Involvement of endocytosis in the transdermal penetration mechanism of ketoprofen nanoparticles

Noriaki Nagai, Fumihiko Ogata, Miyu Ishii, Yuya Fukuoka, Hiroko Otake, Yosuke Nakazawa, Naohito Kawasaki

Research output: Contribution to journalArticle

5 Citations (Scopus)

Abstract

We previously designed a novel transdermal formulation containing ketoprofen solid nanoparticles (KET-NPs formulation), and showed that the skin penetration from the KET-NPs formulation was higher than that of a transdermal formulation containing ketoprofen microparticles (KET-MPs formulation). However, the precise mechanism for the skin penetration from the KET-NPs formulation was not clear. In this study we investigated whether energy-dependent endocytosis relates to the transdermal delivery from a 1.5% KET-NPs formulation. Transdermal formulations were prepared by a bead mill method using additives including methylcellulose and carbopol 934. The mean particle size of the ketoprofen nanoparticles was 98.3 nm. Four inhibitors of endocytosis dissolved in 0.5% DMSO (54 µM nystatin, a caveolae-mediated endocytosis inhibitor; 40 µM dynasore, a clathrin-mediated endocytosis inhibitor; 2 µM rottlerin, a macropinocytosis inhibitor; 10 µM cytochalasin D, a phagocytosis inhibitor) were used in this study. In the transdermal penetration study using a Franz diffusion cell, skin penetration through rat skin treated with cytochalasin D was similar to the control (DMSO) group. In contrast to the results for cytochalasin D, skin penetration from the KET-NPs formulation was significantly decreased by treatment with nystatin, dynasore or rottlerin with penetrated ketoprofen concentration-time curves (AUC) values 65%, 69% and 73% of control, respectively. Furthermore, multi-treatment with all three inhibitors (nystatin, dynasore and rottlerin) strongly suppressed the skin penetration from the KET-NPs formulation with an AUC value 13.4% that of the control. In conclusion, we found that caveolae-mediated endocytosis, clathrin-mediated endocytosis and macropinocytosis are all related to the skin penetration from the KET-NPs formulation. These findings provide significant information for the design of nanomedicines in transdermal formulations.

Original languageEnglish
Article number2138
JournalInternational Journal of Molecular Sciences
Volume19
Issue number7
DOIs
Publication statusPublished - 2018 Jul 23

Fingerprint

Ketoprofen
Endocytosis
Nanoparticles
Skin
penetration
formulations
nanoparticles
Nystatin
Cytochalasin D
inhibitors
Caveolae
Clathrin
Dimethyl Sulfoxide
Area Under Curve
Nanomedicine
Medical nanotechnology
Methylcellulose
Phagocytosis
Particle Size
Rats

Keywords

  • Endocytosis
  • Ketoprofen
  • Nanoparticle
  • Pharmacological inhibitor
  • Transdermal delivery system

ASJC Scopus subject areas

  • Catalysis
  • Molecular Biology
  • Spectroscopy
  • Computer Science Applications
  • Physical and Theoretical Chemistry
  • Organic Chemistry
  • Inorganic Chemistry

Cite this

Involvement of endocytosis in the transdermal penetration mechanism of ketoprofen nanoparticles. / Nagai, Noriaki; Ogata, Fumihiko; Ishii, Miyu; Fukuoka, Yuya; Otake, Hiroko; Nakazawa, Yosuke; Kawasaki, Naohito.

In: International Journal of Molecular Sciences, Vol. 19, No. 7, 2138, 23.07.2018.

Research output: Contribution to journalArticle

Nagai, Noriaki ; Ogata, Fumihiko ; Ishii, Miyu ; Fukuoka, Yuya ; Otake, Hiroko ; Nakazawa, Yosuke ; Kawasaki, Naohito. / Involvement of endocytosis in the transdermal penetration mechanism of ketoprofen nanoparticles. In: International Journal of Molecular Sciences. 2018 ; Vol. 19, No. 7.
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abstract = "We previously designed a novel transdermal formulation containing ketoprofen solid nanoparticles (KET-NPs formulation), and showed that the skin penetration from the KET-NPs formulation was higher than that of a transdermal formulation containing ketoprofen microparticles (KET-MPs formulation). However, the precise mechanism for the skin penetration from the KET-NPs formulation was not clear. In this study we investigated whether energy-dependent endocytosis relates to the transdermal delivery from a 1.5{\%} KET-NPs formulation. Transdermal formulations were prepared by a bead mill method using additives including methylcellulose and carbopol 934. The mean particle size of the ketoprofen nanoparticles was 98.3 nm. Four inhibitors of endocytosis dissolved in 0.5{\%} DMSO (54 µM nystatin, a caveolae-mediated endocytosis inhibitor; 40 µM dynasore, a clathrin-mediated endocytosis inhibitor; 2 µM rottlerin, a macropinocytosis inhibitor; 10 µM cytochalasin D, a phagocytosis inhibitor) were used in this study. In the transdermal penetration study using a Franz diffusion cell, skin penetration through rat skin treated with cytochalasin D was similar to the control (DMSO) group. In contrast to the results for cytochalasin D, skin penetration from the KET-NPs formulation was significantly decreased by treatment with nystatin, dynasore or rottlerin with penetrated ketoprofen concentration-time curves (AUC) values 65{\%}, 69{\%} and 73{\%} of control, respectively. Furthermore, multi-treatment with all three inhibitors (nystatin, dynasore and rottlerin) strongly suppressed the skin penetration from the KET-NPs formulation with an AUC value 13.4{\%} that of the control. In conclusion, we found that caveolae-mediated endocytosis, clathrin-mediated endocytosis and macropinocytosis are all related to the skin penetration from the KET-NPs formulation. These findings provide significant information for the design of nanomedicines in transdermal formulations.",
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