Pharmacokinetics & tissue distribution of temperature-sensitive liposomal doxorubicin in tumor-bearing mice triggered with mild hyperthermia

Drug-loaded temperature-sensitive liposomes (TSL) in combination with hyperthermia (HT) have attracted considerable attention for cancer treatment. Different TSL systems have been designed with wide variations in their temperature sensitivity and drug release profile. Low temperature-sensitive liposomes (LTSL) with the capacity for ultrafast drug release, traditional temperature-sensitive (TTSL) with intermediate drug release properties and non-temperature-sensitive liposomes (NTSL) (no drug release) were dual-labeled with 3H-cholesteryl hexadecyl ether (3H-CHE) lipid and loaded with 14C-doxorubicin (14C-Dox). Their blood profile, serum stability, tissue distribution and tumor localization (B16F10 melanoma) were studied after intravenous administration and mild HT treatment. LTSL showed higher affinity for the liver compared to TTSL and NTSL which were uptaken mainly by spleen. Under normal conditions (no HT) Dox leakage from liposomes was expected, higher for LTSL, less for TTSL and minimal for NTSL. Localized HT did not affect the overall blood circulation or organ accumulation for all TSL studied. Since LTSL showed ultrafast Dox release kinetics at 42 °C, the highest drug accumulation in tumors was observed using this system immediately after HT, however decreased significantly after 24 h. In contrast, TTSL and NTSL showed 2-3 fold increase in both liposome and Dox levels that indicated enhanced tumor extravasation of intact Dox-loaded liposomes during the 60 min HT applications. More interestingly, high levels of drug tumor accumulation were achieved 24 h post-HT. This study offers further understanding on how the mechanisms of drug release from temperature-sensitive liposomes affect their pharmacological profile under mild hyperthermia.