Ying Han, Zhonggao Gao, Liqing Chen, Lin Kang, Wei Huang, Mingji Jin, Qiming Wang, You Han Bae. Multifunctional oral delivery systems for enhanced bioavailability of therapeutic peptides/proteins[J]. Acta Pharmaceutica Sinica B, 2019, 9(5): 902-922

Multifunctional oral delivery systems for enhanced bioavailability of therapeutic peptides/proteins
Ying Hana, Zhonggao Gaoa, Liqing Chena, Lin Kanga, Wei Huanga, Mingji Jina, Qiming Wanga, You Han Baeb
a State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Department of Pharmaceutics, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, China;
b Department of Pharmaceutics and Pharmaceutical Chemistry, the University of Utah, Salt Lake City, UT 84108, USA
In last few years, therapeutic peptides/proteins are rapidly growing in drug market considering their higher efficiency and lower toxicity than chemical drugs. However, the administration of therapeutic peptides/proteins is mainly limited in parenteral approach. Oral therapy which was hampered by harsh gastrointestinal environment and poorly penetrating epithelial barriers often results in low bioavailability (less than 1%-2%). Therefore, delivery systems that are rationally designed to overcome these challenges in gastrointestinal tract and ameliorate the oral bioavailability of therapeutic peptides/proteins are seriously promising. In this review, we summarized various multifunctional delivery systems, including lipid-based particles, polysaccharide-based particles, inorganic particles, and synthetic multifunctional particles that achieved effective oral delivery of therapeutic peptides/proteins.
Key words:    Multifunctional delivery systems    Oral    Bioavailability    Macromolecules    Peptides and proteins    Gastrointestinal environment    Epithelial barriers    Nanoparticles   
Received: 2018-09-18     Revised: 2018-10-28
DOI: 10.1016/j.apsb.2019.01.004
Funds: This work was financially supported by the CAMS Innovation Fund for Medical Sciences (CAMS-2017-12M-1-011, China), National Natural Science Foundation of China (81373342), the Fundamental Research Funds for the Central Universities and PUMC Youth Fund (2017350003, China) and PUMC Basic Fund (2018PT35002, China).
Corresponding author: Zhonggao Gao
Author description:
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Ying Han
Zhonggao Gao
Liqing Chen
Lin Kang
Wei Huang
Mingji Jin
Qiming Wang
You Han Bae

1. Aguirre TA, Teijeiro-Osorio D, Rosa M, Coulter IS, Alonso MJ, Brayden DJ. Current status of selected oral peptide technologies in advanced preclinical development and in clinical trials. Adv Drug Deliv Rev 2016;106:223-41.
2. Malhaire H, Gimel JC, Roger E, Benoit JP, Lagarce F. How to design the surface of peptide-loaded nanoparticles for efficient oral bioavailability?. Adv Drug Deliv Rev 2016;106:320-36.
3. Rekha MR, Sharma CP. Oral delivery of therapeutic protein/peptide for diabetes-future perspectives. Int J Pharm 2013;440:48-62.
4. Brayden DJ, Alonso MJ. Oral delivery of peptides:opportunities and issues for translation. Adv Drug Deliv Rev 2016;106:193-5.
5. Gaowa A, Horibe T, Kohno M, Kawakami K. Bile acid as an effective absorption enhancer for oral delivery of epidermal growth factor receptor-targeted hybrid peptide. J Pharm Sci 2018;107:1322-9.
6. Uhl P, Pantze S, Storck P, Parmentier J, Witzigmann D, Hofhaus G, et al. Oral delivery of vancomycin by tetraether lipid liposomes. Eur J Pharm Sci 2017;108:111-8.
7. Uhl P, Helm F, Hofhaus G, Brings S, Kaufman C, Leotta K, et al. A liposomal formulation for the oral application of the investigational hepatitis B drug myrcludex B. Eur J Pharm Biopharm 2016;103:159-66.
8. Parmentier J, Hofhaus G, Thomas S, Cuesta LC, Gropp F, Schroder R, et al. Improved oral bioavailability of human growth hormone by a combination of liposomes containing bio-enhancers and tetraether lipids and omeprazole. J Pharm Sci 2014;103:3985-93.
