Generic placeholder image

Current Molecular Medicine

Author(s): Ana Macedo, Patrícia Filipe, Natália G. Thomé, João Vieira, Carolina Oliveira, Catarina Teodósio, Raquel Ferreira, Luís Roque and Pedro Fonte*

DOI: 10.2174/1566524019666191010095522

DownloadDownload PDF Flyer Cite As
A Brief Overview of the Oral Delivery of Insulin as an Alternative to the Parenteral Delivery

Page: [134 - 143] Pages: 10

  • * (Excluding Mailing and Handling)

Abstract

Diabetes mellitus greatly affects the quality of life of patients and has a worldwide prevalence. Insulin is the most commonly used drug to treat diabetic patients and is usually administered through the subcutaneous route. However, this route of administration is ineffective due to the low concentration of insulin at the site of action. This route of administration causes discomfort to the patient and increases the risk of infection due to skin barrier disturbance caused by the needle. The oral administration of insulin has been proposed to surpass the disadvantages of subcutaneous administration. In this review, we give an overview of the strategies to deliver insulin by the oral route, from insulin conjugation to encapsulation into nanoparticles. These strategies are still under development to attain efficacy and effectiveness that are expected to be achieved in the near future.

Keywords: Diabetes mellitus, insulin, oral delivery, nanoparticle, absorption enhancer, enzyme inhibitor, intestinal patch.

[1]
World Health Statistics 2017: Monitoring Health for The Sustainable Development Goals. World Health Organization 2017.
[2]
Saeedi Borujeni MJ, Esfandiary E, Baradaran A, et al. Molecular aspects of pancreatic β-cell dysfunction: Oxidative stress, microRNA, and long noncoding RNA. J Cell Physiol 2019; 234(6): 8411-25.
[http://dx.doi.org/10.1002/jcp.27755] [PMID: 30565679]
[3]
Saeedi Borujeni MJ, Esfandiary E, Taheripak G, Codoñer-Franch P, Alonso-Iglesias E, Mirzaei H. Molecular aspects of diabetes mellitus: Resistin, microRNA, and exosome. J Cell Biochem 2018; 119(2): 1257-72.
[http://dx.doi.org/10.1002/jcb.26271] [PMID: 28688216]
[4]
Wong CY, Martinez J, Dass CR. Oral delivery of insulin for treatment of diabetes: status quo, challenges and opportunities. J Pharm Pharmacol 2016; 68(9): 1093-108.
[http://dx.doi.org/10.1111/jphp.12607] [PMID: 27364922]
[5]
Meetoo D. Clinical skills: empowering people with diabetes to minimize complications. Br J Nurs 2004; 13(11): 644-51.
[http://dx.doi.org/10.12968/bjon.2004.13.11.13222] [PMID: 15218429]
[6]
Meetoo D, McGovern P, Safadi R. An epidemiological overview of diabetes across the world. Br J Nurs 2007; 16(16): 1002-7.
[http://dx.doi.org/10.12968/bjon.2007.16.16.27079] [PMID: 18026039]
[7]
Samper Bernal D, Monerris Tabasco MM, Homs Riera M, Soler Pedrola M. Etiología y manejo de la neuropatía diabética dolorosa. RESED 2010; 17: 286-96.
[http://dx.doi.org/10.1016/j.resed.2010.06.002]
[8]
Heinemann L, Jacques Y. Oral insulin and buccal insulin: a critical reappraisal. J Diabetes Sci Technol 2009; 3(3): 568-84.
[http://dx.doi.org/10.1177/193229680900300323] [PMID: 20144297]
[9]
Sousa F, Castro P, Fonte P, Sarmento B. How to overcome the limitations of current insulin administration with new non-invasive delivery systems. Ther Deliv 2015; 6(1): 83-94.
[http://dx.doi.org/10.4155/tde.14.82] [PMID: 25565442]
[10]
Saraiya N, Martin ST. New options in insulin therapy. Conn Med 2015; 79(9): 553-60.
