Topical delivery of anti-sense oligonucleotides using low-frequency sonophoresis.
OBJECTIVE
Topical delivery of oligonucleotides, though attractive for the treatment of skin disorders, is limited by the low permeability of the stratum corneum. Herein, we assessed the potential of low-frequency ultrasound (20 kHz, 2.4 W/cm2) in delivering therapeutically significant quantities of anti-sense oligonucleotides into skin.


METHODS
Dermal penetration of oligonucleotides penetration was quantified in vitro using radiolabeled oligonucleotides.


RESULTS
Estimated concentrations of oligonucleotides (ODNs) in the superficial layers of the skin ranged from approximately 0.5% to 5% of the donor concentration after a 10-min application of ultrasound and ODN. Microscopic evaluations using fluorescently labeled oligonucleotides and sulforhodamine B revealed heterogeneous penetration into the skin. Heterogenous penetration led to the formation of localized transport pathways (LTPs), which occupied about 5% of the total exposed skin area. Immuno-histochemical studies using an oligonucleotide that reacts specifically with an antibody also confirmed penetration of ODNs into LTPs. Histologic studies revealed that no gross structural changes were induced in the skin due to ultrasound application.


CONCLUSIONS
These results show successful delivery of anti-sense oligonucleotides using low-frequency ultrasound.
Tezel
Ahmet
A
Department of Chemical Engineering, University of California Santa Barbara, Santa Barbara, California 93106, USA.
Dokka
Sujatha
S
Kelly
Susan
S
Hardee
Gregory E
GE
Mitragotri
Samir
S
D000287:Administration, Topical; D000818:Animals; D016503:Drug Delivery Systems / Q000379:methods*; D016376:Oligonucleotides, Antisense / Q000008:administration & dosage* / Q000493:pharmacokinetics; D015612:Phonophoresis / Q000379:methods*; D012869:Skin Absorption / Q000187:drug effects* / Q000502:physiology; D013552:Swine
D016376:Oligonucleotides, Antisense