AAPS PharmSciTech

, 20:30 | Cite as

5β-Cholanic Acid/Glycol Chitosan Self-Assembled Nanoparticles (5β-CHA/GC-NPs) for Enhancing the Absorption of FDs and Insulin by Rat Intestinal Membranes

  • Chengyun Yan
  • Jiwei Gu
  • Yuguang Lv
  • Weiguo Shi
  • Zhan Huang
  • Ying Liao
Research Article


The absorption-enhancing effects of glycol chitosan modified by 5β-cholanic acid nanoparticles (5β-CHA/GC-NPs) on a drug with poor absorption in the intestine were studied by the method of in situ closed loop. We chose fluorescein isothiocyanate-labeled dextrans (FDs) and insulin as the model drugs. 5β-CHA/GC-NPs loaded to different drugs were prepared by the dialysis method, and the physicochemical characteristics and in vitro release profiles of nanoparticles were also estimated. The results showed that 5β-CHA/GC-NPs markedly increased the absorption of insulin and FDs in the jejunum, ileum, and colon. The ratios of absorption for all the drugs in the jejunum were higher than those in the ileum and colon. In addition, the enhancing effect of 5β-CHA/GC-NPs for the absorption of FDs from the jejunum was decreased with increasing molecular weights. In the toxicity test, 5β-CHA/GC-NPs did not significantly increase the release of protein and the activities of LDH, indicating that the nanoparticles did not cause any membrane damage to the intestine. These findings suggested that 5β-CHA/GC-NPs were safe and useful carriers for enhancing the absorption of the drug with poor absorption by intestinal membranes.


5β-cholanic acid/glycol chitosan self-assembled nanoparticles intestinal absorption poorly absorbable drugs 


Funding Information

We sincerely thank the National Natural Science Foundation of China (No. 31860266) and the Program of GuangXi Provincial Natural Science Foundation of China (No. 2018JJA140093) for the financial support.