[PMID: 26630709]
[11]
Khafagy S, Morishita M, Onuki Y, Takayama K. Current challenges in non-invasive insulin delivery systems: a comparative review. Adv Drug Deliv Rev 2007; 59(15): 1521-46.
[http://dx.doi.org/10.1016/j.addr.2007.08.019] [PMID: 17881081]
[12]
Hoffman A, Ziv E. Pharmacokinetic considerations of new insulin formulations and routes of administration. Clin Pharmacokinet 1997; 33(4): 285-301.
[http://dx.doi.org/10.2165/00003088-199733040-00004] [PMID: 9342504]
[13]
Strack T. The pharmacokinetics of alternative insulin delivery systems. Curr Opin Investig Drugs 2010; 11(4): 394-401.
[PMID: 20336587]
[14]
Wan F, Horn Møller E, Yang M, Jørgensen L. Formulation technologies to overcome unfavorable properties of peptides and proteins for pulmonary delivery. Drug Discov Today Technol 2012; 9(2): e71-e174.
[http://dx.doi.org/10.1016/j.ddtec.2011.12.003] [PMID: 24064274]
[15]
Benedict C, Frey WH II, Schiöth HB, Schultes B, Born J, Hallschmid M. Intranasal insulin as a therapeutic option in the treatment of cognitive impairments. Exp Gerontol 2011; 46(2-3): 112-5.
[http://dx.doi.org/10.1016/j.exger.2010.08.026] [PMID: 20849944]
[16]
Nobels FR, Hermans MP, De Leeuw I. Insulin lispro (Humalog), a novel fast-acting insulin analogue: guidelines for its practical use. Acta Clin Belg 1999; 54(5): 246-54.
[http://dx.doi.org/10.1080/17843286.1999.11754241] [PMID: 10555382]
[17]
Toth EL, Lee KC. Guidelines for using insulin lispro. Can Fam Physician 1998; 44: 2444-9.
[PMID: 9839062]
[18]
Lee P, Chang A, Blaum C, Vlajnic A, Gao L, Halter J. Comparison of safety and efficacy of insulin glargine and neutral protamine hagedorn insulin in older adults with type 2 diabetes mellitus: results from a pooled analysis. J Am Geriatr Soc 2012; 60(1): 51-9.
[http://dx.doi.org/10.1111/j.1532-5415.2011.03773.x] [PMID: 22239291]
[19]
Bota VM, Hirsch IB. Insulin glargine or neutral protamine Hagedorn in patients with severe insulin resistance: Is there a benefit? Endocr Pract 2012; 18(3): e49-51.
[http://dx.doi.org/10.4158/EP11302.CR] [PMID: 22232027]
[20]
Lau E, Salem A, Chan JCN, et al. Insulin glargine compared to neutral protamine Hagedorn (NPH) insulin in patients with type-2 diabetes uncontrolled with oral anti-diabetic agents alone in Hong Kong: a cost-effectiveness analysis. Cost Eff Resour Alloc 2019; 17(1): 13.
[http://dx.doi.org/10.1186/s12962-019-0180-9] [PMID: 31303866]
[21]
Owens DR. New horizons--alternative routes for insulin therapy. Nat Rev Drug Discov 2002; 1(7): 529-40.
[http://dx.doi.org/10.1038/nrd836] [PMID: 12120259]
[22]
Siekmeier R, Scheuch G. Inhaled insulin--does it become reality? J Physiol Pharmacol 2008; 59(Suppl. 6): 81-113.
[PMID: 19218634]
[23]
Rave K, Heise T, Heinemann L, Boss AH. Inhaled technosphere insulin in comparison to subcutaneous regular human insulin: time action profile and variability in subjects with type 2 diabetes. J Diabetes Sci Technol 2008; 2(2): 205-12.
[http://dx.doi.org/10.1177/193229680800200206] [PMID: 19885344]
[24]
Wong CY, Al-Salami H, Dass CR. Potential of insulin nanoparticle formulations for oral delivery and diabetes treatment. J Control Release 2017; 264: 247-75.
