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.

治疗性细胞的移植具有治愈或缓解各种疾病的巨大潜力。在