Development and Characterization of Novel LipoCEST Agents Based on Thermosensitive Liposomes

To develop a novel probe for chemical exchange saturation transfer magnetic resonance imaging (CEST MRI) based on thermosensitive liposomes (lipoCEST) for theranostics, in which diagnostics and therapy are integrated into a single platform.

We developed two kinds of lipoCEST agents. The first kind encapsulated dysprosium (Dy)-1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA)-Na·3NaCl, terbium-DOTA-Na·3NaCl, or thulium-DOTA-Na·3NaCl into the inner cavity of thermosensitive liposomes, while the second kind encapsulated Dy-DOTA-Na and incorporated amphiphilic metal complex [thulium-diethylenetriamine pentaacetic acid-bis (stearylamide) (Tm-DTPA-BSA)] as a membrane constituent. The nuclear magnetic resonance (NMR)- and Z-spectra of these lipoCEST agents were acquired at various temperatures on a 9.4T MRI scanner. To investigate their applicability to the drug release induced by hyperthermia, we also encapsulated a fluorescent dye (calcein) into the inner cavity of liposomes and measured calcein release after warming them.

The intra- and extraliposomal water signals could be differentiated in all agents from their NMR- and Z-spectra. The agent incorporating Tm-DTPA-BSA showed the largest chemical shift (approximately 15 ppm) derived from the intraliposomal water protons. The calcein retained in this agent was successfully released at 44°C. The agent incorporating 30 mol% of Tm-DTPA-BSA in its membrane released more calcein at 42-44ºC than that of the agent incorporating 10 mol%.

We developed novel thermosensitive lipoCEST agents and characterized them. Our preliminary results suggest that they are useful and can be applied to theranostics.