[http://dx.doi.org/10.1016/j.jconrel.2017.09.003] [PMID: 28887133]
[25]
Shah RB, Patel M, Maahs DM, Shah VN. Insulin delivery methods: Past, present and future. Int J Pharm Investig 2016; 6(1): 1-9.
[http://dx.doi.org/10.4103/2230-973X.176456] [PMID: 27014614]
[26]
Carino GP, Mathiowitz E. Oral insulin delivery. Adv Drug Deliv Rev 1999; 35(2-3): 249-57.
[http://dx.doi.org/10.1016/S0169-409X(98)00075-1] [PMID: 10837700]
[27]
Muheem A, Shakeel F, Jahangir MA, et al. A review on the strategies for oral delivery of proteins and peptides and their clinical perspectives. Saudi Pharm J 2016; 24(4): 413-28.
[http://dx.doi.org/10.1016/j.jsps.2014.06.004] [PMID: 27330372]
[28]
Al Rubeaan K, Rafiullah M, Jayavanth S. Oral insulin delivery systems using chitosan-based formulation: a review. Expert Opin Drug Deliv 2016; 13(2): 223-37.
[http://dx.doi.org/10.1517/17425247.2016.1107543] [PMID: 26549528]
[29]
Larhed AW, Artursson P, Björk E. The influence of intestinal mucus components on the diffusion of drugs. Pharm Res 1998; 15(1): 66-71.
[http://dx.doi.org/10.1023/A:1011948703571] [PMID: 9487548]
[30]
Camenisch G, Alsenz J, van de Waterbeemd H, Folkers G. Estimation of permeability by passive diffusion through Caco-2 cell monolayers using the drugs’ lipophilicity and molecular weight. Eur J Pharm Sci 1998; 6(4): 317-24.
[http://dx.doi.org/10.1016/S0928-0987(97)10019-7] [PMID: 9795088]
[31]
Madara JL. Loosening tight junctions. Lessons from the intestine. J Clin Invest 1989; 83(4): 1089-94.
[http://dx.doi.org/10.1172/JCI113987] [PMID: 2649511]
[32]
Salama NN, Eddington ND, Fasano A. Tight junction modulation and its relationship to drug delivery. Adv Drug Deliv Rev 2006; 58(1): 15-28.
[http://dx.doi.org/10.1016/j.addr.2006.01.003] [PMID: 16517003]
[33]
Evans DF, Pye G, Bramley R, Clark AG, Dyson TJ, Hardcastle JD. Measurement of gastrointestinal pH profiles in normal ambulant human subjects. Gut 1988; 29(8): 1035-41.
[http://dx.doi.org/10.1136/gut.29.8.1035] [PMID: 3410329]
[34]
Langguth P, Bohner V, Heizmann J, et al. The challenge of proteolytic enzymes in intestinal peptide delivery. J Control Release 1997; 46(1): 39-57.
[http://dx.doi.org/10.1016/S0168-3659(96)01586-6]
[35]
Sood A, Panchagnula R. Peroral route: an opportunity for protein and peptide drug delivery. Chem Rev 2001; 101(11): 3275-303.
[http://dx.doi.org/10.1021/cr000700m] [PMID: 11840987]
[36]
Schilling RJ, Mitra AK. Degradation of insulin by trypsin and alpha-chymotrypsin. Pharm Res 1991; 8(6): 721-7.
[http://dx.doi.org/10.1023/A:1015893832222] [PMID: 2062801]
[37]
Binder C, Lauritzen T, Faber O, Pramming S. Insulin pharmacokinetics. Diabetes Care 1984; 7(2): 188-99.
[http://dx.doi.org/10.2337/diacare.7.2.188] [PMID: 6376015]
[38]
Bruno BJ, Miller GD, Lim CS. Basics and recent advances in peptide and protein drug delivery. Ther Deliv 2013; 4(11): p. : 1443-67.
