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Review Articles

Cellular assays and applied technologies for characterisation of orally administered protein nanoparticles: a systematic review

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Pages 585-599 | Received 10 Dec 2019, Accepted 02 Feb 2020, Published online: 12 Feb 2020

References

  • Lopes MA, Abrahim BA, Cabral LM, et al. Intestinal absorption of insulin nanoparticles: Contribution of m cells. Nanomedicine. 2014;10(6):1139–1151.
  • Ioannidis JPA, Kim BYS, Trounson A. How to design preclinical studies in nanomedicine and cell therapy to maximize the prospects of clinical translation. Nat Biomed Eng. 2018;2(11):797–809.
  • Wong CY, Luna G, Martinez J, et al. Bio-nanotechnological advancement of orally administered insulin nanoparticles: comprehensive review of experimental design for physicochemical characterization. Int J Pharm. 2019;572:118720.
  • 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.
  • Zhang Z, Li H, Xu G, et al. Liver-targeted delivery of insulin-loaded nanoparticles via enterohepatic circulation of bile acids. Drug Deliv. 2018;25(1):1224–1233.
  • Boushra M, Tous S, Fetih G, et al. Methocel-lipid hybrid nanocarrier for efficient oral insulin delivery. J Pharm Sci. 2016;105(5):1733–1740.
  • Sheng J, He H, Han L, et al. Enhancing insulin oral absorption by using mucoadhesive nanoparticles loaded with LMWP-linked insulin conjugates. J Control Release. 2016;233:181–190. 10
  • Chen S, Guo F, Deng T, et al. Eudragit s100-coated chitosan nanoparticles co-loading tat for enhanced oral colon absorption of insulin. AAPS PharmSciTech. 2017;18(4):1277–1287.
  • Sambuy Y, De Angelis I, Ranaldi G, et al. The Caco-2 cell line as a model of the intestinal barrier: influence of cell and culture-related factors on Caco-2 cell functional characteristics. Cell Biol Toxicol. 2005;21(1):1–26.
  • Briske-Anderson MJ, Finley JW, Newman SM. The influence of culture time and passage number on the morphological and physiological development of Caco-2 cells. Proc Soc Exp Biol Med. 1997;214(3):248–257.
  • Ranaldi G, Consalvo R, Sambuy Y, et al. Permeability characteristics of parental and clonal human intestinal Caco-2 cell lines differentiated in serum-supplemented and serum-free media. Toxicol In Vitro. 2003;17(5–6):761–767.
  • Ke Z, Guo H, Zhu X, et al. Efficient peroral delivery of insulin via vitamin B12 modified trimethyl chitosan nanoparticles. J Pharm Pharm Sci. 2015;18(2):155–170.
  • Wu J, Zheng Y, Liu M, et al. Biomimetic viruslike and charge reversible nanoparticles to sequentially overcome mucus and epithelial barriers for oral insulin delivery. ACS Appl Mater Interfaces. 2018;10(12):9916–9928.
  • Zhang Y, Du X, Zhang Y, et al. Thiolated eudragit-based nanoparticles for oral insulin delivery: preparation, characterization, and evaluation using intestinal epithelial cells in vitro. Macromol Biosci. 2014;14(6):842–852.
  • Sgorla D, Lechanteur A, Almeida A, et al. Development and characterization of lipid-polymeric nanoparticles for oral insulin delivery. Expert Opin Drug Deliv. 2018;15(3):213–222.
  • Cone RA. Barrier properties of mucus. Adv Drug Delivery Rev. 2009;61(2):75–85.
  • Lea T. Caco-2 cell line. In: Verhoeckx K, Cotter P, López-Expósito I, et al., editors. The impact of food bioactives on health: in vitro and ex vivo models. Cham (Switzerland): Springer International Publishing; 2015. p. 103–111.
  • Behrens I, Pena AI, Alonso MJ, et al. Comparative uptake studies of bioadhesive and non-bioadhesive nanoparticles in human intestinal cell lines and rats: The effect of mucus on particle adsorption and transport. Pharm Res. 2002;19(8):1185–1193.
