In vivo targeted delivery of large payloads with an ultrasound clinical scanner.
OBJECTIVE
Performing drug-delivery with an ultrasonic imaging scanner in situ could drastically simplify treatment and improve its specificity. Our objective is to deliver large amounts of an encapsulated agent in vivo using a clinical ultrasound scanner with a millimetric resolution. This study describes the encapsulation of fluorescein within ultrasound-inducible composite droplets and its targeted release in predefined zones in the liver of rats.


METHODS
An aqueous solution of fluorescein was encapsulated within perfluorocarbon liquid in 4 μm monodisperse droplets using a microfluidic system. The agent was then injected within the femoral vein of 12 rats. After exploratory ultrasound imaging, the sonographer defined five zones in the liver and a release sequence was initiated on the same apparatus. The surface of the liver was observed under fluorescence macroscopy and intraoperative fluorescence camera in vivo, before liver samples were sliced for pathology.


RESULTS
Following the conversion of the droplets, a 25 dB increase in contrast was observed in the zones selected by the sonographer. These hyperechoic regions were colocalized with the bright fluorescent spots observed on the surface of the liver. A minimum peak-negative pressure of 2.6 MPa, which is within regulations for imaging pulses, was required for the delivery of the content of the droplets. The tissue and cellular structures were not affected by the exposure to the release sequence.


CONCLUSIONS
Since composite droplets can carry various therapeutic and imaging agents, they could deliver such agents specifically in any organ accessible to ultrasound.
Institut Langevin, ESPCI, 10 rue Vauquelin, Paris 75005, France. olivier.couture@espci.fr
Olivier
O
Couture
Alan
A
Urban
Alice
A
Bretagne
Lucie
L
Martinez
Mickael
M
Tanter
Patrick
P
Tabeling
D000818:Animals; D004337:Drug Carriers; D016503:Drug Delivery Systems; D019793:Fluorescein / Q000494:pharmacology; D005456:Fluorescent Dyes / Q000494:pharmacology; D008099:Liver / Q000473:pathology; D008297:Male; D044085:Microfluidics; D011336:Probability; D051381:Rats; D017207:Rats, Sprague-Dawley; D015203:Reproducibility of Results; D013997:Time Factors; D014465:Ultrasonics; D014463:Ultrasonography / Q000295:instrumentation* / Q000379:methods*
D004337:Drug Carriers; D005456:Fluorescent Dyes; D019793:Fluorescein