Enhancement of oral bioavailability and anti-colitis effect of luteolin-loaded polymer micelles with RA (rosmarinic acid)-SS-mPEG as carrier

AbstractObjective Polymer micelles were prepared (L-RSPMs) with luteolin and synthetic RA-SS-mPEG polymeric material before evaluation of their anti-inflammatory effect on 2, 4, 6-trinitro-benzene-sulfonic acid (TNBS)-induced ulcerative colitis (UC) model in rats.Methods The synthetic RA-SS-mPEG was characterized with NMR spectroscopy, before preparation of luteolin-coated RA-SS-mPEG polymer micelles. The in vitro characterization and evaluation of the formulation were accomplished, couple with its pharmacokinetic parameters. The levels of PEG2, MDA, CRP and GSH, as well as concentrations of TNF-α, IL1-β, IL-6 and IL-10 in serum and colon tissue were detected via ELISA kit. The degree of colon injury and inflammation was evaluated via histopathologic examination.Results L-RSPMs displayed small average droplet size (133.40 ± 4.52 nm), uniformly dispersed (PDI: 0.163 ± 0.011), good stability, slow release and enhanced solubility. We observed 353.28% increase in the relative bioavailability of L-RSPMs compared to free luteolin, while the half-life of the micelle was extended by 6.16h. Compared to model (M) group, luteolin (low and high doses) and L-RSPMs (low and high doses) significantly reduced levels of MDA, PEG2, CRP, TNF-α, IL-6 and IL-1β in colon tissue and serum of colitic rats but dose dependently increased IL-10 and SOD levels (p < 0.01). Histopathologic examination of colon showed that luteolin (low and high doses) and L-RSPMs (low and high doses) improved colonic inflammation in colitic rats to varying degrees compared to M group.Conclusion L-RSPMs could improve TNBS-induced colon inflammation by enhancing bioavailability, promoting antioxidant effects and regulating cytokine release, which may become a potential agent for UC treatment in clinical settings.Keywords: Polymeric micellesbioavailabilityRA-SS-mPEGluteolinulcerative colitis AcknowledgementsThe authors are gracious to the ethics committee of Jiangsu University for guiding the conduct of animal experiments.Ethical approvalResearch experiments conducted in this article with animals or humans were approved by the Ethical Committee and responsible authorities of our research organization(s) following all guidelines, regulations, legal, and ethical standards as required for humans or animals.Author contributionsConceptualization, Zhaomin Lu, Juan Liu, Liangjian Zhao, Chenli Wang, Feng Shi, Zhengqi Li, Xuesong Liu and Zhiwei Miao; Methodology, Zhaomin Lu; Validation, Juan Liu and Liangjian Zhao; Formal Analysis, Zhaomin Lu, Juan Liu and Liangjian Zhao; Data Curation, Feng Shi and Zhengqi Li; Writing – Original Draft Preparation, Zhaomin Lu and Juan Liu; Writing – Review & Editing, Zhiwei Miao; Project Administration, Xuesong Liu.Disclosure statementNo potential conflict of interest was reported by the author(s).Data availability statementThe data presented in this study are available on request from the corresponding author.Additional informationFundingThis research was funded by the National Natural Science Foundation of China [82104792]; Natural Science Foundation of Jiangsu Province [BK20210134]; Natural Science Foundation of Nanjing University of Chinese Medicine [XZR2020059]; Industry university cooperation collaborative education project, Ministry of Education [202102242007]; and the Project of National Clinical Research Base of Traditional Chinese Medicine in Jiangsu Province,China [JD2022SZ19].