Overcoming oral insulin delivery barriers: application of cell penetrating peptide and silica-based nanoporous composites

  • Huining He
  • Junxiao Ye
  • Jianyong Sheng
  • Jianxin Wang
  • Yongzhuo Huang
  • Guanyi Chen
  • Jingkang Wang
  • Victor C. Yang
Review Article


Oral insulin delivery has received the most attention in insulin formulations due to its high patient compliance and, more importantly, to its potential to mimic the physiologic insulin secretion seen in non-diabetic individuals. However, oral insulin delivery has two major limitations: the enzymatic barrier that leads to rapid insulin degradation, and the mucosal barrier that limits insulin’s bioavailability. Several approaches have been actively pursued to circumvent the enzyme barrier, with some of them receiving promising results. Yet, thus far there has been no major success in overcoming the mucosal barrier, which is the main cause in undercutting insulin’s oral bioavailability. In this review of our group’s research, an innovative silica-based, mucoadhesive oral insulin formulation with encapsulated-insulin/cell penetrating peptide (CPP) to overcome both enzyme and mucosal barriers is discussed, and the preliminary and convincing results to confirm the plausibility of this oral insulin delivery system are reviewed. In vitro studies demonstrated that the CPPinsulin conjugates could facilitate cellular uptake of insulin while keeping insulin’s biologic functions intact. It was also confirmed that low molecular weight protamine (LMWP) behaves like a CPP peptide, with a cell translocation potency equivalent to that of the widely studied TAT. The mucoadhesive properties of the produced silica-chitosan composites could be controlled by varying both the pH and composition; the composite consisting of chitosan (25 wt-%) and silica (75 wt-%) exhibited the greatest mucoadhesion at gastric pH. Furthermore, drug release from the composite network could also be regulated by altering the chitosan content. Overall, the universal applicability of those technologies could lead to development of a generic platform for oral delivery of many other bioactive compounds, especially for peptide or protein drugs which inevitably encounter the poor bioavailability issues.