9. Parmentier J, Thewes B, Gropp F, Fricker G. Oral peptide delivery by tetraether lipid liposomes. Int J Pharm 2011;415:150-7.
10. Bonengel S, Jelkmann M, Abdulkarim M, Gumbleton M, Reinstadler V, Oberacher H, et al. Impact of different hydrophobic ion pairs of octreotide on its oral bioavailability in pigs. J Control Release 2018;273:21-9.
11. Koetting MC, Guido JF, Gupta M, Zhang A, Peppas NA. pHresponsive and enzymatically-responsive hydrogel microparticles for the oral delivery of therapeutic proteins:effects of protein size, crosslinking density, and hydrogel degradation on protein delivery. J Control Release 2016;221:18-25.
12. Li N, Li XR, Zhou YX, Li WJ, Zhao Y, Ma SJ, et al. The use of polyion complex micelles to enhance the oral delivery of salmon calcitonin and transport mechanism across the intestinal epithelial barrier. Biomaterials 2012;33:8881-92.
13. Koetting MC, Peppas NA. pH-Responsive poly(itaconic acid-co-Nvinylpyrrolidone) hydrogels with reduced ionic strength loading solutions offer improved oral delivery potential for high isoelectric point-exhibiting therapeutic proteins. Int J Pharm 2014;471:83-91.
14. Gradauer K, Barthelmes J, Vonach C, Almer G, Mangge H, Teubl B, et al. Liposomes coated with thiolated chitosan enhance oral peptide delivery to rats. J Control Release 2013;172:872-8.
15. Garg V, Kaur P, Singh SK, Kumar B, Bawa P, Gulati M, et al. Solid self-nanoemulsifying drug delivery systems for oral delivery of polypeptide-k:formulation, optimization, in-vitro and in-vivo antidiabetic evaluation. Eur J Pharm Sci 2017;109:297-315.
16. Zupancic O, Rohrer J, Thanh Lam H, Griessinger JA, BernkopSchnurch A. Development and in vitro characterization of selfemulsifying drug delivery system (SEDDS) for oral opioid peptide delivery. Drug Dev Ind Pharm 2017;43:1694-702.
17. Lollo G, Gonzalez-Paredes A, Garcia-Fuentes M, Calvo P, Torres D, Alonso MJ. Polyarginine nanocapsules as a potential oral peptide delivery carrier. J Pharm Sci 2017;106:611-8.
18. Yoshida M, Kamei N, Muto K, Kunisawa J, Takayama K, Peppas NA, et al. Complexation hydrogels as potential carriers in oral vaccine delivery systems. Eur J Pharm Biopharm 2017;112:138-42.
19. Suksamran T, Ngawhirunpat T, Rojanarata T, Sajomsang W, Pitaksuteepong T, Opanasopit P. Methylated N-(4-N,N-dimethylaminocinnamyl) chitosan-coated electrospray OVA-loaded microparticles for oral vaccination. Int J Pharm 2013;448:19-27.
20. Ma T, Wang L, Yang T, Ma G, Wang S. M-cell targeted polymeric lipid nanoparticles containing a Toll-like receptor agonist to boost oral immunity. Int J Pharm 2014;473:296-303.
21. Song Y, Chen L. Effect of net surface charge on physical properties of the cellulose nanoparticles and their efficacy for oral protein delivery. Carbohydr Polym 2015;121:10-7.
22. Kowapradit J, Apirakaramwong A, Ngawhirunpat T, Rojanarata T, Sajomsang W, Opanasopit P. Methylated N-(4-N,N-dimethylaminobenzyl) chitosan coated liposomes for oral protein drug delivery. Eur J Pharm Sci 2012;47:359-66.
23. Mohy Eldin MS, Kamoun EA, Sofan MA, Elbayomi SM. L-Arginine grafted alginate hydrogel beads:a novel pH-sensitive system for specific protein delivery. Arab J Chem 2015;8:355-65.