  • Behrens I, Stenberg P, Artursson P, et al. Transport of lipophilic drug molecules in a new mucus-secreting cell culture model based on ht29-mtx cells. Pharm Res. 2001;18(8):1138–1145.
  • Shan W, Zhu X, Liu M, et al. Overcoming the diffusion barrier of mucus and absorption barrier of epithelium by self-assembled nanoparticles for oral delivery of insulin. ACS Nano. 2015;9(3):2345–2356.
  • Jintapattanakit A, Junyaprasert VB, Kissel T. The role of mucoadhesion of trimethyl chitosan and pegylated trimethyl chitosan nanocomplexes in insulin uptake. J Pharm Sci. 2009;98(12):4818–4830.
  • Sheng J, Han L, Qin J, et al. N-trimethyl chitosan chloride-coated PLGA nanoparticles overcoming multiple barriers to oral insulin absorption. ACS Appl Mater Interfaces. 2015;7(28):15430–15441.
  • Keely S, Rullay A, Wilson C, et al. In vitro and ex vivo intestinal tissue models to measure mucoadhesion of poly (methacrylate) and n-trimethylated chitosan polymers. Pharm Res. 2005;22(1):38–49.
  • Alfatama M, Lim LY, Wong TW. Alginate-c18 conjugate nanoparticles loaded in tripolyphosphate-cross-linked chitosan-oleic acid conjugate-coated calcium alginate beads as oral insulin carrier. Mol Pharm. 2018;15(8):3369–3382.
  • Grenha A, Grainger CI, Dailey LA, et al. Chitosan nanoparticles are compatible with respiratory epithelial cells in vitro. Eur J Pharm Sci. 2007;31(2):73–84. Jun
  • Woitiski CB, Sarmento B, Carvalho RA, et al. Facilitated nanoscale delivery of insulin across intestinal membrane models. Int J Pharm. 2011;412(1–2):123–131.
  • Kleiveland CR. Co-cultivation of Caco-2 and ht-29mtx. In: Verhoeckx K, Cotter P, Lopez-Exposito I, et al., editors. The impact of food bioactives on health: in vitro and ex vivo models. Cham (Switzerland): Springer; 2015. p. 135–140.
  • Ferraretto A, Bottani M, De Luca P, et al. Morphofunctional properties of a differentiated Caco2/ht-29 co-culture as an in vitro model of human intestinal epithelium. Biosci Rep. 2018;38(2):BSR20171497.
  • Lopes M, Shrestha N, Correia A, et al. Dual chitosan/albumin-coated alginate/dextran sulfate nanoparticles for enhanced oral delivery of insulin. J Control Release. 2016;232:29–41.
  • Mesiha MS, Sidhom MB, Fasipe B. Oral and subcutaneous absorption of insulin poly(isobutylcyanoacrylate) nanoparticles. Int J Pharm. 2005;288(2):289–293.
  • 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):1093–1108.
  • Wong CY, Al-Salami H, Dass CR. Microparticles, microcapsules and microspheres: a review of recent developments and prospects for oral delivery of insulin. Int J Pharm. 2018;537(1–2):223–244.
  • Wong CY, Al-Salami H, Dass CR. Recent advancements in oral administration of insulin-loaded liposomal drug delivery systems for diabetes mellitus. Int J Pharm. 2018;549(1–2):201–217.
  • Wong CY, Al-Salami H, Dass CR. Potential of insulin nanoparticle formulations for oral delivery and diabetes treatment. J Control Release. 2017;264:247–275.
  • Bhumkar DR, Joshi HM, Sastry M, et al. Chitosan reduced gold nanoparticles as novel carriers for transmucosal delivery of insulin. Pharm Res. 2007;24(8):1415–1426.
  • Fonte P, Nogueira T, Gehm C, et al. Chitosan-coated solid lipid nanoparticles enhance the oral absorption of insulin. Drug Deliv and Transl Res. 2011;1(4):299–308.
  • Lin YH, Chen CT, Liang HF, et al. Novel nanoparticles for oral insulin delivery via the paracellular pathway. Nanotechnology. 2007;18(10):105102.
