Abstract
MUC1 gene encodes a transmembrane mucin glycoprotein that is overexpressed in human breast cancer and colon cancer. The objective of this study was to develop an in situ gel delivery system containing paclitaxel (PTX) and mucoadhesives for sustained and targeted delivery of anticancer drugs. The delivery system consisted of chitosan and glyceryl monooleate (GMO) in 0.33M citric acid containing PTX. The in vitro release of PTX from the gel was performed in presence and absence of Tween 80 at drug loads of 0.18%, 0.30%, and 0.54% (wt/wt), in Sorensen’s phosphate buffer (pH 7.4) at 37°C. Different mucin-producing cell lines (Calu-3>Caco-2) were selected for PTX transport studies. Transport of PTX from solution and gel delivery system was performed in side by side diffusion chambers from apical to basal (A-B) and basal to apical (B-A) directions. In vitro release studies revealed that within 4 hours, only 7.61%±0.19%, 12.0%±0.98%, 31.7%±0.40% of PTX were released from 0.18%, 0.30%, and 0.54% drugloaded gel formulation, respectively, in absence of Tween 80. However, in presence of surfactant (0.05% wt/vol) in the dissolution medium, percentages of PTX released were 28.1%±4.35%, 44.2%±6.35%, and 97.1%±1.22%, respectively. Paclitaxel has shown a polarized transport in all the cell monolayers with B-A transport 2 to 4 times higher than in the A-B direction. The highest mucin-producing cell line (Calu-3) has shown the lowest percentage of PTX transport from gels as compared with Caco-2 cells. Transport of PTX from mucoadhesive gels was shown to be influenced by the mucin-producing capability of cell.
Keywords: paclitaxel, in situ gel, Caco-2, Calu-3, mucin
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References
- 1.Gendler SJ. MUC 1, the renaissance molecule. J Mammary Gland Biol Neoplasia. 2001;6:339–353. doi: 10.1023/A:1011379725811. [DOI] [PubMed] [Google Scholar]
- 2.Schroeder JA, Thompson MC, Gardner MM, Gendler S. Transgenic MUC1 interacts with epidermal growth factor receptor and correlates with mitogen-activated protein kinase activation in the mouse mammary gland. J Biol Chem. 2001;276:13057–13064. doi: 10.1074/jbc.M011248200. [DOI] [PubMed] [Google Scholar]
- 3.Hamada T, Matsukita S, Goto M, et al. Mucin expression in pleomorphic adenoma of salivarygland: a potential role for MUC1 as a marker to predict recurrence. J Clin Pathol. 2006;57:813–821. doi: 10.1136/jcp.2003.014043. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 4.Schiff PB, Horwitz SB. Taxol stabilizes microtubules in mouse fibroblast cells. Proc Natl Acad Sci USA. 1980;77:1561–1565. doi: 10.1073/pnas.77.3.1561. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 5.Schiff PB, Horwitz SB. Promotion of microtubule assembly in vitro by Taxol. Nature. 1979;277:665–667. doi: 10.1038/277665a0. [DOI] [PubMed] [Google Scholar]
- 6.Eiseman JL, Edington ND, Leslie J, et al. Plasma pharmokinetics and tissue distribution of paclitaxel in CD2 F1 mice. Can Chemother Pharmacol. 1994;34:465–471. doi: 10.1007/BF00685656. [DOI] [PubMed] [Google Scholar]
- 7.Brooks TA, Minderman H, O’Loughlin KL, et al. Taxane-based reversal agents modulate drug resistance mediated by P-glycoprotein, multidrug resistant protein, and breast cancer resistance protein. Mol Cancer Ther. 2003;2:1195–1205. [PubMed] [Google Scholar]
- 8.Trissel LA. Pharmaceutical properties of paclitaxel and their effects on preparation and administration. Pharmacotherapy. 1997;17:133s–139s. [PubMed] [Google Scholar]
- 9.Chandy T, Sharma CP. Chitosan—as a biomaterial. Biomater Artif Cells Artif Organs. 1990;18:1–24. doi: 10.3109/10731199009117286. [DOI] [PubMed] [Google Scholar]
- 10.Fiebrig I, Harding SE, Rowe AJ, Hyman SC, Davis SS. Transmission electron microscopy on pig gastric mucin and its interaction with chitosan. Carbohydr Polym. 1995;28:239–244. doi: 10.1016/0144-8617(95)00105-0. [DOI] [Google Scholar]
- 11.He P, Davis SS, Illum L. In vitro evaluation of the mucoadhesive properties of chitosan microspheres. Int J Pharm. 1998;166:75–88. doi: 10.1016/S0378-5173(98)00027-1. [DOI] [Google Scholar]
- 12.Lueßen HL, Lehr CM, Rentel CO, et al. Bioadhesive polymers for the peroral delivery of peptides drugs. J Control Release. 1994;29:329–338. doi: 10.1016/0168-3659(94)90078-7. [DOI] [Google Scholar]
- 13.Shah JC, Sadhale Y, Chilukuri DM. Cubic phase gels as drug delivery systems. Adv Drug Deliv Rev. 2001;47:229–250. doi: 10.1016/S0169-409X(01)00108-9. [DOI] [PubMed] [Google Scholar]
- 14.Dash AK, Gong Z, Miller DW, Huai-Yan H, Laforet J. Development of a rectal nicotine delivery system for the treatment of ulcerative colitis. Int J Pharm. 1999;190:21–34. doi: 10.1016/S0378-5173(99)00221-5. [DOI] [PubMed] [Google Scholar]
- 15.Nielsen LS, Schubert L, Hansen J. Bioadhesive drug delivery systems in characterization of mucoadhesive properties of systems based on glyceryl monooleate and glyceryl monolinoleate. Eur J Pharm Sci. 1998;6:231–239. doi: 10.1016/S0928-0987(97)10004-5. [DOI] [PubMed] [Google Scholar]
- 16.Ganguly S, Dash AK. A novel in situ gel for sustained drug delivery and targeting. Int J Pharm. 2006;276:83–92. doi: 10.1016/j.ijpharm.2004.02.014. [DOI] [PubMed] [Google Scholar]
- 17.Dash AK, Miller DW, Huai-Yan H, Carnazzo J, Stout JR. Evaluation of creatine transport using Caco-2 monolayers as an in vitro model for intestinal absorption. J Pharm Sci. 2001;90:1593–1598. doi: 10.1002/jps.1109. [DOI] [PubMed] [Google Scholar]
- 18.Higuchi T. Rate of release of medicaments from ointment bases containing drugs in suspensions. J Pharm Sci. 1961;50:874–875. doi: 10.1002/jps.2600501018. [DOI] [PubMed] [Google Scholar]
- 19.Cho YW, Lee J, Lee SC, Huh KM, Park K. Hydrotropic agents for study of in vitro Paclitaxel release from polymeric micelles. J Control Release. 2006;97:249–257. doi: 10.1016/j.jconrel.2004.03.013. [DOI] [PubMed] [Google Scholar]
- 20.Walle UK, Walle T. Taxol transport by human intestinal epithelial Caco-2 cells. Drug Metab Dispos. 1998;26:343–346. [PubMed] [Google Scholar]
- 21.Hamilton KO, Backstrom G, Yazdanian MA, Audus KL. P-glycoprotein efflux pump expression and activity in Calu-3 cells. J Pharm Sci. 2001;90:647–658. doi: 10.1002/1520-6017(200105)90:5<647::AID-JPS1021>3.0.CO;2-G. [DOI] [PubMed] [Google Scholar]