DIACEST Islet Cell Capsules for Immunoprotection, MR Detection, and pH Sensing

描述（由申请人提供）：良好的血糖控制对于减少I型糖尿病（TIDM）的终末期并发症至关重要，因此，近年来胰岛移植（ITx）受到了相当大的关注，治疗中的并发症之一涉及寻找有效的方法来预防排斥反应。胰岛的免疫隔离提供了一种减少或完全避免免疫抑制治疗的方法。在最常用的免疫隔离方法微囊化中，单个胰岛被薄藻酸盐膜包围，该膜可渗透胰岛素和代谢物，但不可渗透天然抗体。然而，这些胰岛的活力，特别是胰岛素分泌对于治疗的成功是至关重要的，并且对于监测治疗方案的改进是重要的。该提案的重点是生产微米尺寸的CEST MR可检测的藻酸盐胶囊，其含有适于治疗T1 DM的胰岛和间充质干细胞。这些胶囊将具有内置于胶囊中的CEST MR造影剂，以允许：1）检测，2）在包封的胰岛和间充质干细胞之间进行区分，以及3）远程感测环境的pH。CEST造影剂的来源将是6-24个氨基酸长的肽和嵌入藻酸盐内的CEST脂质体。我们将使用糖尿病的裸小鼠模型进行临床前研究，以允许通过萤火虫荧光素酶表达监测包封的胰岛/间充质细胞的状态。 公共卫生相关性：近年来，胰岛移植（ITx）在治疗1型糖尿病（T1 DM）方面受到了相当大的关注。该提案的重点是生产免疫保护性胰岛细胞胶囊，其适用于治疗，并允许使用可生物降解的CEST造影剂对这些胰岛的pH值进行MR监测。

DESCRIPTION (provided by applicant): Good glycemic control is critical in reducing the end-stage complications of Type I Diabetes Mellitus (TIDM) and, for this reason, islet transplantation (ITx) has received considerable attention in recent years, with one of the complications in the treatment involves finding an effective means to prevent rejection. Immuno-isolation of islets provides a means to reduce or avoid immunosuppressive therapy altogether. In the most commonly used method of immuno-isolation, microencapsulation, individual islets are surrounded with thin alginate membranes that are permeable to insulin and metabolites, but are impermeable to native antibodies. However, the viability and in particular the insulin secretion of these islets are critical for the success of the therapy, and would be important to monitor for refinement of the treatment protocol. This proposal is focused on the production of micron sized CEST MR detectable alginate capsules containing both islet and mesenchymal stem cells which are appropriate for the treatment of T1DM. These capsules will have CEST MR contrast agents built into the capsule to allow: 1) detection, 2) discrimination between encapsulated islet and mesynchymal stem cells and 3) remote sensing of the pH of the environment. The source of the CEST contrast will be 6-24 amino acid long peptides and CEST liposomes embedded within the alginate. We will perform pre-clinical studies using a nude based mouse model of diabetes to allow monitoring of the status of encapsulated islets/ mesenchymal cells through firefly luciferase expression. PUBLIC HEALTH RELEVANCE: Islet transplantation (ITx) has received considerable attention in recent years for treatment of Type 1 Diabetes Melitus (T1DM). This proposal is focused on the production of immunoprotective islet cell capsules which are appropriate for treatment and allow MR monitoring of the pH these islets using biodegradable CEST contrast agents.