Dromi Sergio, Frenkel Victor, Luk Alfred, Traughber Bryan, Angstadt Mary, Bur Monica, Poff Jason, Xie Jianwu, Libutti Steven K, Li King C P, Wood Bradford J
Diagnostic Radiology Department, Clinical Center, National Cancer Institute, NIH, Bethesda, Maryland 20892, USA.
Clin Cancer Res. 2007 May 1;13(9):2722-7. doi: 10.1158/1078-0432.CCR-06-2443.
To determine if pulsed-high intensity focused ultrasound (HIFU) could effectively serve as a source of hyperthermia with thermosensitive liposomes to enhance delivery and efficacy of doxorubicin in tumors.
Comparisons in vitro and in vivo were carried out between non-thermosensitive liposomes (NTSL) and low temperature-sensitive liposomes (LTSL). Liposomes were incubated in vitro over a range of temperatures and durations, and the amount of doxorubicin released was measured. For in vivo experiments, liposomes and free doxorubicin were injected i.v. in mice followed by pulsed-HIFU exposures in s.c. murine adenocarcinoma tumors at 0 and 24 h after administration. Combinations of the exposures and drug formulations were evaluated for doxorubicin concentration and growth inhibition in the tumors.
In vitro incubations simulating the pulsed-HIFU thermal dose (42 degrees C for 2 min) triggered release of 50% of doxorubicin from the LTSLs; however, no detectable release from the NTSLs was observed. Similarly, in vivo experiments showed that pulsed-HIFU exposures combined with the LTSLs resulted in more rapid delivery of doxorubicin as well as significantly higher i.t. concentration when compared with LTSLs alone or NTSLs, with or without exposures. Combining the exposures with the LTSLs also significantly reduced tumor growth compared with all other groups.
Combining low-temperature heat-sensitive liposomes with noninvasive and nondestructive pulsed-HIFU exposures enhanced the delivery of doxorubicin and, consequently, its antitumor effects. This combination therapy could potentially produce viable clinical strategies for improved targeting and delivery of drugs for treatment of cancer and other diseases.
确定脉冲高强度聚焦超声（HIFU）能否有效地作为热敏感脂质体的热疗源，以增强阿霉素在肿瘤中的递送和疗效。
对非热敏脂质体（NTSL）和低温敏感脂质体（LTSL）进行体外和体内比较。脂质体在一系列温度和持续时间下进行体外孵育，并测量阿霉素的释放量。对于体内实验，将脂质体和游离阿霉素静脉注射到小鼠体内，然后在给药后0小时和24小时对皮下小鼠腺癌肿瘤进行脉冲HIFU照射。评估照射和药物制剂的组合对肿瘤中阿霉素浓度和生长抑制的影响。
模拟脉冲HIFU热剂量（42℃，2分钟）的体外孵育促使50%的阿霉素从LTSL中释放；然而，未观察到NTSL有可检测到的释放。同样，体内实验表明，与单独使用LTSL或NTSL相比，无论有无照射，脉冲HIFU照射与LTSL联合使用能使阿霉素更快地递送，肿瘤内浓度也显著更高。与所有其他组相比，将照射与LTSL联合使用还显著降低了肿瘤生长。
将低温热敏脂质体与无创且无损的脉冲HIFU照射相结合，可增强阿霉素的递送，从而增强其抗肿瘤作用。这种联合疗法可能为改进癌症和其他疾病治疗药物的靶向性和递送提供可行的临床策略。
