Improving efficiency of adriamycin crossing blood brain barrier by combination of thermosensitive liposomes and hyperthermia.

Adriamycin (ADM)-encapsulated thermosensitive liposomes (ts-lip-ADM) and common liposomes (lip-ADM) were developed and evaluated. The encapsulation efficiency of the two liposomes were above 99%, and the average sizes of liposomes were about 120 nm. Temperature-dependent drug release from loaded liposomes in vitro was investigated: more than 90% of loaded ADM was released from ts-lip-ADM within 30 min at 42°C, while less than 3% was released from lip-ADM at 42°C beyond 120 min. An in vitro model of blood brain barrier (BBB) was established and evaluated by permeability and transendothelial electrical resistance (TEER). The model was employed to study the permeability of liposomes in vitro. The permeability of ts-lip-ADM could be increased significantly after the temperature was raised to 42°C, which was about 10-16, 22-38, 38-45, 50-105 fold to that of ts-lip-ADM (37°C), lip-ADM (42°C), lip-ADM (37°C) and free ADM, respectively. C6 glioma-bearing mice model was developed and used to evaluate body distribution and anti-tumor efficacy in vivo. Mice were IV injected at a drug dose of 10 mg/kg. After administration the heads of mice were heated in water bath at 42°C for 30 min. The maximum brain concentration of ts-lip-ADM was 6.4, 3.7 fold compared with that of ADM solution and lip-ADM, respectively. The survival time of mice administered ts-lip-ADM (44 d) was remarkably longer than that of other three groups. This study indicates that ADM-encapsulated thermosensitive liposomes combined hyperthermia could enhance ADM delivery across BBB and prolong survival time of glioma-bearing mice.