24. Xu B, Zhang W, Chen Y, Xu Y, Wang B, Zong L. Eudragit® L100-coated mannosylated chitosan nanoparticles for oral protein vaccine delivery. Int J Biol Macromol 2018;113:534-42.
25. de Kruif JK, Ledergerber G, Garofalo C, Fasler-Kan E, Kuentz M. On prilled nanotubes-in-microgel oral systems for protein delivery. Eur J Pharm Biopharm 2016;101:90-102.
26. Christophersen PC, Birch D, Saarinen J, Isomaki A, Nielsen HM, Yang M, et al. Investigation of protein distribution in solid lipid particles and its impact on protein release using coherent anti-stokes Raman scattering microscopy. J Control Release 2015;197:111-20.
27. Christophersen PC, Zhang L, Yang M, Nielsen HM, Mullertz A, Mu H. Solid lipid particles for oral delivery of peptide and protein drugs I -elucidating the release mechanism of lysozyme during lipolysis. Eur J Pharm Biopharm 2013;85:473-80.
28. Lee S, Kim YC, Park JH. Zein-alginate based oral drug delivery systems:protection and release of therapeutic proteins. Int J Pharm 2016;515:300-6.
29. Dunnhaupt S, Barthelmes J, Iqbal J, Perera G, Thurner CC, Friedl H, et al. In vivo evaluation of an oral drug delivery system for peptides based on S-protected thiolated chitosan. J Control Release 2012;160:477-85.
30. Park H, Cho S, Janat-Amsbury MM, Bae YH. Enhanced thermogenic program by non-viral delivery of combinatory browning genes to treat diet-induced obesity in mice. Biomaterials 2015;73:32-41.
31. Sneh-Edri H, Likhtenshtein D, Stepensky D. Intracellular targeting of PLGA nanoparticles encapsulating antigenic peptide to the endoplasmic reticulum of dendritic cells and its effect on antigen crosspresentation in vitro. Mol Pharm 2011;8:1266-75.
32. Soudry-Kochavi L, Naraykin N, Nassar T, Benita S. Improved oral absorption of exenatide using an original nanoencapsulation and microencapsulation approach. J Control Release 2015;217:202-10.
33. Sukyung A, In-Hyun L, Eunhye L, Hyungjun K, Yong-Chul K, Sangyong J. Oral delivery of an anti-diabetic peptide drug via conjugation and complexation with low molecular weight chitosan. J Control Release 2013;170:226-32.
34. Nguyen HN, Wey SP, Juang JH, Sonaje K, Ho YC, Chuang EY, et al. The glucose-lowering potential of exendin-4 orally delivered via a pH-sensitive nanoparticle vehicle and effects on subsequent insulin secretion in vivo. Biomaterials 2011;32:2673-82.
35. Kong JH, Oh EJ, Chae SY, Lee KC, Hahn SK. Long acting hyaluronate-exendin 4 conjugate for the treatment of type 2 diabetes. Biomaterials 2010;31:4121-8.
36. Zhang L, Shi Y, Song Y, Sun X, Zhang X, Sun K, et al. The use of low molecular weight protamine to enhance oral absorption of exenatide. Int J Pharm 2018;547:265-73.
37. Mengshu W, Yong Z, Bingxue S, Yanan S, Xin G, Yongge W, et al. Permeability of exendin-4-loaded chitosan nanoparticles across MDCK cell monolayers and rat small intestine. Biol Pharm Bull 2014;37:740-7.
38. Menzel C, Holzeisen T, Laffleur F, Zaichik S, Abdulkarim M, Gumbleton M, et al. In vivo evaluation of an oral self-emulsifying drug delivery system (SEDDS) for exenatide. J Control Release 2018;277:165-72.
39. Araujo F, Shrestha N, Shahbazi MA, Liu D, Herranz-Blanco B, Makila EM. Microfluidic assembly of a multifunctional tailorable composite system designed for site specific combined oral delivery of peptide drugs. ACS Nano 2015;9:8291-302.