  1. 1.
    Niu Z, Conejos-Sánchez I, Griffin BT, O’Driscoll CM, Alonso MJ. Lipid-based nanocarriers for oral peptide delivery. Adv Drug Deliv Rev. 2016;106(PtB):337–54.CrossRefGoogle Scholar
  2. 2.
    Yin T, Zhang Y, Liu Y, Chen Q, Fu Y, Liang J, et al. The efficiency and mechanism of N-octyl-O, N-carboxymethyl chitosan-based micelles to enhance the oral absorption of silybin. Int J Pharm. 2017;536(1):231–40.CrossRefGoogle Scholar
  3. 3.
    Arafat M, Kirchhoefer C, Mikov M, Sarfraz M, Löbenberg R. Nanosized liposomes containing bile salt: a vesicular nanocarrier for enhancing oral bioavailability of BCS class III drug. J Pharm Pharm Sci. 2017;20:305–18.CrossRefGoogle Scholar
  4. 4.
    Pooja D, Kulhari H, Kuncha M, Rachamalla SS, Adams DJ, Bansal V, et al. Improving efficacy, oral bioavailability, and delivery of paclitaxel using protein-grafted solid lipid nanoparticles. Mol Pharm. 2016;13(11):3903–12.CrossRefGoogle Scholar
  5. 5.
    Mooranian A, Negrulj R, Mathavan S, Martinez J, Sciarretta J, Chen-Tan N, et al. An advanced microencapsulated system: a platform for optimized oral delivery of antidiabetic drug-bile acid formulations. Pharm Dev Technol. 2015;20(6):702–9.CrossRefGoogle Scholar
  6. 6.
    Janes KA, Calvo P, Alonso MJ. Polysaccharide colloidal particles as delivery systems for macromolecules. Adv Drug Deliv Rev. 2001;47:83–97.CrossRefGoogle Scholar
  7. 7.
    Lehr CM, Bouwstra JA, Schacht E, Junginger HE. In vitro evaluation of mucoadhesive properties of chitosan and some other natural polymers. Int J Pharm. 1992;78:43–8.CrossRefGoogle Scholar
  8. 8.
    Aspden TJ, Mason JD, Jones NS. Chitosan as a nasal delivery system: the effect of chitosan solutions on in vitro and in vivo mucociliary transport rates in human turbinates and volunteers. J Pharm Sci. 1997;86:509–13.CrossRefGoogle Scholar
  9. 9.
    Barbari GR, Dorkoosh FA, Amini M, Sharifzadeh M, Atyabi F, Balalaie S, et al. A novel nanoemulsion-based method to produce ultrasmall, water-dispersible nanoparticles from chitosan, surface modified with cell-penetrating peptide for oral delivery of proteins and peptides. Int J Nanomedicine. 2017;12:3471–83.CrossRefGoogle Scholar
  10. 10.
    Hecq J, Siepmann F, Siepmann J, Amighi K, Goole J. Development and evaluation of chitosan and chitosan derivative nanoparticles containing insulin for oral administration. Drug Dev Ind Pharm. 2015;41(12):2037–44.CrossRefGoogle Scholar
  11. 11.
    Sonaje K, Chuang EY, Lin KJ, Yen TC, Su FY, Tseng MT, et al. Opening of epithelial tight junctions and enhancement of paracellular permeation by chitosan: microscopic, ultrastructural, and computed-tomographic observations. Mol Pharm. 2012;9(5):1271–9.CrossRefGoogle Scholar
  12. 12.
    Mao HQ, Roy K, Troung-Le VL, Janes KA, Lin KY, Wang Y, et al. Chitosan-DNA nanoparticles as gene carriers: synthesis, characterization and transfection efficiency. J Control Release. 2001;70:399–421.CrossRefGoogle Scholar
  13. 13.
    Yinbo P, Chenlu S, Chuanfeng Y, Qige G, Min Y. Low molecular weight chitosan-coated silver nanoparticles are effective for the treatmentof MRSA-infected wounds. Int J Nanomedicine. 2017;12:295–304.Google Scholar
  14. 14.
    Zeng L, Qin C, Wang W, Chi W, Li W. Absorption and distribution of chitosan in mice after oral administration. Carbohydr Polym. 2008;71:435–40.CrossRefGoogle Scholar
  15. 15.
    Prego C, Torres D, Fernandez-Megia E, Novoa-Carballal R, Quiñoá E, Alonso MJ. Chitosan–PEG nanocapsules as new carriers for oral peptide delivery. Effect of chitosan pegylation degree. J Control Release. 2006;111(3):299–308.CrossRefGoogle Scholar
  16. 16.
    Yhee JY, Son S, Kim SH, Park K, Choi K, Kwon IC. Self-assembled glycol chitosan nanoparticles for disease-specific theranostics. J Control Release. 2014;193:202–13.CrossRefGoogle Scholar
  17. 17.
    Lee SJ, Koo H, Jeong H, Huh MS, Choi Y, Jeong SY, et al. Comparative study of photosensitizer loaded and conjugated glycol chitosan nanoparticles for cancer therapy. J Control Release. 2011;152:21–9.CrossRefGoogle Scholar
  18. 18.
    Tieshi L, Lara L, Froilan GM, Timothy JM, Yun Y, Anna S. Use of glycol chitosan modified by 5β-cholanic acid nanoparticles for the sustained release of proteins during murine embryonic limb skeletogenesis. J Control Release. 2010;144(1):101–8.CrossRefGoogle Scholar
  19. 19.
    Hyung GJ, Kyung HM, Tae HN, Seong JN, Jae HP, Seo YJ. Prolonged antidiabetic effect of zinc-crystallized insulin loaded glycol chitosan nanoparticles in type 1 diabetic rats. Arch Pharm Res. 2008;31(7):918–23.CrossRefGoogle Scholar
