Abstract
In this study, nanocomplexes composed of glycyrrhizic acid (GA) derived from the root of the licorice plant (Glycyrrhiza glabra) were formulated for the delivery of curcumin (CUR). Sonication of amphiphilic GA solution with hydrophobic CUR resulted in the production of nanosized complexes with a size of 164.8 ± 51.7 nm, which greatly enhanced the solubility of CUR in aqueous solution. A majority of the CURs were released from these GA/ CUR nanocomplexes within 12 h. GA/CUR nanocomplexes exhibited excellent intracellular uptake in human breast cancer cells (Michigan cancer foundation-7/multi-drug resistant cells), indicating enhanced anti-cancer effects compared to that of free CUR. In addition, GA/CUR nanocomplexes demonstrated high intracellular uptake into macrophages (RAW264.7 cells), consequently reducing the release of the pro-inflammatory cytokine tumor necrosis factor-α. Furthermore, GA/CUR nanocomplexes successfully reduced the levels of serum pro-inflammatory cytokines and splenomegaly in a rheumatoid arthritis model.
Article PDF
Similar content being viewed by others
References
Zhou, X., S. W. Seto, D. Chang, H. Kiat, V. Razmovski-Naumovski, K. Chan, and A. Bensoussan (2016) Synergistic effects of Chinese herbal medicine: a comprehensive review of methodology and current research. Front. Pharmacol. 7: 201.
Jermini, M., J. Dubois, P. Y. Rodondi, K. Zaman, T. Buclin, C. Csajka, A. Orcurto, and L. E. Rothuizen (2019) Complementary medicine use during cancer treatment and potential herb-drug interactions from a cross-sectional study in an academic centre. Sci. Rep. 9: 5078.
Wang, X., H. Zhang, L. Chen, L. Shan, G. Fan, and X. Gao (2013) Liquorice, a unique “guide drug” of traditional Chinese medicine: a review of its role in drug interactions. J. Ethnopharmacol. 150: 781–790.
Song, W., X. Qiao, K. Chen, Y. Wang, S. Ji, J. Feng, K. Li, Y. Lin, and M. Ye (2017) Biosynthesis-based quantitative analysis of 151 secondary metabolites of licorice to differentiate medicinal Glycyrrhiza species and their hybrids. Anal. Chem. 89: 3146–3153.
Tong, T., H. Hu, J. Zhou, S. Deng, X. Zhang, W. Tang, L. Fang, S. Xiao, and J. Liang (2020) Glycyrrhizic-acid-based carbon dots with high antiviral activity by multisite inhibition mechanisms. Small. 16: e1906206.
Zhao, Z., Y. Xiao, L. Xu, Y. Liu, G. Jiang, W. Wang, B. Li, T. Zhu, Q. Tan, L. Tang, H. Zhou, X. Huang, and H. Shan (2021) Glycyrrhizic acid nanoparticles as antiviral and anti-inflammatory agents for COVID-19 treatment. ACS Appl. Mater. Interfaces. 13: 20995–21006.
Ming, L. J. and A. C. Y. Yin (2013) Therapeutic effects of glycyrrhizic acid. Nat. Prod. Commun. 8: 415–418.
Selyutina, O. Y. and N. E. Polyakov (2019) Glycyrrhizic acid as a multifunctional drug carrier - from physicochemical properties to biomedical applications: a modern insight on the ancient drug. Int. J. Pharm. 559: 271–279.
Abdollahi, E., A. A. Momtazi, T. P. Johnston, and A. Sahebkar (2018) Therapeutic effects of curcumin in inflammatory and immune-mediated diseases: a nature-made jack-of-all-trades?. J. Cell. Physiol. 233: 830–848.
Rauf, A., M. Imran, I. E. Orhan, and S. Bawazeer (2018) Health perspectives of a bioactive compound curcumin: a review. Trends Food Sci. Technol. 74: 33–45.
Kharat, M. and D. J. McClements (2019) Recent advances in colloidal delivery systems for nutraceuticals: a case study - Delivery by Design of curcumin. J. Colloid Interface Sci. 557: 506–518.