[39]
Marschütz MK, Bernkop-Schnürch A. Oral peptide drug delivery: polymer-inhibitor conjugates protecting insulin from enzymatic degradation in vitro. Biomaterials 2000; 21(14): 1499-507.
[http://dx.doi.org/10.1016/S0142-9612(00)00039-9] [PMID: 10872779]
[40]
Garcia-Fuentes M, Torres D, Alonso MJ. Design of lipid nanoparticles for the oral delivery of hydrophilic macromolecules. Colloid Surface B 2003; 27(2-3): 159-68.
[http://dx.doi.org/10.1016/S0927-7765(02)00053-X]
[41]
Sarmento B, Martins S, Ferreira D, Souto EB. Oral insulin delivery by means of solid lipid nanoparticles. Int J Nanomedicine 2007; 2(4): 743-9.
[PMID: 18203440]
[42]
Zhang N, Ping Q, Huang G, Xu W, Cheng Y, Han X. Lectin-modified solid lipid nanoparticles as carriers for oral administration of insulin. Int J Pharm 2006; 327(1-2): 153-9.
[http://dx.doi.org/10.1016/j.ijpharm.2006.07.026] [PMID: 16935443]
[43]
Kisel MA, Kulik LN, Tsybovsky IS, et al. Liposomes with phosphatidylethanol as a carrier for oral delivery of insulin: studies in the rat. Int J Pharm 2001; 216(1-2): 105-14.
[http://dx.doi.org/10.1016/S0378-5173(01)00579-8] [PMID: 11274812]
[44]
Axt J, Sarrach D, Zipper J. Biopharmaceutical studies on phospholipid liposomes as carriers for the oral administration of insulin. Pharmazie 1983; 38(4): 246-8.
[PMID: 6346346]
[45]
Das N, Basu MK, Das MK. Oral application of insulin encapsulated liposomes. Biochem Int 1988; 16(6): 983-9.
[PMID: 3052457]
[46]
Takeuchi H, Yamamoto H, Niwa T, Hino T, Kawashima Y. Mucoadhesion of polymer-coated liposomes to rat intestine in vitro. Chem Pharm Bull (Tokyo) 1994; 42(9): 1954-6.
[http://dx.doi.org/10.1248/cpb.42.1954] [PMID: 7954945]
[47]
Pan Y, Zheng JM, Zhao HY, Li YJ, Xu H, Wei G. Relationship between drug effects and particle size of insulin-loaded bioadhesive microspheres. Acta Pharmacol Sin 2002; 23(11): 1051-6.
[PMID: 12421485]
[48]
Sarmento B, Ribeiro A, Veiga F, Sampaio P, Neufeld R, Ferreira D. Alginate/chitosan nanoparticles are effective for oral insulin delivery. Pharm Res 2007; 24(12): 2198-206.
[http://dx.doi.org/10.1007/s11095-007-9367-4] [PMID: 17577641]
[49]
Lin YH, Mi FL, Chen CT, et al. Preparation and characteri-zation of nanoparticles shelled with chitosan for oral insulin delivery. Biomacromolecules 2007; 8(1): 146-52.
[http://dx.doi.org/10.1021/bm0607776] [PMID: 17206800]
[50]
Makhlof A, Tozuka Y, Takeuchi H. Design and evaluation of novel pH-sensitive chitosan nanoparticles for oral insulin delivery. Eur J Pharm Sci 2011; 42(5): 445-51.
[http://dx.doi.org/10.1016/j.ejps.2010.12.007] [PMID: 21182939]
[51]
Katsuma M, Watanabe S, Kawai H, Takemura S, Sako K. Effects of absorption promoters on insulin absorption through colon-targeted delivery. Int J Pharm 2006; 307(2): 156-62.
[http://dx.doi.org/10.1016/j.ijpharm.2005.09.028] [PMID: 16289574]
[52]
Mesiha M, Sidhom M. Increased oral absorption enhancement of insulin by medium viscosity hydroxypropyl cellulose. Int J Pharm 1995; 114(2): 137-40.