insulin cell penetrating peptide mucoadhesive composites oral delivery 


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  1. 1.
    Capaldi B. Treatments and devices for future diabetes management. Nursing Times, 2005, 101(18): 30–32Google Scholar
  2. 2.
    Cobble M E. Initiating and intensifying insulin therapy for type 2 diabetes: why, when, and how. American Journal of Therapeutics, 2009, 16(1): 56–64CrossRefGoogle Scholar
  3. 3.
    Prevention Cf DCa. National diabetes fact sheet general information and national estimates on diabetes in the United States. Centers for Disease Control and Prevention, 2003Google Scholar
  4. 4.
    Heinemann L. New ways of insulin delivery. International Journal of Clinical Practice. Supplement, 2011, 65(170): 31–46CrossRefGoogle Scholar
  5. 5.
    Gordon Still J. Development of oral insulin: progress and current status. Diabetes/Metabolism Research and Reviews, 2002, 18(S1): S29–S37CrossRefGoogle Scholar
  6. 6.
    Heinemann L. New ways of insulin delivery. International Journal of Clinical Practice. Supplement, 2010, 64: 29–40CrossRefGoogle Scholar
  7. 7.
    Reis C P, Damge C. Nanotechnology as a promising strategy for alternative routes of insulin delivery. Methods in Enzymology, 2012, 508: 271–294CrossRefGoogle Scholar
  8. 8.
    Fonte P, Andrade F, Araujo F, Andrade C, Neves J, Sarmento B. Chitosan-coated solid lipid nanoparticles for insulin delivery. Methods in Enzymology, 2012, 508: 295–314CrossRefGoogle Scholar
  9. 9.
    Card J W, Magnuson B A. A review of the efficacy and safety of nanoparticle-based oral insulin delivery systems. American Journal of Physiology. Gastrointestinal and Liver Physiology, 2011, 301(6): G956–G967CrossRefGoogle Scholar
  10. 10.
    He P, Tang Z, Lin L, Deng M, Pang X, Zhuang X, Chen X. Novel biodegradable and pH-sensitive poly(ester amide) microspheres for oral insulin delivery. Macromolecular Bioscience, 2012, 12(4): 547–556CrossRefGoogle Scholar
  11. 11.
    Cefalu W T. Concept, strategies, and feasibility of noninvasive insulin delivery. Diabetes Care, 2004, 27(1): 239–246CrossRefGoogle Scholar
  12. 12.
    Krishnankutty R K, Mathew A, Sedimbi S K, Suryanarayan S, Sanjeevi C B. Alternative routes of insulin delivery. Zhong Nan Da Xue Xue Bao. Yi Xue Ban, 2009, 34(10): 933–948Google Scholar
  13. 13.
    Bellary S, Barnett A H. Inhaled insulin: new technology, new possibilities. International Journal of Clinical Practice, 2006, 60(6): 728–734CrossRefGoogle Scholar
  14. 14.
    Cefalu W T. Evolving strategies for insulin delivery and therapy. Drugs, 2004, 64(11): 1149–1161CrossRefGoogle Scholar
  15. 15.
    Sajeesh S, Bouchemal K, Marsaud V, Vauthier C, Sharma C P. Cyclodextrin complexed insulin encapsulated hydrogel microparticles: An oral delivery system for insulin. Journal of Controlled Release, 2010, 147(3): 377–384CrossRefGoogle Scholar
  16. 16.
    Yadav N, Morris G, Harding S E, Ang S, Adams G G. Various non-injectable delivery systems for the treatment of diabetes mellitus. Endocrine, Metabolic & Immune Disorders Drug Targets, 2009, 9(1): 1–13CrossRefGoogle Scholar
  17. 17.
    Banting F G, Best C H, Collip J B, Campbell W R, Fletcher A A. Pancreatic extracts in the treatment of diabetes mellitus. Canadian Medical Association Journal, 1922, 12(3): 141–146Google Scholar
  18. 18.
    Del Curto M D, Maroni A, Palugan L, Zema L, Gazzaniga A, Sangalli M E. Oral delivery system for two-pulse colonic release of protein drugs and protease inhibitor/absorption enhancer compounds. Journal of Pharmaceutical Sciences, 2011, 100(8): 3251–3259CrossRefGoogle Scholar
  19. 19.
    Jelvehgari M, Milani P Z, Siahi-Shadbad M R, Monajjemzadeh F, Nokhodchi A, Azari Z, Valizadeh H. In vitro and in vivo evaluation of insulin microspheres containing protease inhibitor. Arzneimittel-Forschung, 2011, 61(1): 14–22CrossRefGoogle Scholar
  20. 20.
    Su F Y, Lin K J, Sonaje K, Wey S P, Yen T C, Ho Y C, Panda N, Chuang E Y, Maiti B, Sung HW. Protease inhibition and absorption enhancement by functional nanoparticles for effective oral insulin delivery. Biomaterials, 2012, 33(9): 2801–2811CrossRefGoogle Scholar
  21. 21.
    Marschutz M K, Bernkop-Schnurch A. Oral peptide drug delivery: polymer-inhibitor conjugates protecting insulin from enzymatic degradation in vitro. Biomaterials, 2000, 21(14): 1499–1507CrossRefGoogle Scholar
  22. 22.
    Saudek C D. Novel forms of insulin delivery. Endocrinology and Metabolism Clinics of North America, 1997, 26(3): 599–610CrossRefGoogle Scholar
  23. 23.
