (MPI) 实现 EV 体内跟踪我们的 EVDS 的设计采用模块化设计。系统的每个主要组件都可以独立修改以适应不同的目的。用于治疗 1 型和晚期 2 型糖尿病的胰岛移植的两种 EVDS 设计 - LipoCap。和 MICap – 建议通过门静脉将 LipoCaps (500 μm) 注入肝脏（经过临床测试）。胰岛移植方案）用于与胰岛共同植入，或用于移植后的后续剂量。 (900 µm) 适用于体积较大的植入部位，例如腹腔内。 LipoCaps 和 MICaps 的目标是获得本地持续的 EV 输送，该产品将由超纯化组成。海藻酸盐，FDA 批准的食品、化妆品和药品赋形剂。从藻酸盐基质释放后，EVs将被附近的脂肪和组织特异性吸收，并被装载到胰岛内在藻酸盐封装之前靶向脂质体，这将通过将脂质体缀合来实现。 exendin-4，胰高血糖素样肽-1 受体的配体，在胰岛表面大量表达此外，EV 还将用临床级超小型超顺磁性氧化铁进行标记。促进 MPI 成像的纳米颗粒（USPIO）是一种提供“热点”的新兴模式。可视化以及 EV 量化，与 PET 和 SPECT 非常相似，无需使用放射性试剂。与 1H MRI 不同，MPI 不会出现血池背景伪影和运动效应的问题。据报道比 19F MRI 和 CT 更敏感，因此可以减少引入的标签数量 MPI 可以让医生了解 EV 的时间和空间行为，而这反过来又可以使医生了解 EV 的时间和空间行为。为了系统地研究该项目的可行性，我们提出了三个具体目标。建议： 1) 合成和表征携带 MSC-EV 的 LipoCap 和 MICap，并测试它们对体外人类胰岛存活和功能的影响；2) 开发一种可保存的 USPIO 标记方法 EV 属性，同时最大化 MPI 检测灵敏度；3) 测试所提出的 EVDS 是否可以改善胰岛通过 MPI 追踪免疫缺陷 NU/J 小鼠的存活率和功能。