[http://dx.doi.org/10.1016/0378-5173(94)00229-X]
[53]
Mesiha M, Plakogiannis F, Vejosoth S. Enhanced oral absorption of insulin from desolvated fatty acid-sodium glycocholate emulsions. Int J Pharm 1994; 111(3): 213-6.
[http://dx.doi.org/10.1016/0378-5173(94)90343-3]
[54]
Rehmani S, Dixon JE. Oral delivery of anti-diabetes therapeutics using cell penetrating and transcytosing peptide strategies. Peptides 2018; 100: 24-35.
[http://dx.doi.org/10.1016/j.peptides.2017.12.014] [PMID: 29412825]
[55]
Kristensen M, Nielsen HM. Cell-penetrating peptides as carriers for oral delivery of biopharmaceuticals. Basic Clin Pharmacol Toxicol 2016; 118(2): 99-106.
[http://dx.doi.org/10.1111/bcpt.12515] [PMID: 26525297]
[56]
Guo F, Ouyang T, Peng T, et al. Enhanced oral absorption of insulin using colon-specific nanoparticles co-modified with amphiphilic chitosan derivatives and cell-penetrating peptides. Biomater Sci 2019; 7(4): 1493-506.
[http://dx.doi.org/10.1039/C8BM01485J] [PMID: 30672923]
[57]
Banerjee A, Lee J, Mitragotri S. Intestinal mucoadhesive devices for oral delivery of insulin. Bioeng Transl Med 2016; 1(3): 338-46.
[http://dx.doi.org/10.1002/btm2.10015] [PMID: 29313019]
[58]
Kim BY, Jeong JH, Park K, Kim JD. Bioadhesive interaction and hypoglycemic effect of insulin-loaded lectin-microparticle conjugates in oral insulin delivery system. J Control Release 2005; 102(3): 525-38.
[http://dx.doi.org/10.1016/j.jconrel.2004.10.032] [PMID: 15681076]
[59]
Sung HW, Sonaje K, Liao ZX, Hsu LW, Chuang EY. pH-responsive nanoparticles shelled with chitosan for oral delivery of insulin: from mechanism to therapeutic applications. Acc Chem Res 2012; 45(4): 619-29.
[http://dx.doi.org/10.1021/ar200234q] [PMID: 22236133]
[60]
Czuba E, Diop M, Mura C, et al. Oral insulin delivery, the challenge to increase insulin bioavailability: Influence of surface charge in nanoparticle system. Int J Pharm 2018; 542(1-2): 47-55.
[http://dx.doi.org/10.1016/j.ijpharm.2018.02.045] [PMID: 29501738]
[61]
Xu Y, Zheng Y, Wu L, Zhu X, Zhang Z, Huang Y. Novel solid lipid nanoparticle with endosomal escape function for oral delivery of insulin. ACS Appl Mater Interfaces 2018; 10(11): 9315-24.
[http://dx.doi.org/10.1021/acsami.8b00507] [PMID: 29484890]
[62]
Müller RH, Mäder K, Gohla S. Solid lipid nanoparticles (SLN) for controlled drug delivery - a review of the state of the art. Eur J Pharm Biopharm 2000; 50(1): 161-77.
[http://dx.doi.org/10.1016/S0939-6411(00)00087-4] [PMID: 10840199]
[63]
Ismail R, Csóka I. Novel strategies in the oral delivery of antidiabetic peptide drugs - Insulin, GLP 1 and its analogs. Eur J Pharm Biopharm 2017; 115: 257-67.
[http://dx.doi.org/10.1016/j.ejpb.2017.03.015] [PMID: 28336368]
[64]
Grigoras AG. Polymer-lipid hybrid systems used as carriers for insulin delivery. Nanomedicine (Lond) 2017; 13(8): 2425-37.
[http://dx.doi.org/10.1016/j.nano.2017.08.005] [PMID: 28821465]
[65]
Fonte P, Araújo F, Silva C, et al. Polymer-based nanoparticles for oral insulin delivery: Revisited approaches. Biotechnol Adv 2015; 33(6 Pt 3): 1342-54.
