Influence of injection site, microvascular pressure and ultrasound variables on microbubble-mediated delivery of microspheres to muscle.
OBJECTIVE
Our objective was to test the hypothesis that the ultrasound pulsing interval (PI), microbubble injection site and microvascular pressure significantly influence the transport of 100-nm microspheres to muscle through extravasation sites created by the destruction of microbubbles with ultrasound.


BACKGROUND
Microbubbles show promise as targeted drug and gene delivery agents; however, designing optimal microbubble-based therapies will require an understanding of the factors that influence the transport of microbubble-delivered, gene-bearing vehicles to tissue.


METHODS
Ultrasound at 1 MHz, with a peak negative pressure amplitude of 0.75 MPa, was applied to microbubbles and 100-nm microspheres in exteriorized rat spinotrapezius muscle. Ultrasound PIs of 1, 3, 5 and 10 s, arterial microsphere injection times of 10 or 40 s and arterial versus venous injection sites were tested.


RESULTS
Extravasation point creation and microsphere delivery were greatest when the ultrasound PI was 5 or 10 s. No significant differences in extravasation point creation or microsphere delivery were observed with arterial versus venous microbubble injection, but a trend toward increased microsphere delivery with arterial injection may exist. Decreasing the arterial injection time from 40 to 10 s increased microvascular pressure, which, in turn, substantially enhanced microsphere transport to tissue, without a concomitant increase in the number of extravasation points.


CONCLUSIONS
The ultrasound PI and microvascular pressure significantly influence the creation of extravasation points and the transport of microspheres to tissue. These factors may be important in designing and optimizing contrast ultrasound-based therapies.
Song
Ji
J
Department of Biomedical Engineering, University of Virginia, Charlottesville, Virginia, USA.
Chappell
John C
JC
Qi
Ming
M
VanGieson
Eric J
EJ
Kaul
Sanjiv
S
Price
Richard J
RJ
D000818:Animals; D001794:Blood Pressure / Q000502:physiology*; D002199:Capillary Permeability / Q000502:physiology*; D009202:Cardiomyopathies / Q000000981:diagnostic imaging* / Q000503:physiopathology / Q000628:therapy*; D004195:Disease Models, Animal; D004337:Drug Carriers / Q000008:administration & dosage*; D016503:Drug Delivery Systems; D005119:Extravasation of Diagnostic and Therapeutic Materials / Q000503:physiopathology; D005260:Female; D007269:Injections, Intra-Arterial; D007273:Injections, Intramuscular; D008863:Microspheres; D018482:Muscle, Skeletal / Q000000981:diagnostic imaging* / Q000503:physiopathology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D018617:Ultrasonography, Doppler, Pulsed
D004337:Drug Carriers