Stohs, S. J., O. Chen, S. D. Ray, J. Ji, L. R. Bucci, and H. G. Preuss (2020) Highly bioavailable forms of curcumin and promising avenues for curcumin-based research and application: a review. Molecules. 25: 1397.
Naksuriya, O., S. Okonogi, R. M. Schiffelers, and W. E. Hennink (2014) Curcumin nanoformulations: a review of pharmaceutical properties and preclinical studies and clinical data related to cancer treatment. Biomaterials. 35: 3365–3383.
Wang, Y., Y. Li, L. He, B. Mao, S. Chen, V. Martinez, X. Guo, X. Shen, B. Liu, and C. Li (2021) Commensal flora triggered target anti-inflammation of alginate-curcumin micelle for ulcerative colitis treatment. Colloids Surf. B Biointerfaces. 203: 111756.
Wang, Y., B. Zhao, S. Wang, Q. Liang, Y. Cai, F. Yang, and G. Li (2016) Formulation and evaluation of novel glycyrrhizic acid micelles for transdermal delivery of podophyllotoxin. Drug Deliv. 23: 1623–1635.
Yang, F. H., Q. Zhang, Q. Y. Liang, S. Q. Wang, B. X. Zhao, Y. T. Wang, Y. Cai, and G. F. Li (2015) Bioavailability enhancement of paclitaxel via a novel oral drug delivery system: paclitaxelloaded glycyrrhizic acid micelles. Molecules. 20: 4337–4356.
Kharat, M., Z. Du, G. Zhang, and D. J. McClements (2017) Physical and chemical stability of curcumin in aqueous solutions and emulsions: impact of pH, temperature, and molecular environment. J. Agric. Food Chem. 65: 1525–1532.
Tima, S., S. Anuchapreeda, C. Ampasavate, C. Berkland, and S. Okonogi (2017) Stable curcumin-loaded polymeric micellar formulation for enhancing cellular uptake and cytotoxicity to FLT3 overexpressing EoL-1 leukemic cells. Eur. J. Pharm. Biopharm. 114: 57–68.
Choi, E. S., Y. Y. Kang, and H. Mok (2018) Evaluation of the enhanced antioxidant activity of curcumin within exosomes by fluorescence monitoring. Biotechnol. Bioprocess Eng. 23: 150–157.
You, G., Y. Kim, J. H. Lee, J. Song, and H. Mok (2020) Exosomemodified PLGA microspheres for improved internalization into dendritic cells and macrophages. Biotechnol. Bioprocess Eng. 25: 521–527.
Yao, Y. D., X. Y. Shen, J. Machado, J. F. Luo, Y. Dai, C. K. Lio, Y. Yu, Y. Xie, P. Luo, J. X. Liu, X. S. Yao, Z. Q. Liu, and H. Zhou (2019) Nardochinoid B inhibited the activation of RAW264.7 macrophages stimulated by lipopolysaccharide through activating the Nrf2/HO-1 pathway. Molecules. 24: 2482.
Brand, D. D., K. A. Latham, and E. F. Rosloniec (2007) Collagen-induced arthritis. Nat. Protoc. 2: 1269–1275.
Arora, R., A. Kuhad, I. P. Kaur, and K. Chopra (2015) Curcumin loaded solid lipid nanoparticles ameliorate adjuvant-induced arthritis in rats. Eur. J. Pain. 19: 940–952.
Kang, Y. Y., J. Song, J. Y. Kim, H. Jung, W. S. Yeo, Y. Lim, and H. Mok (2019) Byakangelicin as a modulator for improved distribution and bioactivity of natural compounds and synthetic drugs in the brain. Phytomedicine. 62: 152963.
Ma, Y., J. Hao, K. Zhao, Y. Ju, J. Hu, Y. Gao, and F. Du (2019) Biobased polymeric surfactant: natural glycyrrhizic acid-appended homopolymer with multiple pH-responsiveness. J. Colloid Interface Sci. 541: 93–100.
Seidi Damyeh, M., R. Mereddy, M. E. Netzel, and Y. Sultanbawa (2020) An insight into curcumin-based photosensitization as a promising and green food preservation technology. Compr. Rev. Food Sci. Food Saf. 19: 1727–1759.