[http://dx.doi.org/10.1016/j.biotechadv.2015.02.010] [PMID: 25728065]
[66]
Ward PD, Tippin TK, Thakker DR. Enhancing paracellular permeability by modulating epithelial tight junctions. Pharm Sci Technol Today 2000; 3(10): 346-58.
[http://dx.doi.org/10.1016/S1461-5347(00)00302-3] [PMID: 11050459]
[67]
Jin J, Song M, Hourston DJ. Novel chitosan-based films cross-linked by genipin with improved physical properties. Biomacromolecules 2004; 5(1): 162-8.
[http://dx.doi.org/10.1021/bm034286m] [PMID: 14715022]
[68]
Roy K, Mao HQ, Huang SK, Leong KW. Oral gene delivery with chitosan--DNA nanoparticles generates immunologic protection in a murine model of peanut allergy. Nat Med 1999; 5(4): 387-91.
[http://dx.doi.org/10.1038/7385] [PMID: 10202926]
[69]
Ding Y, Xia XH, Zhang C. Synthesis of metallic nanoparticles protected with N,N,N-trimethyl chitosan chloride via a relatively weak affinity. Nanotechnology 2006; 17(16): 4156-62.
[http://dx.doi.org/10.1088/0957-4484/17/16/027] [PMID: 21727553]
[70]
Prego C, Fabre M, Torres D, Alonso MJ. Efficacy and mechanism of action of chitosan nanocapsules for oral peptide delivery. Pharm Res 2006; 23(3): 549-56.
[http://dx.doi.org/10.1007/s11095-006-9570-8] [PMID: 16525861]
[71]
Eiamtrakarn S, Itoh Y, Kishimoto J, et al. Gastrointestinal mucoadhesive patch system (GI-MAPS) for oral administration of G-CSF, a model protein. Biomaterials 2002; 23(1): 145-52.
[http://dx.doi.org/10.1016/S0142-9612(01)00089-8] [PMID: 11762832]
[72]
Fonte P, Andrade F, Araújo F, Andrade C. Neves Jd, Sarmento B. Chitosan-coated solid lipid nanoparticles for insulin delivery. Methods Enzymol 2012; 508: 295-314.
[http://dx.doi.org/10.1016/B978-0-12-391860-4.00015-X] [PMID: 22449932]
[73]
Sarmento B, Ribeiro A, Veiga F, Ferreira D, Neufeld R. Oral bioavailability of insulin contained in polysaccharide nanoparticles. Biomacromolecules 2007; 8(10): 3054-60.
[http://dx.doi.org/10.1021/bm0703923] [PMID: 17877397]
[74]
Goswami S, Bajpai J, Bajpai AK. Calcium alginate nanocarriers as possible vehicles for oral delivery of insulin. J Exp Nanosci 2014; 9(4): 337-56.
[http://dx.doi.org/10.1080/17458080.2012.661472]
[75]
Takeuchi H, Yamamoto H, Kawashima Y. Mucoadhesive nanoparticulate systems for peptide drug delivery. Adv Drug Deliv Rev 2001; 47(1): 39-54.
[http://dx.doi.org/10.1016/S0169-409X(00)00120-4] [PMID: 11251244]
[76]
Ukiya M, Kawaguchi T, Ishii K, et al. Cytotoxic activities of amino acid-conjugate derivatives of abietane-type diterpenoids against human cancer cell lines. Chem Biodivers 2013; 10(7): 1260-8.
[http://dx.doi.org/10.1002/cbdv.201300043] [PMID: 23847070]
[77]
Agarwal V, Nazzal S, Reddy IK, Khan MA. Transport studies of insulin across rat jejunum in the presence of chicken and duck ovomucoids. J Pharm Pharmacol 2001; 53(8): 1131-8.