  20. 20.
    Park JH, Cho YW, Chung H, Kwon IC, Jeong SY. Synthesis and characterization of sugar-bearing chitosan derivatives: aqueous solubility and biodegradability. Biomacromolecules. 2003;4(4):1087–91.CrossRefGoogle Scholar
  21. 21.
    Zheng Y, Wu Y, Yang W, Wang C, Fu S, Shen X. Preparation, characterization, and drug release in vitro of chitosan-glycyrrhetic acid nanoparticles. J Pharm Sci. 2005;95(1):181–91.CrossRefGoogle Scholar
  22. 22.
    Farnaz E, Mohammad HG, Behnaz E, Mohammad RK, Fatemeh A, Rassoul D. PLGA nanoparticles of different surface properties: preparation and evaluation of their body distribution. Int J Pharmaceut. 2008;349(1):249–55.Google Scholar
  23. 23.
    Fetih G, Habib F, Okada N, Fujita T, Attia M, Yamamoto A. Nitricoxide donors can enhance the intestinal transport and absorption of insulin and [Asu1,7]-eel calcitonin in rats. J Control Release. 2005;106:287–97.CrossRefGoogle Scholar
  24. 24.
    Chengyun Y, Jiwei G, Yuguang L, Weiguo S, Hongying J. Improved intestinal absorption of water-soluble drugs by acetylation of G2 PAMAM dendrimer nanocomplexes in rat. Drug Deliv Transl Res. 2017;7:408–15.CrossRefGoogle Scholar
  25. 25.
    Koo H, Min KH, Lee SC, Park JH, Park K, Jeong SY, et al. Enhanced drug-loading and therapeutic efficacy of hydrotropic oligomer-conjugated glycol chitosan nanoparticles for tumor-targeted paclitaxel delivery. J Control Release. 2013;172:823–31.CrossRefGoogle Scholar
  26. 26.
    Lamprecht A, Schafer U, Lehr CM. Size-dependent bioadhesion of micro- and nanoparticulate carriers to the inflamed colonic mucosa. Pharm Res. 2001;18:788–93.CrossRefGoogle Scholar
  27. 27.
    Kim JH, Kim YS, Kim S, Park JH, Kim K, Choi K, et al. Hydrophobically modified glycol chitosan nanoparticles as carriers for paclitaxel. J Control Release. 2006;111:228–34.CrossRefGoogle Scholar
  28. 28.
    Kwon S, Park JH, Chung H, Kwon IC, Jeong SY. Physicochemical characteristics of self-assembled nanoparticles based on glycol chitosan bearing 5-cholanic acid. Langmuir. 2003;19(24):10188–93.CrossRefGoogle Scholar
  29. 29.
    Takeuchi H, Yamamoto H, Kawashima Y. Mucoadhesive nanoparticulate systems for peptide drug delivery. Adv Drug Deliv Rev. 2001;47:39–55.CrossRefGoogle Scholar
  30. 30.
    Takeuchi H, Matsui Y, Yamamoto H, Kawashima Y. Mucoadhesive liposomes coated with chitosan or carbopol for oral administration of peptide drugs. In: Proceedings of 26th international symposiumon controlled release of bioactive materials; 1999. p. 988–9.Google Scholar
  31. 31.
    Park JH, Kwon S, Nam JO, Park RW, Chung H, Seo SB, et al. Self-assembled nanoparticles based on glycol chitosan bearing 5beta-cholanic acid for RGD peptide delivery. J Control Release. 2004;95:579–88.CrossRefGoogle Scholar
  32. 32.
    Kim JH, Kim YS, Park K, Kang E, Lee S, Nam HY, et al. Self-assembled glycol chitosan nanoparticles for the sustained and prolonged delivery of antiangiogenic small peptide drugs in cancer therapy. Biomaterials. 2008;29:1920–30.CrossRefGoogle Scholar
  33. 33.
    Yuan Z, Ye Y, Gao F, Yuan H, Lan M, Lou K, et al. Chitosan-graft-β-cyclodextrin nanoparticles as a carrier for controlled drug release. Int J Pharm. 2013;446:191–8.CrossRefGoogle Scholar
  34. 34.
    Park K, Hong HY, Moon HJ, Lee BH, Kim IS, Kwon IC, et al. A new atherosclerotic lesion probe based on hydrophobically modified chitosan nanoparticles functionalized by the atherosclerotic plaque targeted peptides. J Control Release. 2008;128(3):217–23.CrossRefGoogle Scholar
  35. 35.
    Yamabe K, Kato Y, Onishi H, Machida Y. Potentiality of double liposomes containing salmon calcitonin as an oral dosage form. J Control Release. 2003;20:429–36.CrossRefGoogle Scholar
  36. 36.
    Lee VHL, Yamamoto A, Kompella UB. Mucosal penetration enhancers for facilitation of peptide and protein drug absorption. Crit Rev Ther Drug Carrier Syst. 1991;8:91–2.PubMedGoogle Scholar

Copyright information

© American Association of Pharmaceutical Scientists 2019

Authors and Affiliations

  • Chengyun Yan
    • 1
  • Jiwei Gu
    • 2
  • Yuguang Lv
    • 3
  • Weiguo Shi
    • 3
  • Zhan Huang
    • 2
  • Ying Liao
    • 1
  1. 1.College of PharmacyGuilin Medical UniversityGuilinChina
  2. 2.First Affiliated Hospital of Jiamusi UniversityJiamusiChina
  3. 3.College of PharmacyJiamusi UniversityJiamusiChina

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