Transdermal delivery of a readthrough-inducing drug: a new approach of gentamicin administration for the treatment of nonsense mutation-mediated disorders.
To induce the readthrough of premature termination codons, aminoglycoside antibiotics such as gentamicin have attracted interest as potential therapeutic agents for diseases caused by nonsense mutations. The transdermal delivery of gentamicin is considered unfeasible because of its low permeability through the dermis. However, if the skin permeability of gentamicin could be improved, it would allow topical application without the need for systemic delivery. In this report, we demonstrated that the skin permeability of gentamicin increased with the use of a thioglycolate-based depilatory agent. After transdermal administration, the readthrough activity in skeletal muscle, as determined using a lacZ/luc reporter system, was found to be equivalent to systemic administration when measured in transgenic mice. Transdermally applied gentamicin was detected by liquid chromatography-tandem mass spectrometry in the muscles and sera of mice only after depilatory agent-treatment. In addition, expansion of the intercellular gaps in the basal and prickle-cell layers was observed by electron microscopy only in the depilatory agent-treated mice. Depilatory agent-treatment may be useful for the topical delivery of readthough-inducing drugs for the rescue of nonsense mutation-mediated genetic disorders. This finding may also be applicable for the transdermal delivery of other pharmacologically active molecules.
Shiozuka
Masataka
M
Department of Life Sciences, Graduate school of Arts and Sciences, The University of Tokyo, 3-8-1 Komaba, Meguro-ku, Tokyo, Japan.
Wagatsuma
Akira
A
Kawamoto
Tadafumi
T
Sasaki
Hiroyuki
H
Shimada
Kenichi
K
Takahashi
Yoshikazu
Y
Nonomura
Yoshiaki
Y
Matsuda
Ryoichi
R
D000279:Administration, Cutaneous; D000818:Animals; D001485:Basement Membrane / Q000187:drug effects / Q000648:ultrastructure; D018389:Codon, Nonsense / Q000187:drug effects*; D016189:Dystrophin / Q000235:genetics; D004817:Epidermis / Q000187:drug effects / Q000648:ultrastructure; D005110:Extracellular Space / Q000187:drug effects; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects; D017930:Genes, Reporter; D030342:Genetic Diseases, Inborn / Q000188:drug therapy*; D005839:Gentamicins / Q000008:administration & dosage* / Q000097:blood / Q000378:metabolism / Q000493:pharmacokinetics*; D006204:Hair Removal / Q000379:methods; D008297:Male; D051379:Mice; D008812:Mice, Hairless; D008822:Mice, Transgenic; D018482:Muscle, Skeletal / Q000187:drug effects / Q000378:metabolism; D010539:Permeability; D014176:Protein Biosynthesis / Q000187:drug effects*; D012879:Skin Physiological Phenomena / Q000187:drug effects; D013864:Thioglycolates / Q000494:pharmacology; D014018:Tissue Distribution; D051598:Whole Body Imaging
D018389:Codon, Nonsense; D016189:Dystrophin; D005839:Gentamicins; D013864:Thioglycolates