[http://dx.doi.org/10.1211/0022357011776522] [PMID: 11518023]
[78]
Korbecki J, Bajdak-Rusinek K. The effect of palmitic acid on inflammatory response in macrophages: an overview of molecular mechanisms. Inflamm Res. 2019. In Print
[http://dx.doi.org/10.1007/s00011-019-01273-5]
[79]
Bunn RC, Cockrell GE, Ou Y, Thrailkill KM, Lumpkin CK Jr, Fowlkes JL. Palmitate and insulin synergistically induce IL-6 expression in human monocytes. Cardiovasc Diabetol 2010; 9(73): 73.
[http://dx.doi.org/10.1186/1475-2840-9-73] [PMID: 21054880]
[80]
Nielsen EJ, Yoshida S, Kamei N, et al. In vivo proof of concept of oral insulin delivery based on a co-administration strategy with the cell-penetrating peptide penetratin. J Control Release 2014; 189: 19-24.
[http://dx.doi.org/10.1016/j.jconrel.2014.06.022] [PMID: 24973720]
[81]
Kamei N, Nielsen EJ, Khafagy S, Takeda-Morishita M. Noninvasive insulin delivery: the great potential of cell-penetrating peptides. Ther Deliv 2013; 4(3): 315-26.
[http://dx.doi.org/10.4155/tde.12.164] [PMID: 23442079]
[82]
Grabovac V, Föger F, Bernkop-Schnürch A. Design and in vivo evaluation of a patch delivery system for insulin based on thiolated polymers. Int J Pharm 2008; 348(1-2): 169-74.
[http://dx.doi.org/10.1016/j.ijpharm.2007.06.052] [PMID: 17706903]
[83]
Whitehead K, Shen Z, Mitragotri S. Oral delivery of macromolecules using intestinal patches: applications for insulin delivery. J Control Release 2004; 98(1): 37-45.
[http://dx.doi.org/10.1016/j.jconrel.2004.04.013] [PMID: 15245887]
[84]
Venkatesan N, Uchino K, Amagase K, Ito Y, Shibata N, Takada K. Gastro-intestinal patch system for the delivery of erythropoietin. J Control Release 2006; 111(1-2): 19-26.
[http://dx.doi.org/10.1016/j.jconrel.2005.11.009] [PMID: 16377018]
[85]
Gupta V, Hwang BH, Doshi N, Banerjee A, Anselmo AC, Mitragotri S. Delivery of exenatide and insulin using mucoadhesive intestinal devices. Ann Biomed Eng 2016; 44(6): 1993-2007.
[http://dx.doi.org/10.1007/s10439-016-1558-x] [PMID: 26864536]
[86]
Banerjee A, Wong J, Gogoi R, Brown T, Mitragotri S. Intestinal micropatches for oral insulin delivery. J Drug Target 2017; 25(7): 608-15.
[http://dx.doi.org/10.1080/1061186X.2017.1300664] [PMID: 28266884]
[87]
Yang NJ, Hinner MJ. Getting across the cell membrane: an overview for small molecules, peptides, and proteins. Methods Mol Biol 2015; 1266: 29-53.
[http://dx.doi.org/10.1007/978-1-4939-2272-7_3] [PMID: 25560066]
[88]
Ke Y, Xiang C. Transferrin receptor-targeted HMSN for sorafenib delivery in refractory differentiated thyroid cancer therapy. Int J Nanomedicine 2018; 13: 8339-54.
[http://dx.doi.org/10.2147/IJN.S187240] [PMID: 30584304]
[89]
Zhang L, Zhu X, Wu S, et al. Fabrication and evaluation of a γ-PGA-based self-assembly transferrin receptor-targeting anticancer drug carrier. Int J Nanomedicine 2018; 13: 7873-89.
[http://dx.doi.org/10.2147/IJN.S181121] [PMID: 30538465]
[90]
Chen Q, Liu J. Transferrin and folic acid co-modified bufalin-loaded nanoliposomes: preparation, characterization, and application in anticancer activity. Int J Nanomedicine 2018; 13: 6009-18.
[http://dx.doi.org/10.2147/IJN.S176012] [PMID: 30323588]
[91]
Choudhury H, Pandey M, Chin PX, et al. Transferrin receptors-targeting nanocarriers for efficient targeted delivery and transcytosis of drugs into the brain tumors: a review of recent advancements and emerging trends. Drug Deliv Transl Res 2018; 8(5): 1545-63.
