Fabrication of deoxycholic acid-modified polymeric micelles and their transmembrane transport

doi:10.5246/jcps.2021.01.002

Abstract

Abstract:

Oral administration is the best way for the most patients due to the good compliance, and intestinal epithelium is the main barrier of oral drug absorption. In order to overcome the small intestine epithelial barrier to orally deliver water-insoluble drugs, deoxycholic acid (DA), a substrate of the intestinal bile acid transporters, conjugated poly(2-ethyl-2-oxazoline)-poly(D,L-lactide) (DA-PEOz-PLA) was designed and synthesized, and deoxycholic acid-modified polymeric micelles composed of DA-PEOz-PLA and mPEG-PLA were fabricated to encapsulate model drug coumarin 6 (C6) based on intestinal bile acid pathway. The structure of DA-PEOz-PLA was confirmed using 1H NMR and TLC, and the molecular weight measured by GPC was 10 034 g/mol with a PDI of 1.51. The C6-loaded polymeric micelles with drug loading content of 0.085% were characterized to have 40.11 nm in diameter and uniform spherical morphology observed by TEM. Furthermore, the deoxycholic acid-modified polymeric micelles were demonstrated to further enhance the transmembrane transport efficiency. The mechanic study evidenced that anchorage of deoxycholic acid onto the micelles surface enriched their transcellular transport pathway. Therefore, the designed deoxycholic acid-modified polymeric micelles might have a promising potential for oral delivery of water-insoluble drugs.

Key words: Deoxycholic acid, Intestinal bile acid transporter, Polymeric micelles, Oral nano drug delivery system, Transmembrane transport

Supporting:

Qi Liu, Leqi Wang, Xinping Hu, Chuhang Zhou, Yingwei Tang, Yining Ma, Xiaoxiao Wang, Yan Liu. Fabrication of deoxycholic acid-modified polymeric micelles and their transmembrane transport[J]. Journal of Chinese Pharmaceutical Sciences, 2021, 30(1): 17-26.

Figures/Tables 6

References 19

[1]	Gaucher, G.; Satturwar, P.; Jones, M.C.; Furtos, A.; Leroux, J.C. Polymeric micelles for oral drug delivery. Eur. J. Pharm. Biopharm. 2010, 76, 147–158.
[2]	Deng, Y.Q. Preparation and characterization of intestine PepT1-targeted calcium carbonate nanoparticles. J. Chin. Pharm. Sci. 2018, 27, 397–407.
[3]	Savjani, K.T.; Gajjar, A.K.; Savjani, J.K. ChemInform abstract: drug solubility: importance and enhancement techniques. ChemInform. 2013, doi: 10.1002/chin.201326246.
[4]	Kalepu, S.; Nekkanti, V. Insoluble drug delivery strategies: review of recent advances and business prospects. Acta Pharm. Sin. B. 2015, 5, 442–453
[5]	Reddy, M.S.; Gurram, A.K.; Deshpande, P.B.; Kar, S.S.; Nayak, U.; Udupa, N. Role of components in the formation of self-microemulsifying drug delivery systems. Indian J. Pharm. Sci. 2015, 77, 249.
[6]	Pridgen, E.M.; Alexis, F.; Farokhzad, O.C. Polymeric nanoparticle drug delivery technologies for oral delivery applications. Expert. Opin. Drug Deliv. 2015, 12, 1459–1473.
[7]	Atuma, C.; Strugala, V.; Allen, A.; Holm, L. The adherent gastrointestinal mucus gel layer: thickness and physical state in vivo. Am. J. Physiol. Gastrointest. Liver Physiol. 2001, 280, G922–G929.
[8]	Varma, M.V.S.; Ambler, C.M.; Ullah, M.; Rotter, C.J.; Sun, H.; Litchfield, J.; Fenner, K.S.; El-Kattan, A. Targeting intestinal transporters for optimizing oral drug absorption. Curr. Drug Metab. 2010, 11, 730–742.
[9]	Jin, Y.; Liu, Q.; Zhou, C.H.; Hu, X.P.; Wang, L.Q.; Han, S.D.; Zhou, Y.H.; Liu, Y. Intestinal oligopeptide transporter PepT1-targeted polymeric micelles for further enhancing the oral absorption of water-insoluble agents. Nanoscale. 2019, 11, 21433–21448.
[10]	He, C.Y. Preparation and characterization of intestinal transporter-targeted polymeric micelles. J. Chin. Pharm. Sci. 2018, 27, 490–497.
[11]	Alrefai, W.A.; Gill, R.K. Bile acid transporters: structure, function, regulation and pathophysiological implications. Pharm. Res. 2007, 24, 1803–1823.
[12]	Balakrishnan, A.; Polli, J.E. Apical sodium dependent bile acid transporter (ASBT, SLC10A2): a potential prodrug target. Mol. Pharmaceutics. 2006, 3, 223–230.
[13]	Chiang, J.Y. Bile Acid Metabolism and Signaling. Compr Physiol. 2013, 3, 1191–1212.
[14]	Park, J.W.; Jeon, O.C.; Kim, S.K.; Al-Hilal, T.A.; Jin, S.J.; Moon, H.T.; Yang, V.C.; Kim, S.Y.; Byun, Y. High antiangiogenic and low anticoagulant efficacy of orally active low molecular weight heparin derivatives. J. Control. Release. 2010, 148, 317–326.
[15]	Fan, W.W.; Xia, D.N.; Zhu, Q.L.; Li, X.Y.; He, S.F.; Zhu, C.L.; Guo, S.Y.; Hovgaard, L.; Yang, M.S.; Gan, Y. Functional nanoparticles exploit the bile acid pathway to overcome multiple barriers of the intestinal epithelium for oral insulin delivery. Biomaterials. 2018, 151, 13–23.
[16]	Park, J.; Choi, J.U.; Kim, K.; Byun, Y. Bile acid transporter mediated endocytosis of oral bile acid conjugated nanocomplex. Biomaterials. 2017, 147, 145–154.
[17]	Fan, W.W.; Xia, D.N.; Zhu, Q.L.; Hu, L.; Gan, Y. Intracellular transport of nanocarriers across the intestinal epithelium. Drug Discov. Today. 2016, 21, 856–863.
[18]	He, B.; Lin, P.; Jia, Z.R.; Du, W.W.; Qu, W.; Yuan, L.; Dai, W.B.; Zhang, H.; Wang, X.Q.; Wang, J.C.; Zhang, X.; Zhang, Q. The transport mechanisms of polymer nanoparticles in Caco-2 epithelial cells. Biomaterials. 2013, 34, 6082–6098.
[19]	Annaba, F.; Sarwar, Z.; Kumar, P.; Saksena, S.; Turner, J.R.; Dudeja, P.K.; Gill, R.K.; Alrefai, W.A. Modulation of ileal bile acid transporter (ASBT) activity by depletion of plasma membrane cholesterol: association with lipid rafts. Am. J. Physiol. Gastrointest. Liver Physiol. 2008, 294, G489–G497.