  • Cereijido M, Shoshani L, Contreras RG. Molecular physiology and pathophysiology of tight junctions. I. Biogenesis of tight junctions and epithelial polarity. Am J Physiol Gastrointest Liver Physiol. 2000;279(3):477–482.
  • Yamamoto T, Harada N, Kano K, et al. The ras target af-6 interacts with zo-1 and serves as a peripheral component of tight junctions in epithelial cells. J Cell Biol. 1997;139(3):785–795.
  • Rekha MR, Sharma CP. Synthesis and evaluation of lauryl succinyl chitosan particles towards oral insulin delivery and absorption. J Control Release. 2009;135(2):144–151.
  • Wong CY, Al-Salami H, Dass CR. The role of chitosan on oral delivery of peptide-loaded nanoparticle formulation. J Drug Target. 2018;26(7):551–562.
  • Wong CY, Martinez J, Al-Salami H, et al. Quantification of bsa-loaded chitosan/oligonucleotide nanoparticles using reverse-phase high-performance liquid chromatography. Anal Bioanal Chem. 2018;410(27):6991–7006.
  • Wong CY, Martinez J, Carnagarin R, et al. In-vitro evaluation of enteric coated insulin tablets containing absorption enhancer and enzyme inhibitor. J Pharm Pharmacol. 2017;69(3):285–294.
  • Liu L, Zhang Y, Yu S, et al. Dual stimuli-responsive nanoparticle-incorporated hydrogels as an oral insulin carrier for intestine-targeted delivery and enhanced paracellular permeation. ACS Biomater Sci Eng. 2018;4(8):2889–2902.
  • Zhang P, Xu Y, Zhu X, et al. Goblet cell targeting nanoparticle containing drug-loaded micelle cores for oral delivery of insulin. Int J Pharm. 2015;496(2):993–1005.
  • Lin YH, Mi FL, Chen CT, et al. Preparation and characterization of nanoparticles shelled with chitosan for oral insulin delivery. Biomacromolecules. 2007;8(1):146–152.
  • Mi FL, Wu YY, Lin YH, et al. Oral delivery of peptide drugs using nanoparticles self-assembled by poly(gamma-glutamic acid) and a chitosan derivative functionalized by trimethylation. Bioconjugate Chem. 2008;19(6):1248–1255.
  • Thanou M, Verhoef JC, Junginger HE. Chitosan and its derivatives as intestinal absorption enhancers. Adv Drug Deliv Rev. 2001;50:91–101.
  • Prusty A, Sahu SK. Development and evaluation of insulin incorporated nanoparticles for oral administration. ISRN Nanotechnol. 2013;2013:1–6.
  • Sung HW, Sonaje K, Liao ZX, et al. Ph-responsive nanoparticles shelled with chitosan for oral delivery of insulin: from mechanism to therapeutic applications. Acc Chem Res. 2012;45(4):619–629.
  • Liu M, Wu L, Shan W, et al. Iron-mimic peptide converts transferrin from foe to friend for orally targeting insulin delivery. J Mater Chem B. 2018;6(4):593–601.
  • Liu M, Zhang J, Zhu X, et al. Efficient mucus permeation and tight junction opening by dissociable “mucus-inert” agent coated trimethyl chitosan nanoparticles for oral insulin delivery. J Control Release. 2016;222:67–77.
  • Song M, Wang H, Chen K, et al. Oral insulin delivery by carboxymethyl-β-cyclodextrin-grafted chitosan nanoparticles for improving diabetic treatment. Artif Cells Nanomed Biotechnol. 2018;46(sup3):S774–S782.
  • Tian H, He Z, Sun C, et al. Uniform core-shell nanoparticles with thiolated hyaluronic acid coating to enhance oral delivery of insulin. Adv Healthcare Mater. 2018;7(17):e1800285.
  • Conner SD, Schmid SL. Regulated portals of entry into the cell. Nature. 2003;422(6927):37–44.
  • Herce HD, Garcia AE. Cell penetrating peptides: how do they do it? J Biol Phys. 2007;33(5–6):345–356.