[http://dx.doi.org/10.1007/s13346-018-0552-2] [PMID: 29916012]
[92]
Kumari P, Rompicharla SVK, Muddineti OS, Ghosh B, Biswas S. Transferrin-anchored poly(lactide) based micelles to improve anticancer activity of curcumin in hepatic and cervical cancer cell monolayers and 3D spheroids. Int J Biol Macromol 2018; 116: 1196-213.
[http://dx.doi.org/10.1016/j.ijbiomac.2018.05.040] [PMID: 29753013]
[93]
Tang J, Wang Q, Yu Q, et al. A stabilized retro-inverso peptide ligand of transferrin receptor for enhanced liposome-based hepatocellular carcinoma-targeted drug delivery. Acta Biomater 2019; 83: 379-89.
[http://dx.doi.org/10.1016/j.actbio.2018.11.002] [PMID: 30395963]
[94]
Liang M, Gao C, Wang Y, et al. Enhanced blood-brain barrier penetration and glioma therapy mediated by T7 peptide-modified low-density lipoprotein particles. Drug Deliv 2018; 25(1): 1652-63.
[http://dx.doi.org/10.1080/10717544.2018.1494223] [PMID: 30394123]
[95]
Kohata A, Hashim PK, Okuro K, Aida T. Transferrin-Appended Nanocaplet for Transcellular siRNA Delivery into Deep Tissues. J Am Chem Soc 2019; 141(7): 2862-6.
[http://dx.doi.org/10.1021/jacs.8b12501] [PMID: 30724083]
[96]
Voigt AP, Whitmore SS, Flamme-Wiese MJ, et al. Molecular characterization of foveal versus peripheral human retina by single-cell RNA sequencing. Exp Eye Res 2019; 184: 234-42.
[http://dx.doi.org/10.1016/j.exer.2019.05.001] [PMID: 31075224]
[97]
Zhang T, Guo W, Zhang C, et al. Transferrin-dressed virus-like ternary nanoparticles with aggregation-induced emission for targeted delivery and rapid cytosolic release of siRNA. ACS Appl Mater Interfaces 2017; 9(19): 16006-14.
[http://dx.doi.org/10.1021/acsami.7b03402] [PMID: 28447465]
[98]
Li Y, Lee RJ, Huang X, et al. Single-step microfluidic synthesis of transferrin-conjugated lipid nanoparticles for siRNA delivery. Nanomedicine (Lond) 2017; 13(2): 371-81.
[http://dx.doi.org/10.1016/j.nano.2016.09.014] [PMID: 27720989]
[99]
Zhang W, Müller K, Kessel E, et al. Targeted siRNA Delivery Using a Lipo-Oligoaminoamide Nanocore with an Influenza Peptide and Transferrin Shell. Adv Healthc Mater 2016; 5(12): 1493-504.
[http://dx.doi.org/10.1002/adhm.201600057] [PMID: 27109317]
[100]
Xia CQ, Wang J, Shen WC. Hypoglycemic effect of insulin-transferrin conjugate in streptozotocin-induced diabetic rats. J Pharmacol Exp Ther 2000; 295(2): 594-600.
[PMID: 11046093]
[101]
Xia CQ, Shen WC. Tyrphostin-8 enhances transferrin receptor-mediated transcytosis in Caco-2- cells and inreases hypoglycemic effect of orally administered insulin-transferrin conjugate in diabetic rats. Pharm Res 2001; 18(2): 191-5.
[http://dx.doi.org/10.1023/A:1011032502097] [PMID: 11405290]
[102]
Kavimandan NJ, Losi E, Wilson JJ, Brodbelt JS, Peppas NA. Synthesis and characterization of insulin-transferrin conjugates. Bioconjug Chem 2006; 17(6): 1376-84.
[http://dx.doi.org/10.1021/bc050344k] [PMID: 17105214]