Mechanism of intracellular delivery by acoustic cavitation.
Using conditions different from conventional medical imaging or laboratory cell lysis, ultrasound has recently been shown to reversibly increase plasma membrane permeability to drugs, proteins and DNA in living cells and animals independently of cell or drug type, suggesting a ubiquitous mechanism of action. To determine the mechanism of these effects, we examined cells exposed to ultrasound by flow cytometry coupled with electron and fluorescence microscopies. The results show that cavitation generated by ultrasound facilitates cellular incorporation of macromolecules up to 28 nm in radius through repairable micron-scale disruptions in the plasma membrane with lifetimes >1 min, which is a period similar to the kinetics of membrane repair after mechanical wounding. Further data suggest that cells actively reseal these holes using a native healing response involving endogenous vesicle-based membrane resealing. In this way, noninvasively focused ultrasound could deliver drugs and genes to targeted tissues, thereby minimizing side effects, lowering drug dosages, and improving efficacy.
Schlicher
Robyn K
RK
The Wallace H. Coulter Department of Biomedical Engineering at Georgia Tech and Emory University, Georgia Institute of Technology, Atlanta, Georgia 30332-0100, USA.
Radhakrishna
Harish
H
Tolentino
Timothy P
TP
Apkarian
Robert P
RP
Zarnitsyn
Vladimir
V
Prausnitz
Mark R
MR
D000162:Acoustics; D002462:Cell Membrane / Q000378:metabolism / Q000648:ultrastructure; D002463:Cell Membrane Permeability; D016503:Drug Delivery Systems / Q000379:methods*; D018274:Electroporation / Q000379:methods*; D004705:Endocytosis; D004910:Erythrocyte Membrane / Q000378:metabolism; D006801:Humans; D008297:Male; D008855:Microscopy, Electron, Scanning; D013010:Sonication; D014407:Tumor Cells, Cultured