A formulation based on these thermosensitive liposomes took the brand name Thermodox and was further developed by Celsion corporation. Thermodox liposomes can be triggered to release their payload by any heat-based treatment such as radiofrequency thermal ablation (RFA),

microwave hyperthermia, and high intensity focused ultrasound (HIFU). Results from a Phase I study that used Thermodox was recently published [29]. In a Phase I study researchers used escalating dose of Thermodox with radiofrequency Inhibitors,research,lifescience,medical (RF) ablation and concluded that Thermodox can be safely administered at 50mg/m2 in combination with RF ablation. Currently Thermodox in combination with RF ablation is being tested in a large Phase I study to treat hepatocellular carcinoma [30]. The concept of using Inhibitors,research,lifescience,medical liposomes and HIFU was introduced recently, in 2006 when Frenkel et al. used liposomal doxorubicin (Doxil) in combination with pulsed high-intensity focused ultrasound (HIFU) exposures in a murine breast cancer tumor model. Doxil is a stable liposomal preparation that has no response to increased temperature [31] and was developed to minimise doxorubicin’s cardiotoxicity, by encapsulating doxorubicin within stealth liposomes. Although Doxil achieves long circulation Inhibitors,research,lifescience,medical of doxorubicin with minimum cardiotoxicity it does not rapidly release the drug within the tumour.

Pulsed-HIFU exposures were not found to enhance the therapeutic delivery of doxorubicin and did not induce tumour regression. However, a fluorescent dextran CI-1040 purchase showed blood vessels to be dilated as a result of the exposures.

Experiments with polystyrene nanoparticles of similar size to the liposomes showed a greater abundance to be Inhibitors,research,lifescience,medical present in the treated tumours [32]. Although this study did not achieve Inhibitors,research,lifescience,medical or prove a therapeutic advantage of the use of HIFU with temperature stable liposomes it showed clearly that pulsed HIFU induces a substantial increase of permeation of macromolecules and nanoparticles in tumours. In 2007 Dromi et al. presented the first study on thermosensitive liposomes (Low Temperature Sensitive Liposomes (LTSL)) and HIFU. The authors investigated pulsed-high intensity focused ultrasound as a source of hyperthermia with thermosensitive liposomes to enhance delivery and efficacy of doxorubicin in murine adenocarcinoma tumours. In vitro treatments simulating the pulsed-HIFU thermal dose (42°C for 2min) triggered release almost of 50% of doxorubicin from the thermosensitive liposomes; however, no detectable release from the nontemperature sensitive liposomes (similar to Doxil) was observed. Similarly, in vivo experiments showed that pulsed-HIFU exposures combined with the LTSL resulted in more rapid delivery of doxorubicin as well as significantly higher concentration within the tumour when compared with LTSLs alone or nonthermosensitive liposomes, with or without exposures [33].