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Article

Energy-Dependent Endocytosis Is Responsible for Skin Penetration of Formulations Based on a Combination of Indomethacin Nanoparticles and l-Menthol in Rat and Göttingen Minipig

by
Hiroko Otake
1,†,
Mizuki Yamaguchi
1,†,
Fumihiko Ogata
1,
Saori Deguchi
1,
Naoki Yamamoto
2,
Hiroshi Sasaki
2,
Naohito Kawasaki
1 and
Noriaki Nagai
1,*
1
Faculty of Pharmacy, Kindai University, 3-4-1 Kowakae, Higashi-Osaka, Osaka 577-8502, Japan
2
Department of Ophthalmology, Kanazawa Medical University, 1-1 Daigaku, Uchinada, Kahoku, Ishikawa 920-0293, Japan
*
Author to whom correspondence should be addressed.
†
These authors contributed equally to this work.
Int. J. Mol. Sci. 2021, 22(10), 5137; https://doi.org/10.3390/ijms22105137
Submission received: 19 April 2021 / Revised: 10 May 2021 / Accepted: 11 May 2021 / Published: 12 May 2021
(This article belongs to the Special Issue Nano-Materials and Methods 3.0)
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Abstract

We previously designed a Carbopol gel formulation (N-IND/MEN) based on a combination of indomethacin solid nanoparticles (IND-NPs) and l-menthol, and we reported that the N-IND/MEN showed high transdermal penetration. However, the detailed mechanism for transdermal penetration of IND-NPs was not clearly defined. In this study, we investigated whether endocytosis in the skin tissue of rat and Göttingen minipig is related to the transdermal penetration of IND-NPs using pharmacological inhibitors of endocytosis. The pharmacological inhibitors used in this study are as follows: 54 µM nystatin, a caveolae-mediated endocytosis (CavME) inhibitor; 40 µM dynasore, a clathrin-mediated endocytosis (CME) inhibitor; and 2 µM rottlerin, a micropinocytosis (MP) inhibitor. The N-IND/MEN was prepared by a bead mill method, and the particle size of solid indomethacin was 79–216 nm. In both rat and Göttingen minipig skin, skin penetration of approximately 80% IND-NPs was limited by the stratum corneum (SC), although the penetration of SC was improved by the combination of l-menthol. On the other hand, the treatment of nystatin and dynasore decreased the transdermal penetration of indomethacin in rats and Göttingen minipigs treated with N-IND/MEN. Moreover, in addition to nystatin and dynasore, rottlerin attenuated the transdermal penetration of IND-NPs in the Göttingen minipigs’ skin. In conclusion, we found that l-menthol enhanced the SC penetration of IND-NPs. In addition, this study suggests that the SC-passed IND-NPs are absorbed into the skin tissue by energy-dependent endocytosis (CavME, CME, and/or MP pathways) on the epidermis under the SC, resulting in an enhancement in transdermal penetration of IND-NPs. These findings provide significant information for the design of nanomedicines in transdermal formulations.
Keywords: nanoparticle; endocytosis; transdermal delivery system; indomethacin; l-menthol nanoparticle; endocytosis; transdermal delivery system; indomethacin; l-menthol
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MDPI and ACS Style

Otake, H.; Yamaguchi, M.; Ogata, F.; Deguchi, S.; Yamamoto, N.; Sasaki, H.; Kawasaki, N.; Nagai, N. Energy-Dependent Endocytosis Is Responsible for Skin Penetration of Formulations Based on a Combination of Indomethacin Nanoparticles and l-Menthol in Rat and Göttingen Minipig. Int. J. Mol. Sci. 2021, 22, 5137. https://doi.org/10.3390/ijms22105137

AMA Style

Otake H, Yamaguchi M, Ogata F, Deguchi S, Yamamoto N, Sasaki H, Kawasaki N, Nagai N. Energy-Dependent Endocytosis Is Responsible for Skin Penetration of Formulations Based on a Combination of Indomethacin Nanoparticles and l-Menthol in Rat and Göttingen Minipig. International Journal of Molecular Sciences. 2021; 22(10):5137. https://doi.org/10.3390/ijms22105137

Chicago/Turabian Style

Otake, Hiroko, Mizuki Yamaguchi, Fumihiko Ogata, Saori Deguchi, Naoki Yamamoto, Hiroshi Sasaki, Naohito Kawasaki, and Noriaki Nagai. 2021. "Energy-Dependent Endocytosis Is Responsible for Skin Penetration of Formulations Based on a Combination of Indomethacin Nanoparticles and l-Menthol in Rat and Göttingen Minipig" International Journal of Molecular Sciences 22, no. 10: 5137. https://doi.org/10.3390/ijms22105137

APA Style

Otake, H., Yamaguchi, M., Ogata, F., Deguchi, S., Yamamoto, N., Sasaki, H., Kawasaki, N., & Nagai, N. (2021). Energy-Dependent Endocytosis Is Responsible for Skin Penetration of Formulations Based on a Combination of Indomethacin Nanoparticles and l-Menthol in Rat and Göttingen Minipig. International Journal of Molecular Sciences, 22(10), 5137. https://doi.org/10.3390/ijms22105137

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