TY - JOUR
T1 - Transdermal delivery of a readthrough-inducing drug
T2 - A new approach of gentamicin administration for the treatment of nonsense mutation-mediated disorders
AU - Shiozuka, Masataka
AU - Wagatsuma, Akira
AU - Kawamoto, Tadafumi
AU - Sasaki, Hiroyuki
AU - Shimada, Kenichi
AU - Takahashi, Yoshikazu
AU - Nonomura, Yoshiaki
AU - Matsuda, Ryoichi
N1 - Funding Information:
Health and Labour Sciences Research Grant [19A-020] for Research on Psychiatric and Neurological Diseases and Mental Health, and a Research Grant for Nervous and Mental Disorders [20B-13] from the Ministry of Health, Labour and Welfare, Japan.
PY - 2010/4
Y1 - 2010/4
N2 - 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.
AB - 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.
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U2 - 10.1093/jb/mvp185
DO - 10.1093/jb/mvp185
M3 - Article
C2 - 19910311
AN - SCOPUS:77950597660
VL - 147
SP - 463
EP - 470
JO - Journal of Biochemistry
JF - Journal of Biochemistry
SN - 0021-924X
IS - 4
ER -