40. Araujo F, Shrestha N, Gomes MJ, Herranz-Blanco B, Liu D, Hirvonen JJ, et al. In vivo dual-delivery of glucagon like peptide-1(GLP-1) and dipeptidyl peptidase-4(DPP4) inhibitor through composites prepared by microfluidics for diabetes therapy. Nanoscale 2016;8:10706-13.
41. Al-Quraishy S, Dkhil MA, Moneim AEA. Anti-hyperglycemic activity of selenium nanoparticles in streptozotocin-induced diabetic rats. Int J Nanomed 2015;10:6741-56.
42. Alibolandi M, Alabdollah F, Sadeghi F, Mohammadi M, Abnous K, Ramezani M, et al. Dextran-b-poly(lactide-co-glycolide) polymersome for oral delivery of insulin:in vitro and in vivo evaluation. J Control Release 2016;227:58-70.
43. Andreani T, de Souza AL, Kiill CP, Lorenzon EN, Fangueiro JF, Calpena AC, et al. Preparation and characterization of PEG-coated silica nanoparticles for oral insulin delivery. Int J Pharm 2014;473:627-35.
44. Chaturvedi K, Ganguly K, Nadagouda MN, Aminabhavi TM. Polymeric hydrogels for oral insulin delivery. J Control Release 2013;165:129-38.
45. He H, Sheng J, David AE, Kwon YM, Zhang J, Huang Y, et al. The use of low molecular weight protamine chemical chimera to enhance monomeric insulin intestinal absorption. Biomaterials 2013;34:7733-43.
46. He P, Liu H, Tang Z, Deng M, Yang Y, Pang X, et al. Poly(ester amide) blend microspheres for oral insulin delivery. Int J Pharm 2013;455:259-66.
47. Hosseininasab S, Pashaei-Asl R, Khandaghi AA, Nasrabadi HT, Nejati-Koshki K, Akbarzadeh A, et al. Synthesis, characterization, and in vitro studies of PLGA-PEG nanoparticles for oral insulin delivery. Chem Biol Drug Des 2014;84:307-15.
48. Kim SK, Lee S, Jin S, Moon HT, Jeon OC, Lee DY, et al. Diabetes correction in pancreatectomized canines by orally absorbable insulindeoxycholate complex. Mol Pharm 2010;7:708-17.
49. Karamanidou T, Karidi K, Bourganis V, Kontonikola K, Kammona O, Kiparissides C. Effective incorporation of insulin in mucus permeating self-nanoemulsifying drug delivery systems. Eur J Pharm Biopharm 2015;97:223-9.
50. Li X, Guo S, Zhu C, Zhu Q, Gan Y, Rantanen J, et al. Intestinal mucosa permeability following oral insulin delivery using core shell corona nanolipoparticles. Biomaterials 2013;34:9678-87.
51. Maroni A, Del Curto MD, Salmaso S, Zema L, Melocchi A, Caliceti P, et al. In vitro and in vivo evaluation of an oral multiple-unit formulation for colonic delivery of insulin. Eur J Pharm Biopharm 2016;108:76-82.
52. Niu M, Lu Y, Hovgaard L, Guan P, Tan Y, Lian R, et al. Hypoglycemic activity and oral bioavailability of insulin-loaded liposomes containing bile salts in rats:the effect of cholate type, particle size and administered dose. Eur J Pharm Biopharm 2012;81:265-72.
53. Sharma G, van der Walle CF, Ravi Kumar MN. Antacid coencapsulated polyester nanoparticles for peroral delivery of insulin:development, pharmacokinetics, biodistribution and pharmacodynamics. Int J Pharm 2013;440:99-110.
54. Sonaje K, Lin YH, Juang JH, Wey SP, Chen CT, Sung HW. In vivo evaluation of safety and efficacy of self-assembled nanoparticles for oral insulin delivery. Biomaterials 2009;30:2329-39.
55. Zhang X, Qi J, Lu Y, He W, Li X, Wu W. Biotinylated liposomes as potential carriers for the oral delivery of insulin. Nanomedicine 2014;10:167-76.
56. Abuhelwa AY, Williams DB, Upton RN, Foster DJ. Food, gastrointestinal pH, and models of oral drug absorption. Eur J Pharm Biopharm 2017;112:234-48.
