The ability of low frequency ultrasound (LFUS) to trigger the release of drugs from nano sterically stabilized liposomes (nSSL) in vitro, without affecting the drugs' chemical integrity or biological potency, has been previously shown. Herein, the ability of LFUS to (a) trigger the release of cisplatin from nSSL in vivo, and (b) affect the therapeutic efficacy by locally releasing the drug, was studied. For this, nSSL loaded with the anti-cancer chemotherapeutic agent cisplatin were injected intraperitoneally (i.p.) to mice bearing well-developed J6456 murine lymphoma tumors in their peritoneal cavity. Then, LFUS was applied externally to the abdominal wall for 120 s, and drug release was quantified. Nearly 70% of the liposomal cisplatin was released in tumors exposed to LFUS, compared to < 3% in those not exposed to LFUS. The effect of LFUS-induced localized drug release on the therapeutic efficacy was tested on BALB/c mice with C26 colon adenocarcinoma tumors in a footpad. Mice were injected intravenously with nSSL cisplatin, and 24 h later, the tumor was exposed to LFUS. The group treated by liposomal cisplatin combined with LFUS, compared to all other groups (i.e., free cisplatin with or without LFUS, or liposomal cisplatin without LFUS, or LFUS alone, or no treatment) had the best therapeutic score; tumors stopped proliferating and then regressed over time. This work presents a modality for the release of drugs from liposomes in vivo using LFUS. Implications of these findings for clinical applications of LFUS-induced liposomal drug release are discussed.
Bibliographical noteFunding Information:
A.S. thanks the Israel Ministry of Science and Technology for an Eshkol Fellowship. This study was supported in part by the Barenholz Fund. Dinah Tzemach is acknowledged for her technical assistance in the animal work, and Sigmund Geller is thanked with pleasure for his help in editing the manuscript.
- C26 adenocarcinoma
- Controlled release
- J6456 lymphoma
- Low frequency ultrasound
- Murine tumor model
- Passive targeting