Studies of Mucosal Irritation and Cellular Uptake Mechanisms of Xingnaojing Nanoemulsion
DOI:
https://doi.org/10.1590/s2175-97902022e20241Keywords:
Nasal ciliotoxicity, Endocytosis, Energy-dependent, MicropinocytosisAbstract
Xingnaojing (XNJ) injection was used to treat pneumonia and stroke in clinic in China, but with poor patient compliance. Xingnaojing nanoemulsion for intranasal delivery was developed to improve it. This article tried to evaluate the mucosal irritation of Xingnaojing nanoemulsion and investigate cellular uptake mechanism of its encapsulated lipophilic drugs. The toad palate model and rat nasal mucosa model were used to study the nasal ciliotoxicity and nasal mucosal irritation of nanoemulsion to evaluate its safety intranasally. The cellular uptake mechanism was studied by Calu-3 cell model. Coumarin 6 was encapsulated in nanoemulsion and the endocytic pathways were studied by cellular uptake experiments after being treated with different inhibitors. In toad palate model, the cilia movement of Xingnaojing nanoemulsion group last for 467.40 ± 39.02 min, which was obviously longer than deoxycholate group (90.60 ± 15.40 min). Studies on rats showed that the damage caused by nanemulsion is capable of being recovered. Nanoemulsion uptake was reduced obviously when cells were treated with wortmannin, and it also decreased about 13% when the temperature reduced from 37ºC to 4ºC. Mucosal irritation caused by nanoemulsion is low and the damage is recoverable. The cellular uptake of Xingnaojing nanoemulsion is energy-dependent, and macropinocytosis was the most important pathway for cellular uptake.
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Ahmad E, Feng Y, Qi J, Fan W, Ma Y, He H, et al. Evidence of nose-to-brain delivery of nanoemulsions: cargoes but not vehicles. Nanoscale. 2017;9(3):1174-1183.
Batrakova EV, Li S, Elmquist WF, Miller DW, Alakhov VY, Kabanov AV. Mechanism of sensitization of MDR cancer cells by Pluronic block copolymers: Selective energy depletion. Brit J Cancer. 2001;85(12):1987-1997.
Cai Z, Song XR, Sun F, Yang ZX, Hou SX, Liu ZQ. Formulation and evaluation of in situ gelling systems for intranasal administration of gastrodin. AAPS Pharmscitech. 2011;12(4):1102-1109.
Chen ZZ, Gong X, Lu Y, Du SY, Yang ZH, Bai J, et al. Enhancing effect of borneol and muscone on geniposide transport across the human nasal epithelial cell monolayer. PLoS ONE. 2014;9(7):e101414.
Chu K, Chen L, Xu W, Li H, Zhang YQ, Xie WR, et al. Preparation of a paeonol-containing temperature-sensitive in situ gel and its preliminary efficacy on allergic rhinitis. Int J Mol Sci. 2013;14(3):6499-6515.
Comfort C, Garrastazu G, Pozzoli M, Sonvico F. Opportunities and challenges for the nasal administration of nanoemulsions. Curr Top Med Chem. 2015;15(4):356-368.
Eley JG, Pujari VD, Mclane J. Poly (lactideco-glycolide) nanoparticles containing coumarin-6 for suppository delivery: in vitro release profile and in vivo tissue distribution. Drug Deliv. 2004;11(4):255-261.
Foerg C, Ziegler U, Fernandez-Carneado J, Giralt E, Merkle HP. Differentiation Restricted Endocytosis of Cell Penetrating Peptides in MDCK sells Corresponds with Activities of Rho-GTPases. Pharm Res-Dordr. 2007;24(4):628-642.
Graff CL, Pollack GM. Nasal drug administration: potential for targeted central nervous system delivery. J Pharm Sci-US. 2005;94(6):1187-1195.
Gratton SEA, Napier ME, Ropp PA, Tian SM, DeSimone JM. Microfabricated Particles for Engineered Drug Therapies: Elucidation into the Mechanisms of Cellular Internalization of PRINT Particles. Pharm Res. 2008;25(12):2845-2852.
Gromnicova R, Kaya M, Romero IA, Williams P, Satchell S, Sharrack B, et al. Transport of Gold Nanoparticles by Vascular Endothelium from Different Human Tissues. PLoS ONE . 2016;11(8):e0161610.
Huang JJ, Tan D, Wang Y, Liu CH, Xu JM, Wang JY. Egg drop syndrome virus enters duck embryonic fibroblast cells via clathrin-mediated endocytosis. Virus Res. 2015;210:69-76.
Illum L. Is nose-to-brain transport of drugs in man a reality? J Pharm Pharmacol. 2010;56(1):3-17.
Kadan S, Saad B, Sasson Y, Zaid H. In Vitro Evaluations of cytotoxicity of eight antidiabetic medicinal plants and their effect on GLUT4 translocation. Evid-Based Compl Alt. 2013;2013:549345.
Kameswara RS, Rao PBB, Begum SS, Srivani A, Soundarya O, Kanakavally R. Nasal drug delivery: A potential route for brain targeting. Indo Am J Pharm Sci. 2015;2(3):692-698.
