Iron(III)-Based Magnetic Resonance-Imageable Liposomal T1 Contrast Agent for Monitoring Temperature-Induced Image-Guided Drug Delivery.

Abstract

Drug-loaded temperature-sensitive liposomes (TSLs) allow heat-triggered local drug delivery to tumors. When magnetic resonance-guided high-intensity focused ultrasound (MR-HIFU) is applied to heat up the tumor, corelease of a drug together with an MR contrast agent (CA) from TSLs allows for indirect imaging of the drug release with MR imaging. However, liposomal encapsulation of commonly used gadolinium (Gd)-based MR CAs leads to prolonged retention times in the liver and spleen, which could lead to a transmetallation and redistribution of Gd to other organs. Therefore, an alternative non-Gd-containing T1-MR CA based on encapsulated Fe-succinyl deferoxamine (Fe-SDFO) is proposed as a safe alternative for similar Gd-based systems in image-guided drug delivery applications. Temperature-sensitive liposomes were loaded with either doxorubicin or Fe-SDFO. Both systems were characterized in vitro with respect to stability, release kinetics, and MR imaging properties. In an in vivo proof-of-concept study, rats bearing a subcutaneous glioma on their hind limb were injected intravenously with a mixture of TSLs encapsulating doxorubicin or Fe-SDFO. Afterwards, the tumors were subjected to an MR-HIFU treatment (2 × 10-15 minutes at 42°C, n = 5) or a control treatment (n = 5). The release of Fe-SDFO from TSLs was quantified in vivo with R1 maps and correlated with the ex vivo determined tumor doxorubicin concentration. Temperature-sensitive liposomes containing doxorubicin or Fe-SDFO were comparable in diameter and phase transition temperature Tm. Both systems showed a fast release at 42°C and good stability at 37°C. Unheated Fe-SDFO-TSLs displayed an r1 of 0.80 ± 0.01 mMs (T = 37°C, B = 3 T), which increased to 1.35 ± 0.02 mMs after release at 42°C. In MR-HIFU studies, tumor R1 maps showed an average relaxation rate change upon heating of ΔR1 = 0.20 ± 0.04 s. The R1 change across the tumor was not always homogeneous. The doxorubicin uptake in the tumor showed a linear correlation with the induced ΔR1 (Radj = 0.41). Doxorubicin-loaded and Fe-SDFO-loaded TSLs displayed favorable release and stability characteristics in vitro. An in vivo proof-of-concept study showed the feasibility of monitoring drug release using the newly designed iron(III)-based CA loaded TSLs. The measured R1-contrast change correlated with the amount of doxorubicin delivered to the tumor. Moreover, the pattern of R1 change could elucidate the pattern of drug release across the tumor. This new iron(III)-based liposomal MR CA is a promising alternative to comparable Gd-based systems.