title: Controlling liposomal drug release with low frequency ultrasound: mechanism and feasibility.
abstract: The ability of low-frequency ultrasound (LFUS) to release encapsulated drugs from sterically stabilized liposomes in a controlled manner was demonstrated. Three liposomal formulations having identical lipid bilayer compositions and a similar size ( approximately 100 nm) but differing in their encapsulated drugs and methods of drug loading have been tested. Two of the drugs, doxorubicin and methylpredinisolone hemisuccinate, were remote loaded by transmembrane gradients (ammonium sulfate and calcium acetate, respectively). The third drug, cisplatin, was loaded passively into the liposomes. For all three formulations, a short exposure to LFUS (<3 min) released nearly 80% of the drug. The magnitude of drug release was a function of LFUS amplitude and actual exposure time, irrespective of whether irradiation was pulsed or continuous. Furthermore, no change in liposome size distribution or in the chemical properties of the lipids or of the released drugs occurred due to exposure to LFUS. Based on our results, we propose that the mechanism of release is a transient introduction of porelike defects in the liposome membrane, which occurs only during exposure to LFUS, after which the membrane reseals. This explains the observed uptake of the membrane-impermeable fluorophore pyranine from the extraliposomal medium during exposure to LFUS. The implications of these findings for clinical applications of controlled drug release from liposomes are discussed.
authors.affiliation: Department of Chemical Engineering, Ben-Gurion University of the Negev, Beer Sheva 84105, Israel.
authors.forename: Avi
authors.initials: A
authors.lastname: Schroeder
authors.forename: Yuval
authors.initials: Y
authors.lastname: Avnir
authors.forename: Sarah
authors.initials: S
authors.lastname: Weisman
authors.forename: Yousef
authors.initials: Y
authors.lastname: Najajreh
authors.forename: Alberto
authors.initials: A
authors.lastname: Gabizon
authors.forename: Yeshayahu
authors.initials: Y
authors.lastname: Talmon
authors.forename: Joseph
authors.initials: J
authors.lastname: Kost
authors.forename: Yechezkel
authors.initials: Y
authors.lastname: Barenholz
mesh_terms: D000085:Acetates; D000645:Ammonium Sulfate / Q000737:chemistry; D001190:Arylsulfonates / Q000737:chemistry; D017610:Calcium Compounds; D002945:Cisplatin / Q000737:chemistry*; D003692:Delayed-Action Preparations / Q000737:chemistry; D004317:Doxorubicin / Q000737:chemistry*; D008081:Liposomes; D008776:Methylprednisolone Hemisuccinate / Q000737:chemistry*; D014465:Ultrasonics
chemical_list: D000085:Acetates; D001190:Arylsulfonates; D017610:Calcium Compounds; D003692:Delayed-Action Preparations; D008081:Liposomes; D008776:Methylprednisolone Hemisuccinate; D004317:Doxorubicin; C029110:methylprednisolone 17-hemisuccinate; C005047:pyranine; D002945:Cisplatin; D000645:Ammonium Sulfate; C120662:calcium acetate