The effectiveness of synthetic methoxylated isoflavones in delivering to the skin and alleviating psoriasiform lesions via topical absorption

Chih-Hua Tseng; Chwan-Fwu Lin; Ibrahim A Aljuffali; Jhao-Rong Huang; Sien-Hung Yang; Jia-You Fang

doi:10.1016/j.ijpharm.2022.121629

The effectiveness of synthetic methoxylated isoflavones in delivering to the skin and alleviating psoriasiform lesions via topical absorption

Int J Pharm. 2022 Apr 5:617:121629. doi: 10.1016/j.ijpharm.2022.121629. Epub 2022 Mar 1.

Authors

Chih-Hua Tseng¹, Chwan-Fwu Lin², Ibrahim A Aljuffali³, Jhao-Rong Huang⁴, Sien-Hung Yang⁵, Jia-You Fang⁶

Affiliations

¹ Department of Fragrance and Cosmetic Science, College of Pharmacy, Kaohsiung Medical University, Kaohsiung, Taiwan; School of Pharmacy, College of Pharmacy, Kaohsiung Medical University, Kaohsiung, Taiwan; Drug Development and Value Creation Research Center, Kaohsiung Medical University, Kaohsiung, Taiwan; Department of Medical Research, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan; Department of Pharmacy, Kaohsiung Municipal Ta-Tung Hospital, Kaohsiung, Taiwan.
² Department of Cosmetic Science, Chang Gung University of Science and Technology, Kweishan, Taoyuan, Taiwan; Research Center for Food and Cosmetic Safety and Research Center for Chinese Herbal Medicine, Chang Gung University of Science and Technology, Kweishan, Taoyuan, Taiwan; Department of Anesthesiology, Chang Gung Memorial Hospital, Kweishan, Taoyuan, Taiwan.
³ Department of Pharmaceutics, College of Pharmacy, King Saud University, Riyadh, Saudi Arabia.
⁴ Pharmaceutics Laboratory, Graduate Institute of Natural Products, Chang Gung University, Kweishan, Taoyuan, Taiwan.
⁵ School of Traditional Chinese Medicine, College of Medicine, Chang Gung University, Kweishan, Taoyuan, Taiwan; Division of Chinese Internal Medicine, Center for Traditional Chinese Medicine, Chang Gung Memorial Hospital, Kweishan, Taoyuan, Taiwan. Electronic address: dryang@mail.cgu.edu.tw.
⁶ Research Center for Food and Cosmetic Safety and Research Center for Chinese Herbal Medicine, Chang Gung University of Science and Technology, Kweishan, Taoyuan, Taiwan; Department of Anesthesiology, Chang Gung Memorial Hospital, Kweishan, Taoyuan, Taiwan; Pharmaceutics Laboratory, Graduate Institute of Natural Products, Chang Gung University, Kweishan, Taoyuan, Taiwan. Electronic address: fajy@mail.cgu.edu.tw.

PMID: 35245633
DOI: 10.1016/j.ijpharm.2022.121629

Abstract

This study was conducted to appraise the possible potential of synthetic isoflavones (SIFs) on psoriasis treatment. A practical and easy-to-operate approach was employed in synthesizing a series of SIFs, considering that acquiring flavonoids from natural resources is usually expensive, time-consuming, and non-eco-friendly. Seven SIFs derived from daidzein were produced with differences in the location of the hydroxyl groups and degree of methoxylation. The in vitro and in vivo skin absorption of topically applied SIFs was estimated. Further, keratinocytes (HaCaT) were employed as the model to investigate the anti-inflammatory activity of the isoflavones. The lipophilicity was increased from SIF-1 to -7. Noteworthily, there was a parabolic relationship between lipophilicity and skin absorption, with SIF-5 (4',7-dihydroxyisoflavone, daidzein) and SIF-6 (7-hydroxy-3',4'-dimethoxyisoflavone, cladrin) demonstrating the highest retention in pig skin. The methoxylated isoflavone SIF-5 showed the greatest permeation into barrier-deficient skin among the compounds tested, with a 6- and 8-fold increase after lipid and protein removal. The cell-based study exhibited the capability of SIFs to restrain the overexpressed IL-6, IL-8, and CXCL1 in stimulated HaCaT. The therapeutic index (TI) predicted the potential candidates of SIF-5 and SIF-6 for topical application to treat psoriatic inflammation. The imiquimod (IMQ)-driven psoriasiform murine model manifested the inhibition of hyperplasia and immune cell infiltration by topically administered SIF-5 and SIF-6. The epidermal thickness of IMQ-treated skin was decreased from 172 to 40 μm by both isoflavones. This effect was comparable with that of betamethasone, the positive control. The topical treatment of SIF-6 significantly reduced cytokine/chemokine upregulation by IMQ. The methoxylated isoflavone with dramatic anti-inflammatory activity is promising for the development of an antipsoriatic agent.

Keywords: Anti-inflammation; Chemical synthesis; Isoflavone; Percutaneous absorption; Psoriasis.

MeSH terms

Animals
Disease Models, Animal
Imiquimod / pharmacology
Isoflavones* / pharmacology
Keratinocytes
Mice
Mice, Inbred BALB C
Psoriasis* / pathology
Skin
Swine

Substances

Isoflavones
Imiquimod