57. Ensign LM, Cone R, JH. Oral drug delivery with polymeric nanoparticles:the gastrointestinal mucus barriers. Adv Drug Deliv Rev 2012;64:557-70.
58. Wang X, Sherman A, Liao G, Leong KW, Daniell H, Terhorst C, et al. Mechanism of oral tolerance induction to therapeutic proteins. Adv Drug Deliv Rev 2013;65:759-73.
59. Yun Y, Cho YW, Park K. Nanoparticles for oral delivery:targeted nanoparticles with peptidic ligands for oral protein delivery. Adv Drug Deliv Rev 2013;65:822-32.
60. Deep HS, Roychowdhury S, Verma P, Bhandari V. A review on recent advances of enteric coating. J Pharm 2012;2:5-11.
61. Chuang EY, Lin KJ, Lin PY, Chen HL, Wey SP, Mi FL, et al. Selfassembling bubble carriers for oral protein delivery. Biomaterials 2015;64:115-24.
62. Renukuntla J, Vadlapudi AD, Patel A, Boddu SHS, Mitra AK. Approaches for enhancing oral bioavailability of peptides and proteins. Int J Pharm 2013;447:75-93.
63. Grabovac V, Guggi D, Bernkop-Schnurch A. Comparison of the mucoadhesive properties of various polymers. Adv Drug Deliv Rev 2005;57:1713-23.
64. Griffin BT, Guo J, Presas E, Donovan MD, Alonso MJ, O'Driscoll CM. Pharmacokinetic, pharmacodynamic and biodistribution following oral administration of nanocarriers containing peptide and protein drugs. Adv Drug Deliv Rev 2016;106:367-80.
65. Czuba E, Diop M, Mura C, Schaschkow A, Langlois A, Bietiger W, et al. Oral insulin delivery, the challenge to increase insulin bioavailability:influence of surface charge in nanoparticle system. Int J Pharm 2018;542:47-55.
66. 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 Nanomed 2017;12:3471-83.
67. He Z, Santos JL, Tian H, Huang H, Hu Y, Liu L, et al. Scalable fabrication of size-controlled chitosan nanoparticles for oral delivery of insulin. Biomaterials 2017;130:28-41.
68. Hinkley GK, Carpinone P, Munson JW, Powers KW, Roberts SM. Oral absorption of PEG-coated versus uncoated gold nanospheres:does agglomeration matter?. Part Fibre Toxicol 2015;12:9.
69. Choonara BF, Choonara YE, Kumar P, Bijukumar D, du Toit LC, Pillay V. A review of advanced oral drug delivery technologies facilitating the protection and absorption of protein and peptide molecules. Biotechnol Adv 2014;32:1269-82.
70. Kou L, Sun J, Zhai Y, He Z. The endocytosis and intracellular fate of nanomedicines:implication for rational design. Asian J Pharm Sci 2013;8:1-10.
71. Rehmani S, Dixon JE. Oral delivery of anti-diabetes therapeutics using cell penetrating and transcytosing peptide strategies. Peptides 2018;100:24-35.
72. Komin A, Russell LM, Hristova KA, Searson PC. Peptide-based strategies for enhanced cell uptake, transcellular transport, and circulation:mechanisms and challenges. Adv Drug Deliv Rev 2017;110-111:52-64.
73. Lundquist P, Artursson P. Oral absorption of peptides and nanoparticles across the human intestine:opportunities, limitations and studies in human tissues. Adv Drug Deliv Rev 2016;106:256-76.
74. Yameen B, Choi WI, Vilos C, Swami A, Shi J, Farokhzad OC. Insight into nanoparticle cellular uptake and intracellular targeting. J Control Release 2014;190:485-99.
75. Su H, Wang Y, Liu S, Wang Y, Liu Q, Liu G, et al. Emerging transporter-targeted nanoparticulate drug delivery systems. Acta Pharm Sin B 2019;9:49-58.
76. Bae YH, Lee Y-K, Nurunnabi M, Hee SW, Kwag D. Composions and methods for bile acid particles. 2016. Available from:
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