  • Walrant A, Correia I, Jiao CY, et al. Different membrane behaviour and cellular uptake of three basic arginine-rich peptides. Biochim Biophys Acta. 2011;1808(1):382–393.
  • Liu X, Liu C, Zhang W, et al. Oligoarginine-modified biodegradable nanoparticles improve the intestinal absorption of insulin. Int J Pharm. 2013;448(1):159–167.
  • Zhu X, Shan W, Zhang P, et al. Penetratin derivative-based nanocomplexes for enhanced intestinal insulin delivery. Mol Pharm. 2014;11(1):317–328.
  • Damge C, Maincent P, Ubrich N. Oral delivery of insulin associated to polymeric nanoparticles in diabetic rats. J Control Release. 2007;117(2):163–170.
  • Sanderson MJ, Smith I, Parker I, et al. Fluorescence microscopy. Cold Spring Harb Protoc. 2014;2014(10):pdb.top071795–pdb.top071795.
  • Sharma R, Gupta U, Garg NK, et al. Surface engineered and ligand anchored nanobioconjugate: an effective therapeutic approach for oral insulin delivery in experimental diabetic rats. Colloids Surf B Biointerfaces. 2015;127:172–181.
  • Li X, Guo S, Zhu C, et al. Intestinal mucosa permeability following oral insulin delivery using core shell corona nanolipoparticles. Biomaterials. 2013;34(37):9678–9687.
  • Yang L, Li M, Sun Y, et al. A cell-penetrating peptide conjugated carboxymethyl-β-cyclodextrin to improve intestinal absorption of insulin. Int J Biol Macromol. 2018;111:685–695.
  • Reix N, Parat A, Seyfritz E, et al. In vitro uptake evaluation in Caco-2 cells and in vivo results in diabetic rats of insulin-loaded PLGA nanoparticles. Int J Pharm. 2012;437(1–2):213–220.
  • Tan X, Liu X, Zhang Y, et al. Silica nanoparticles on the oral delivery of insulin. Expert Opin Drug Deliv. 2018;15(8):805–820.
  • Zheng Y, Wu J, Shan W, et al. Multifunctional nanoparticles enable efficient oral delivery of biomacromolecules via improving payload stability and regulating the transcytosis pathway. ACS Appl Mater Interfaces. 2018;10(40):34039–34049.
  • Zeng Z, Dong C, Zhao P, et al. Scalable production of therapeutic protein nanoparticles using flash nanoprecipitation. Adv Healthcare Mater. 2019;8:e1801010.
  • Sonaje K, Lin YH, Juang JH, et al. In vivo evaluation of safety and efficacy of self-assembled nanoparticles for oral insulin delivery. Biomaterials. 2009;30(12):2329–2339.
  • Sonaje K, Lin KJ, Wang JJ, et al. Self-assembled ph-sensitive nanoparticles: a platform for oral delivery of protein drugs. Adv Funct Mater. 2010;20(21):3695–3700.
  • Sonaje K, Lin KJ, Wey SP, et al. Biodistribution, pharmacodynamics and pharmacokinetics of insulin analogues in a rat model: oral delivery using ph-responsive nanoparticles vs. subcutaneous injection. Biomaterials. 2010;31(26):6849–6858.
  • Xu Y, Zheng Y, Wu L, et al. Novel solid lipid nanoparticle with endosomal escape function for oral delivery of insulin. ACS Appl Mater Interfaces. 2018;135:46365.
  • Sarmento B, Mazzaglia D, Bonferoni MC, et al. Effect of chitosan coating in overcoming the phagocytosis of insulin loaded solid lipid nanoparticles by mononuclear phagocyte system. Carbohyd Polym. 2011;84(3):919–925.
  • Verma A, Sharma S, Gupta PK, et al. Vitamin B12 functionalized layer by layer calcium phosphate nanoparticles: a mucoadhesive and ph responsive carrier for improved oral delivery of insulin. Acta Biomater. 2016;31:288–300.
  • Yu F, Li Y, Liu CS, et al. