Hyperthermia Induced Gadodiamide Release from Thermosensitive Liposomes in Solid Tumors and Muscle Tissue

Introduction: Thermal dose is the key factor for the synergistic interaction of local hyperthermia (HT) in combination with chemotherapy in tumor therapy (1,2); for targeting and accumulation of liposomes in a target volume, for triggering fast and efficient content release from thermosensitive liposomes (TSL) in that target volume. Thus, for experimental investigation of TSL and for a potential clinical application non-invasive visualization techniques are expected to play a key role. TSL with either encapsulated Gd3+ or Mn2+ have been proposed for therapy monitoring using the thermotropic polymorphism of liposomes. The paramagnetic compounds are released at the gel to liquid-crystalline phase transition temperature (Tm) of TSL and act as T1-shortening MR contrast agent (3,4,5). Recently, a novel formulation for TSL has been successfully developed composed of 1,2-dipalmitoyl-sn-glycero-3-phosphoglyceroglycerol (DPPGOG) for prolonged circulation time and an increased content release at the phase transition temperature Tm of about 42°C, which is consistent with the therapeutical hyperthermia temperature level aimed at combined HT/chemotherapy tumor treatment concepts (6). Recently, we reported MR-characterization of Gd-DTPA-BMA loaded phosphatidylglyceroglycerol-TSL (Gd-TSL) at mild hyperthermia conditions in tumor tissue (7,8). Thereafter a retrospective study comparing results of heated and unheated tumors in relation to normal unheated muscle tissue was performed in order to assess signal response in normal tissue as a reference.