Effect of Liposomal Encapsulation on the Chemical Exchange Properties of Diamagnetic CEST Agents.

Eleni Demetriou,Robin Bofinger,Helen C Hailes,Harriet E Story,Xavier Golay,Alethea B Tabor

doi:10.1021/acs.jpcb.9b02280

Abstract

Exogenous chemical exchange saturation transfer (CEST) contrast agents such as glucose or 2-deoxy-d-glucose (2-DG) have shown high sensitivities and significant potential for monitoring glucose uptake in tumors with MRI. Here, we show that liposome encapsulation of such agents can be exploited to enhance the CEST signal by reducing the overall apparent exchange rate. We have developed a concise analytical model to describe the liposomal contrast dependence on several parameters such as pH, temperature, irradiation amplitude, and intraliposomal water content. This is the first study in which a model has been constructed to measure the exchange properties of diamagnetic CEST agents encapsulated inside liposomes. Experimentally measured exchange rates of glucose and 2-DG in the liposomal system were found to be reduced due to the intermembrane exchange between the intra- and extraliposomal compartments because of restrictions in water transfer imposed by the lipid membrane. These new theoretical and experimental findings will benefit applications of diamagnetic liposomes to image biological processes. In addition, combining this analytical model with measurements of the CEST signal enhancement using liposomes as a model membrane system is an important new general technique for studying membrane permeability.

Highlights

Over the last 10 years, many chemical exchange saturation transfer (CEST) studies have explored different approaches to enhance the sensitivity of contrast agent detection by either optimizing the exchange rate of the exchangeable protons in the agent with water or by increasing the number of exchangeable protons per molecule of the contrast agent
Nonradiolabeled D-glucose has been used at physiologically acceptable quantities to image glucose accumulation in mouse xenografts and successfully discriminate between distinct tumor phenotypes using CEST techniques.[2−4] drawbacks of the technique include low sensitivity, short duration of the signal, and the potential for adverse side effects in response to a large bolus injection of glucose such as hyperglycaemic coma in diabetic patients or deep vein thrombosis.3,4 2-Deoxy-Dglucose (2-DG) is an analogue of glucose in which the 2hydroxyl group is replaced by hydrogen, resulting in several interesting biological consequences. 2-DG enters cells via the same transporters as glucose, mainly GLUT1 and GLUT3 in the brain.[3]
We hypothesized that developing a new generation of GlucoCEST contrast agents, encapsulating high concentrations of monosaccharides inside liposomes, could overcome and facilitate translation of GlucoCEST into the clinic

Summary

Introduction

Over the last 10 years, many chemical exchange saturation transfer (CEST) studies have explored different approaches to enhance the sensitivity of contrast agent detection by either optimizing the exchange rate (kex) of the exchangeable protons in the agent with water or by increasing the number of exchangeable protons per molecule of the contrast agent. The increased uptake of glucose into tumors has been successfully exploited by 18F-labeled fluoro-deoxy-D-Glucose (FDG) PET imaging for over 30 years. Nonradiolabeled D-glucose has been used at physiologically acceptable quantities to image glucose accumulation in mouse xenografts and successfully discriminate between distinct tumor phenotypes using CEST techniques (termed GlucoCEST).[2−4] drawbacks of the technique include low sensitivity, short duration of the signal, and the potential for adverse side effects in response to a large bolus injection of glucose such as hyperglycaemic coma in diabetic patients or deep vein thrombosis.3,4 2-Deoxy-Dglucose (2-DG) is an analogue of glucose in which the 2hydroxyl group is replaced by hydrogen, resulting in several interesting biological consequences. The utility of 2-DG as a CEST agent has been investigated in a number of animal studies,[3,5,6] and doses of up to 0.3 g/kg have been administered in humans with limited adverse side effects.[7]

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