MRI monitoring of drug delivery using thermosensitive magnetoliposomes

Abstract

Since the beginning of the 20th century the constant increase of the cancer incidence in the developed world has led to extensive research to improve the effectiveness of treatments, including chemotherapy. While chemotherapy has shown success in several indications it is also limited by toxicity. Local drug delivery by hyperthermia-induced drug release from thermosensitive liposomes (TSL) may reduce systemic toxicity of chemotherapy, while maintaining or increasing its efficacy. To achieve increased drug concentration locally at the correct location, imaging guidance is necessary, and can be applied to monitoring the accumulation of the carrier, the application of hyperthermia and the release of the drug. In this thesis, labeling of the thermosensitive nanocarriers based on superparamagnetic iron oxide is evaluated. In addition we developed dedicated MRI methods for monitoring the accumulation, as well as for release and temperature monitoring that could be used to guide such a procedure. In chapter 2 the effect of Thermosensitive magnetoliposomes (TSM), i.e. ultrasmall superparamagnetic iron oxide nanoparticles (USPIO) encapsulated in thermosensitive liposomes, on MRI contrast was studied. Monitoring temperature triggered drug release using MR requires dedicated imaging protocols. In chapter 3 the feasibility of using a multi-echo spoiled gradient echo for the time resolved assessment of R1, R2* and temperature maps for use with TSM was developed. The 5s dynamic multi-echo sequence can be used straightforwardly to map R2* from the decreasing echo amplitudes, as well as the temperature based on PRFS using the unwrapped phase change. However, R1 is not directly accessible. The method estimates the R1-change based on the signal magnitude change knowing the value of R2* and compensating for the apparent proton density changes with temperature. In chapter 4, we investigated whether TSM in combination with time-resolved MR relaxation mapping and thermometry techniques implemented previously allowed assessment of intratumoral distribution of nanocarriers as well as their release profile in vivo. In this in vivo study, local hyperthermia was applied for 5 to 15 min in tumor-bearing rats (N=6) using a homemade MR-compatible dual water bath setup that allowed for increasing the temperature into one tumor while maintaining the temperature of the other tumor constant, which could thus serve as a control. In chapter 5 we describe the formulation of a thermosensitive liposome encapsulating both Gd-chelate and citrated-USPIO, so called Gd-TSM. Thus we used citrated USPIOs to label the liposome while Gd-chelates were used to monitor the release. The Gd-TSM formulation was characterized using DLS and Cryo-TEM and compared to two other formulation encapsulating either Gd‑chelate or citrated USPIO alone, and no significant hydrodynamic changes were observed. Contrary to the formulation from chapter 2, the citrated USPIOs were found to stay entrapped in the liposome lumen after a heat-induced phase transition on Cryo-TEM.