Kennedy CR, Tilkens SB, Guan H, Garner JA, Or PMY, Chan AM. Differential sensitivities of glioblastoma cell lines towards metabolic and signaling pathway inhibitions. Cancer Lett. 2013;336(2):299-306.
Kumar M, Misra A, Mishra AK, Mishra P, Pathak K. Mucoadhesive nanoemulsion-based intranasal drug delivery system of olanzapine for brain targeting. J Drug Target. 2008a;16(10):806-814.
Kumar M, Misra A, Babbar AK, Mishra AK, Mishra P, Pathak K. Intranasal nanoemulsion based brain targeting drug delivery system of risperidone. Int J Pharm. 2008b;358(1-2):285-291.
Li P, Zheng GY, Yang Y, Zhang CG, Xiong P, Xu Y, et al. Granzyme B is recovered by natural killer cells via clathrin-dependent endocytosis. Cell Mol Life Sci. 2010;67(18):3197-3208.
Li Y, Song XN, Yi X, Wang RB, Lee SMY, Wang XQ. Zebrafish: A Visual Model To Evaluate the Biofate of Transferrin Receptor-Targeted 7Peptide-Decorated Coumarin 6 Micelles. Acs Appl Mater Inter. 2017;9(44):39048-39058.
Luo C, Sun J, Sun BJ, He ZG. Prodrug-based nanoparticulate drug delivery strategies for cancer therapy. Trends Pharmacol Sci. 2014;35(11):12-22.
Martens K, Hellings PW, Steelant B. Calu-3 epithelial cells exhibit different immune and epithelial barrier responses from freshly isolated primary nasal epithelial cells in vitro Clin Transl Allergy. 2018;8(1):40.
Na LD, Mao SR, Wang J, Sun W. Comparison of different absorption enhancers on the intranasal absorption of isosorbide dinitrate in rats. Int J Pharm . 2010;397(1-2):59-66.
Pangeni R, Sharma S, Mustafa G, Ali J, Baboota S. Vitamin E loaded resveratrol nanoemulsion for brain targeting for the treatment of Parkinson’s disease by reducing oxidative stress. Nanotechnology. 2014;25(48):485102.
Ruigrok MJR, De Lange ECM. Emerging insights for translational pharmacokinetic and pharmacokinetic-pharmacodynamic studies: towards prediction of nose-to-brain transport in humans. AAPS J. 2015;17(3):493-505.
Sanders NN, Smedt SCD, Demeester J. The physical properties of biogels and their permeability for macromolecular drugs and colloidal drug carriers. J Pharm Sci. 2000;89(7):835-849.
Wang AJ, Li X, Wang H. Nasal mucosa and mucociliary toxicity study of compound tetramethylpyrazine. Pharmacol Clin Chin Materia Medica. 2016;32(1):141-145.
Wang S, Du SY, Lu Y, Chen XL, Song X, Li DY. Study on in vitro release of xingnaojing microemulsion. China J Chinese Materia Med. 2011;36(16):2196-2198.
Wang Z, Zhao Z, Li PY, Du SY, Sun J, Lu Y, et al. Determination of adhesive property and release behaviors of Fufang Danshen adhesive pellets. J Liaocheng Univ (Nat Sci Ed). 2019;32(4):6-10+33.
Wen R. Pharmacokinetics and brain targeting of active components of Xingnaojing copolymer modified microemulsion. Master Thesis, Beijing University of Chinese Medicine, Beijing, China, 2014.
Yang B, Du SY, Lu Y, Jia S, Zhao MD, Bai J, et al. Influence of paeoniflorin and menthol on puerarin transport across MDCK and MDCK-MDR1 cells as blood-brain barrier in vitro model. J Pharm Pharmacol . 2017;70(3)349-360.
Zhu KD, Zheng J, Li H, Xu W, Xie WR, Xia YF. Studies on ciliotoxicity of nasal thermosensible gels of Chinese medicine Xingbi. J Pharm Sci-CHN. 2012;21(1):76-80.
Zhang L, Du SY, Lu Y, Liu C, Tian ZH, Yang C, Wu HC, Wang Z. Puerarin transport across a Calu-3 cell monolayer -an in vitro model of nasal mucosa permeability and the influence of paeoniflorin and menthol. Drug Des Dev Ther. 2016;10:2227-2237.
Zhang L, Du SY, Lu Y, Liu C, Wu HC, Tian ZH, et al. Puerarin transport across rat nasal epithelial cells and the influence of compatibility with peoniflorin and menthol. Drug Des Dev Ther . 2017;11:2581-2593.
Zhang Y, Li PY, Xu B, Du SY. Advances and applications in a new drug delivery system-in situ gel. J Liaocheng Univ (Nat Sci Ed) . 2020;33(5):88-96.
Zhang YJ, Peng HS, Huang SH, You FT. Preparation and analysis of fluorescent properties of Coumarin 6-doped polymer/alkoxysilane hybrid nanoparticles. Chin J Lumin. 2013;34(12):1555-1560.
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