Inclusion complex of saikosaponin-d with hydroxypropyl-β-cyclodextrin: Improved physicochemical properties and anti-skin cancer activity

Stephen Chu-Sung Hu; Yi-Chien Lai; Chi-Ling Lin; Wen-Sheng Tzeng; Feng-Lin Yen

doi:10.1016/j.phymed.2018.11.012

Inclusion complex of saikosaponin-d with hydroxypropyl-β-cyclodextrin: Improved physicochemical properties and anti-skin cancer activity

Phytomedicine. 2019 Apr:57:174-182. doi: 10.1016/j.phymed.2018.11.012. Epub 2018 Nov 8.

Authors

Stephen Chu-Sung Hu¹, Yi-Chien Lai², Chi-Ling Lin³, Wen-Sheng Tzeng⁴, Feng-Lin Yen⁵

Affiliations

¹ Department of Dermatology, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan; Department of Dermatology, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan; Department of Medical Research, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan; Translational Research Center, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan.
² Department of Dermatology, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan.
³ Department of Dermatology, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan; Department of Dermatology, Kaohsiung Municipal Hsiao-Kang Hospital, Kaohsiung, Taiwan.
⁴ Department of Radiology, Pingtung Christian Hospital, Pingtung, Taiwan. Electronic address: tws4664@gmail.com.
⁵ Department of Fragrance and Cosmetic Science, College of Pharmacy, Kaohsiung Medical University, Kaohsiung, Taiwan; Institute of Biomedical Sciences, National Sun Yat-Sen University, Kaohsiung, Taiwan. Electronic address: flyen@kmu.edu.tw.

PMID: 30776588
DOI: 10.1016/j.phymed.2018.11.012

Abstract

Background: Saikosaponin-d (SSD) is a triterpene saponin isolated from Bupleurum plants. It has been shown to exhibit antioxidant, anti-inflammatory, and anticancer activities. However, its biomedical applications are limited by its poor water solubility. Cyclodextrins are highly water soluble oligosaccharide compounds which can form inclusion complexes with lipophilic drugs.

Purpose: We complexed SSD with hydroxypropyl-β-cyclodextrin (HPBCD) in various ratios to form SSD-HPBCD inclusion complexes. The inclusion complexes were evaluated for their solubility, physicochemical properties and cytotoxic effects in cutaneous squamous cell carcinoma cells.

Methods: Surface morphology of pure SSD and SSD-HPBCD inclusion complexes was evaluated by scanning electron microscopy. Crystalline structure was determined by X-ray diffractometry. Intermolecular hydrogen bond formation between SSD and HPBCD was investigated by Fourier transform infrared spectroscopy. Human cutaneous squamous cell carcinoma HSC-1 cell viability was determined by the MTS assay, and cell apoptosis by the caspase 3/7 assay. Signal transduction pathways were investigated by Western blotting.

Results: SSD-HPBCD inclusion complexes showed greatly increased water solubility. This was associated with an improvement in physicochemical properties, including transformation of crystalline structure to amorphous form, and formation of hydrogen bonds between SSD and HPBCD. In addition, SSD-HPBCD inclusion complexes induced apoptosis in HSC-1 cells, and this was mediated through activation of MAPK and suppression of Akt-mTOR signaling pathways.

Conclusion: SSD-HPBCD inclusion complex shows improvement in water solubility and physicochemical properties, and exhibits anticancer effects against cutaneous squamous cell carcinoma cells. Therefore, it may be a potential drug formulation for the treatment of skin cancer.

Keywords: Apoptosis; Cutaneous squamous cell carcinoma; Hydroxypropyl-β-cyclodextrin; Saikosaponin-d; Solubility.

MeSH terms

2-Hydroxypropyl-beta-cyclodextrin / chemistry*
Antineoplastic Agents, Phytogenic / chemistry
Antineoplastic Agents, Phytogenic / pharmacology*
Bupleurum / chemistry
Carcinoma, Squamous Cell / drug therapy*
Cell Line, Tumor
Crystallography, X-Ray
Drug Compounding
Humans
Hydrogen Bonding
Magnetic Resonance Spectroscopy
Oleanolic Acid / analogs & derivatives*
Oleanolic Acid / chemistry
Oleanolic Acid / pharmacology
Saponins / chemistry
Saponins / pharmacology*
Skin Neoplasms / drug therapy*
Solubility
Spectroscopy, Fourier Transform Infrared
Water

Substances

Antineoplastic Agents, Phytogenic
Saponins
Water
2-Hydroxypropyl-beta-cyclodextrin
Oleanolic Acid
saikosaponin D