Zinc(II) Sensitive MRI Contrast Agents as Diagnostic Sensors for Tracking Insulin Secretion

点击翻译按钮获取中文摘要

ABSTRACT Significance: Diabetes mellitus type 1 (T1D) and particularly type 2 (T2D, >90% of cases) are becoming an increasing burden on socioeconomic resources with vastly increasing patient numbers all over the world. Insulin-dependent treatment regimen such as regular insulin injections are well established for both T1D and T2D but have been associated with a negative impact on the quality of life of patients with a variety of long- term complications. Apart from insulin administration that represents the standard treatment regimen for T1D, more typical treatment options for T2D involve administration of oral antihyperglycemic drugs, e.g. metformin or acarbose. Current and future research fields focus on the search for insulin-independent treatment options. This important, albeit elusive, scientific goal has been pursued for over 40 years, with promising results particularly in the field of pancreatic islet transplantation. Here, grafting of either entire cadaveric pancreases or encapsulated islets comprised of insulin producing beta cells in a protective capsule has been the main focus of research. However, one major drawback in the grafting success of pancreatic tissue or islets is the monitoring process to quantify insulin secretion of the graft upon transplantation. An imaging technique that could be adapted to gain quantitative information on the insulin secretion, ideally in a minimally invasive fashion, may be invaluable for the future success of islet/pancreas transplantation. Furthermore, such a technique could also be used in order to quantify insulin secretion and to determine the onset of TD1 or TD2, therefore providing diagnostic information on the progression and etiology of diabetes. Hypothesis: We hypothesize that the use of zinc(II) sensitive MRI contrast agents offers the ability to solve these therapeutic and diagnostic problems. In particular, we have already shown that this sensor type exhibits high efficacy, high selectivity and low toxicity when used in small animals or even in primates (e.g. rhesus macaque). Preliminary Data: We have demonstrated that this molecular sensor type represents the vanguard of zinc(II) sensitive MRI contrast agents with the ability to sensitively image insulin secretion in vivo using different animal species, including mice, rats and primates. The preliminary results obtained will be crucial for the further development of this technology in the screening of transplanted islets or whole pancreatic tissue. Specific Aims: The key objectives in Phase I entail the synthesis, purification and characterization of a large amount of CP027 and other structurally similar analogues (Phase I – Aims 1 and 2). All compounds will be used in Phase II for advanced studies on stability, physical properties and biodistribution. The most efficient sensor species will be used for toxicity studies in preparation for submission of an IND to receive approval for a first-in-human clinical trial (Phase II – Aim 1). Furthermore, the most effective compound will be used to quantify insulin secretion in extracted islets in vivo via transplanted pancreatic tissue in nude mice (Phase II – Aim 2). Finally, healthy rats as well as a T1D and T2D rat model using Sprague-Dawley rats will be used for pancreatic imaging over the course of weeks to months. Common anti-hyperglycemic drugs (e.g. Liratuglideâ) will be administered in the T2D model to assess drug efficacy using our sensors (Phase II – Aim 3). Overall Impact: Taken in concert, the technologies developed by VitalQuan will be made available to clinical labs and companies developing new methods and technologies to improve islet graft success. Our agents will also provide direct measures of oscillating phase 1 versus phase 2 insulin secretion and will therefore offer an invaluable tool for those companies currently developing advanced pharmaceuticals that promote or enhance insulin secretion. Furthermore, the use of our agents will also help to establish unprecedented studies designed for in vivo insulin tracking. Taken in concert, these applications will accelerate the commercialization of such MRI contrast agents for clinical use in diabetes research and treatment.