    Avadi M R, Sadeghi A M, Mohammadpour N, Abedin S, Atyabi F, Dinarvand R, Rafiee-Tehrani M. Preparation and characterization of insulin nanoparticles using chitosan and Arabic gum with ionic gelation method. Nanomedicine; Nanotechnology, Biology, and Medicine, 2010, 6(1): 58–63Google Scholar
  24. 24.
    Cui F, He C, He M, Tang C, Yin L, Qian F, Yin C. Preparation and evaluation of chitosan-ethylenediaminetetraacetic acid hydrogel films for the mucoadhesive transbuccal delivery of insulin. Journal of Biomedical Materials Research. Part A, 2009, 89(4): 1063–1071CrossRefGoogle Scholar
  25. 25.
    Cui F, Qian F, Zhao Z, Yin L, Tang C, Yin C. Preparation, characterization, and oral delivery of insulin loaded carboxylated chitosan grafted poly(methyl methacrylate) nanoparticles. Biomacromolecules, 2009, 10(5): 1253–1258CrossRefGoogle Scholar
  26. 26.
    Schilling R, Mitra A. Degradation of insulin by trypsin and alpha-chymotrypsin. Pharmaceutical Research, 1991, 8(6): 721–727CrossRefGoogle Scholar
  27. 27.
    Nishihata T, Rytting J H, Kamada A, Higuchi T. Enhanced intestinal absorption of insulin in rats in the presence of sodium 5-methoxysalicylate. Diabetes, 1981, 30(12): 1065–1067CrossRefGoogle Scholar
  28. 28.
    Cui C Y, Lu W L, Xiao L, Zhang S Q, Huang Y B, Li S L, Zhang R J, Wang G L, Zhang X, Zhang Q. Sublingual delivery of insulin: effects of enhancers on the mucosal lipid fluidity and protein conformation, transport, and in vivo hypoglycemic activity. Biological & Pharmaceutical Bulletin, 2005, 28(12): 2279–2288CrossRefGoogle Scholar
  29. 29.
    Muranishi S. Delivery system design for improvement of intestinal absorption of peptide drugs. Yakugaku Zasshi, 1997, 117(7): 394–414Google Scholar
  30. 30.
    Chung S W, Hil-lal T A, Byun Y. Strategies for non-invasive delivery of biologics. Journal of Drug Targeting, 2012, 20(6): 481–501CrossRefGoogle Scholar
  31. 31.
    Schwarze S R, Ho A, Vocero-Akbani A, Dowdy S F. In vivo protein transduction: delivery of a biologically active protein into the mouse. Science, 1999, 285(5433): 1569–1572CrossRefGoogle Scholar
  32. 32.
    Schwarze S R, Dowdy S F. In vivo protein transduction: intracellular delivery of biologically active proteins, compounds and DNA. Trends in Pharmacological Sciences, 2000, 21(2): 45–48CrossRefGoogle Scholar
  33. 33.
    Cooper I, Sasson K, Teichberg V I, Schnaider-Beeri M, Fridkin M, Shechter Y. Peptide derived from HIV-1 TAT protein, destabilizes a monolayer of endothelial cells in an in vitro model of the bloodbrain barrier, and allows permeation of high molecular weight proteins. Journal of Biological Chemistry, 2012, 287(53): 44676–44678CrossRefGoogle Scholar
  34. 34.
    Yu R, Zeng Z, Guo X, Zhang H, Liu X, Ding Y, Chen J. The TAT peptide endows PACAP with an enhanced ability to traverse biobarriers. Neuroscience Letters, 2012, 527(1): 1–5CrossRefGoogle Scholar
  35. 35.
    Elliott G, O’Hare P. Intercellular trafficking and protein delivery by a herpesvirus structural protein. Cell, 1997, 88(2): 223–233CrossRefGoogle Scholar
  36. 36.
    Min S H, Kim D M, Kim M N, Ge J, Lee D C, Park I Y, Park K C, Hwang J S, Cho CW, Yeom Y I. Gene delivery using a derivative of the protein transduction domain peptide, K-Antp. Biomaterials, 2010, 31(7): 1858–1864CrossRefGoogle Scholar
  37. 37.
    Derossi D, Joliot A H, Chassaing G, Prochiantz A. The third helix of the antennapedia homeodomain translocates through biological membranes. Journal of Biological Chemistry, 1994, 269(14): 10444–10450Google Scholar
  38. 38.
    Jin G S, Zhu G D, Zhao Z G, Liu F S. VP22 enhances the expression of glucocerebrosidase in human Gaucher II fibroblast cells mediated by lentiviral vectors. Clinical and Experimental Medicine, 2012, 12(3): 135–143CrossRefGoogle Scholar
  39. 39.
    Tanaka M, Kato A, Satoh Y, Ide T, Sagou K, Kimura K, Hasegawa H, Kawaguchi Y. Herpes simplex virus 1 VP22 regulates translocation of multiple viral and cellular proteins and promotes neurovirulence. Journal of Virology, 2012, 86(9): 5264–5277CrossRefGoogle Scholar
  40. 40.
    Chang L C, Lee H F, Yang Z, Yang V. Low molecular weight protamine (LMWP) as nontoxic heparin/low molecular weight heparin antidote (I): preparation and characterization. AAPS PharmSci, 2001, 3(3): 7–14CrossRefGoogle Scholar
  41. 41.
    Chang L C, Liang J, Lee H F, Lee L, Yang V. Low molecular weight protamine (LMWP) as nontoxic heparin/low molecular weight heparin antidote (II): in vitro evaluation of efficacy and toxicity. AAPS PharmSci, 2001, 3(3): 15–23CrossRefGoogle Scholar
  42. 42.
