Thermosensitive paramagnetic liposomes for temperature control during MR imaging-guided hyperthermia: In vitro feasibility studies

Abstract

Magnetic resonance (MR) imaging-based temperature monitoring has gained interest for use in general hyperthermia treatment of tumors. Such therapy requires an accurate control of the temperature, which should range from 41 degrees to 45 degrees C. A novel type of thermosensitive MR agent is proposed: liposome-encapsulated gadolinium chelates whose temperature response is linked to the phase-transition properties of the liposome carrier. In vitro relaxometry and MR imaging were used to evaluate the thermosensitivity of the contrast properties of liposomal gadolinium diethylenetriaminepentaacetic acid bis(methylamide) (Gd-DTPA-BMA). T1 relaxivity (rl) measurements of liposomal Gd-DTPA-BMA were undertaken at 0.47 T and at temperatures of 20 degrees-48 degrees C. MR imaging was performed at 2.0 T with a gel phantom containing inserts of liposomes. Diffusion-weighted and T1-weighted gradient-recalled echo images were acquired as the phantom was heated from 22 degrees to about 65 degrees C. At ambient temperature, the r1 of liposomal Gd-DTPA-BMA was exchange limited due to slow water exchange between the liposome interior and exterior. A sharp, marked increase in r1 occurred as the temperature reached and exceeded the gel-to-liquid crystalline phase-transition temperature (Tm) of the liposomes (42 degrees C). The relaxation enhancement was mainly attributable to the marked increase in transmembrane water permeability, yielding fast exchange conditions. There was good correlation between the relaxometric and imaging results; the signal intensity on T1-weighted gradient-recalled echo images increased markedly as the temperature approached Tm. The temperature sensitivity of the diffusion-weighted technique differed from that of the liposome-based T1-weighted approach, with an apparent water diffusion coefficient increasing linearly with temperature. Since the transition from low to high signal intensity occurred in the temperature range of 38 degrees - 42 degrees C, the investigated paramagnetic liposomes have a potential role as "off-on" switches for temperature control during hyperthermia treatment.