Molecular Imaging Agent Design for Quantifying Beta Cell Mass in Type 1 Diabetes

Molecular Imaging Agent Design for Quantifying Beta Cell Mass in Type 1 Diabetes;Chemical Engineering;Science;Chemical Engineering

Zhang, LiangLinderman, Jennifer J ;

University of Michigan

关键词: Molecular Imaging Agent Design for Quantifying Beta Cell Mass in Type 1 Diabetes;    Chemical Engineering;    Science;    Chemical Engineering;   

Others  :  https://deepblue.lib.umich.edu/bitstream/handle/2027.42/140825/liangzha_1.pdf?sequence=1&isAllowed=y

瑞士|英语

来源: The Illinois Digital Environment for Access to Learning and Scholarship

【 摘 要 】

Type 1 diabetes affects over one million Americans and an additional 40,000 new cases are diagnosed each year. The disease is characterized by the destruction of insulin-secreting beta cells in the pancreas by the immune system. Consequently, patients with type 1 diabetes rely on exogenous insulin for life. Due to the small volume of beta cells in healthy pancreas, it is extremely challenging to monitor disease progression (particularly at early stages when adequate control of blood sugar levels is still maintained) and assess treatment efficacy in patients with type 1 diabetes. Therefore, an accurate method to monitor and quantify the beta cell mass (BCM) through imaging has been an important goal of the diabetes community.This thesis describes the unique anatomy and physiology of the beta cells within the Islets of Langerhans and calculates the optimal physicochemical properties needed for a BCM molecular imaging probe. The molecular weight of exendin probes are near ideal for targeting the endocrine pancreas, and this molecule was analyzed in more detail. Receptor trafficking properties and plasma clearance play a major role in determining beta cell targeting versus background signal and were measured for a series of probes. Due to rapid downregulation of the receptor, slow plasma clearance does not allow for continual beta cell uptake and increases background, so more rapid clearance results in higher target to background signal. Additionally, the receptor expression of GLP1-R was measured for the first time and provided evidence for low exocrine expression of GLP1-R in addition to the high endocrine expression. Because this could explain poor clinical contrast of exendin probes, exocrine expression was investigated in more detail. Using a transgenic mouse model, a very low expression of GLP1-R was confirmed on exocrine cells. Although absolute expression is very low (850 receptors per cell on exocrine cells versus 53,000 receptors per cell on beta cells), the much higher prevalence of exocrine cells (99%) relative to beta cells (1%) results in a significant total signal from the exocrine pancreas. Preliminary results show it is possible to preferentially block exocrine uptake to provide more specific beta cell signal. Multiple doses were administered to first saturate the exocrine with non-detectable peptide followed by a imaging agent dose to label the beta cells. The dosing strategy completely blocked exocrine GLP-1R in healthy animal models. Because peptides often have poor stability and lower affinity due to the lack of secondary structure, exendin was used as a model system to study the impact of helix stabilization on improving peptide physicochemical properties. Using a unique cross-linker with exendin and GLP1 peptides, the helicity, protease stability, and affinity could be improved. The increase protease stability of the cross-linked peptides and use of exendin as a therapeutic led us to test the subcutaneous bioavailability. Near-100% bioavailability was achieved through peptide stabilization, and the bioavailability of a slow-clearing version was also improved. The linker lipophilicity could be controlled to modulate the absorption and clearance rates of the fluorescent peptide. Overall, this thesis provides a theoretical analysis of imaging BCM, novel tools to manipulate peptide image probe properties, and experimental evidence of methods to improve the design of molecular imaging agents for beta cell mass.