    Chang L C, Wrobleski S, Wakefield T, Lee L, Yang V. Low molecular weight protamine as nontoxic heparin/low molecular weight heparin antidote (III): preliminary in vivo evaluation of efficacy and toxicity using a canine model. AAPS PharmSci, 2001, 3(3): 24–31CrossRefGoogle Scholar
  43. 43.
    Park Y J, Chang L C, Liang J F, Moon C, Chung C P, Yang V C. Nontoxic membrane translocation peptide from protamine, low molecular weight protamine (LMWP), for enhanced intracellular protein delivery: in vitro and in vivo study. FASEB Journal, 2005, 19(11): 1555–1557Google Scholar
  44. 44.
    Xia H, Gao X, Gu G, Liu Z, Zeng N, Hu Q, Song Q, Yao L, Pang Z, Jiang X, Chen J, Chen H. Low molecular weight protamine-functionalized nanoparticles for drug delivery to the brain after intranasal administration. Biomaterials, 2011, 32(36): 9888–9898CrossRefGoogle Scholar
  45. 45.
    Ramadas MWP, Dileep K J, Ramadas M, Anitha Y, Sharma C P, 0. Lipoinsulin encapsulated alginate-chitosan capsules: intestinal delivery in diabetic rats. Journal of Microencapsulation, 2000, 17(4): 405–411CrossRefGoogle Scholar
  46. 46.
    Kimura T, Sato K, Sugimoto K, Tao R, Murakami T, Kurosaki Y, Nakayama T. Oral administration of insulin as poly(vinyl alcohol)-gel spheres in diabetic rats. Biological & Pharmaceutical Bulletin, 1996, 19(6): 897–900CrossRefGoogle Scholar
  47. 47.
    Mitchell D J, Steinman L, Kim D T, Fathman C G, Rothbard J B. Polyarginine enters cells more efficiently than other polycationic homopolymers. Journal of Peptide Research, 2000, 56(5): 318–325CrossRefGoogle Scholar
  48. 48.
    Futaki S, Nakase I, Suzuki T, Zhang, Sugiura Y. Translocation of branched-chain arginine peptides through cell membranes: flexibility in the spatial disposition of positive charges in membrane-permeable peptides. Biochemistry, 2002, 41(25): 7925–7930CrossRefGoogle Scholar
  49. 49.
    Wong T W. Chitosan and its use in design of insulin delivery system. Recent Patents on Drug Delivery & Formulation, 2009, 3(1): 8–25CrossRefGoogle Scholar
  50. 50.
    Damge C, Maincent P, Ubrich N. Oral delivery of insulin associated to polymeric nanoparticles in diabetic rats. Journal of Controlled Release, 2007, 117(2): 163–170CrossRefGoogle Scholar
  51. 51.
    Sarmento B, Ribeiro A, Veiga F, Sampaio P, Neufeld R, Ferreira D. Alginate/chitosan nanoparticles are effective for oral insulin delivery. Pharmaceutical Research, 2007, 24(12): 2198–2206CrossRefGoogle Scholar
  52. 52.
    Liang J F, Zhen L, Chang L C, Yang V C. A less toxic heparin antagonist-low molecular weight protamine. Biochemistry. Biokhimiia, 2003, 68(1): 116–120CrossRefGoogle Scholar
  53. 53.
    Tsui B, Singh V K, Liang J F, Yang V C. Reduced reactivity towards anti-protamine antibodies of a low molecular weight protamine analogue. Thrombosis Research, 2001, 101(5): 417–420CrossRefGoogle Scholar
  54. 54.
    Carlsson J, Drevin H, Axén R. Protein thiolation and reversible protein-protein conjugation. N-Succinimidyl 3-(2-pyridyldithio)propionate, a new heterobifunctional reagent. Biochemical Journal, 1978, 173(3): 723–737Google Scholar
  55. 55.
    Chickering D E, Mathiowitz E. Bioadhesive microspheres I. A novel electrobalance-based method to study adhesive interactions between individual microspheres and intestinal mucosa. Journal of Controlled Release, 1995, 34(3): 251–262Google Scholar
  56. 56.
    Sudhakar Y, Kuotsu K, Bandyopadhyay A K. Buccal bioadhesive drug delivery-a promising option for orally less efficient drugs. Journal of Controlled Release, 2006, 114(1): 15–40CrossRefGoogle Scholar

Copyright information

© Higher Education Press and Springer-Verlag Berlin Heidelberg 2013

Authors and Affiliations

  • Huining He
    • 1
    • 4
    • 5
  • Junxiao Ye
    • 1
  • Jianyong Sheng
    • 2
  • Jianxin Wang
    • 2
  • Yongzhuo Huang
    • 2
    • 3
  • Guanyi Chen
    • 4
  • Jingkang Wang
    • 1
  • Victor C. Yang
    • 5
    • 6
  1. 1.School of Chemical Engineering and TechnologyTianjin UniversityTianjinChina
  2. 2.Department of Pharmaceutics, School of PharmacyFudan University; Key Laboratory of Smart Drug Delivery, Ministry of Education & PLAShanghaiChina
  3. 3.Shanghai Institute of Materia MedicaChinese Academy of SciencesShanghaiChina
  4. 4.School of Environmental Science and EngineeringState Key Laboratory of Engines Tianjin UniversityTianjinChina
  5. 5.Tianjin Key Laboratory on Technologies Enabling Development of Clinical Therapeutics and Diagnostics, School of PharmacyTianjin Medical UniversityTianjinChina
  6. 6.Department of Pharmaceutical Sciences, College of PharmacyUniversity of MichiganMichiganUSA

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