Selyutina, O. Y., A. V. Mastova, E. A. Shelepova, and N. E. Polyakov (2021) pH-sensitive glycyrrhizin based vesicles for nifedipine delivery. Molecules. 26: 1270.
Kang, Y. Y., J. Y. Kim, J. Song, and H. Mok (2019) Enhanced intracellular uptake and stability of umbelliferone in compound mixtures from Angelica gigas in vitro. J. Pharmacol. Sci. 140: 8–13.
Cai, S., Z. Bi, Y. Bai, H. Zhang, D. Zhai, C. Xiao, Y. Tang, L. Yang, X. Zhang, K. Li, R. Yang, Y. Liu, S. Chen, T. Sun, H. Liu, and C. Yang (2020) Glycyrrhizic acid-induced differentiation repressed stemness in hepatocellular carcinoma by targeting c-Jun N-terminal kinase 1. Front. Oncol. 9: 1431.
Cai, J., S. Luo, X. Lv, Y. Deng, H. Huang, B. Zhao, Q. Zhang, and G. Li (2019) Formulation of injectable glycyrrhizic acidhydroxycamptothecin micelles as new generation of DNA topoisomerase I inhibitor for enhanced antitumor activity. Int. J. Pharm. 571: 118693.
Wang, C. Y., T. C. Kao, W. H. Lo, and G. C. Yen (2011) Glycyrrhizic acid and 18β-glycyrrhetinic acid modulate lipopolysaccharide-induced inflammatory response by suppression of NF-κB through PI3K p110d and p110γ inhibitions. J. Agric. Food Chem. 59: 7726–7733.
Fu, Y., E. Zhou, Z. Wei, X. Song, Z. Liu, T. Wang, W. Wang, N. Zhang, G. Liu, and Z. Yang (2014) Glycyrrhizin inhibits lipopolysaccharide-induced inflammatory response by reducing TLR4 recruitment into lipid rafts in RAW264.7 cells. Biochim. Biophys. Acta. 1840: 1755–1764.
Wang, Q., C. Ye, S. Sun, R. Li, X. Shi, S. Wang, X. Zeng, N. Kuang, Y. Liu, Q. Shi, and R. Liu (2019) Curcumin attenuates collagen-induced rat arthritis via anti-inflammatory and apoptotic effects. Int. Immunopharmacol. 72: 292–300.
Williams, R. O., L. Marinova-Mutafchieva, M. Feldmann, and R. N. Maini (2000) Evaluation of TNF-alpha and IL-1 blockade in collagen-induced arthritis and comparison with combined anti-TNF-alpha/anti-CD4 therapy. J. Immunol. 165: 7240–7245.
Liu, J., Y. Liu, W. Pan, and Y. Li (2021) Angiotensin-(1-7) attenuates collagen-induced arthritis via inhibiting oxidative stress in rats. Amino Acids. 53: 171–181.
Huang, B., Q. T. Wang, S. S. Song, Y. J. Wu, Y. K. Ma, L. L. Zhang, J. Y. Chen, H. X. Wu, L. Jiang, and W. Wei (2012) Combined use of etanercept and MTX restores CD4+/CD8+ ratio and Tregs in spleen and thymus in collagen-induced arthritis. Inflamm. Res. 61: 1229–1239.
Acknowledgements
This study was supported by a grant (NRF-2020R1A2B5B 01001677) from the National Research Foundation funded by the Ministry of Education, Science, and Technology, Korea.
Author information
Authors and Affiliations
Corresponding author
Ethics declarations
The authors declare no conflict of interest.
Neither ethical approval nor informed consent was required for this study.
Additional information
Publisher’s Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Rights and permissions
About this article
Cite this article
Song, J., Kim, J.Y., You, G. et al. Formulation of Glycyrrhizic Acid-based Nanocomplexes for Enhanced Anti-cancer and Anti-inflammatory Effects of Curcumin. Biotechnol Bioproc E 27, 163–170 (2022). https://doi.org/10.1007/s12257-021-0198-7
Received:
Revised:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s12257-021-0198-7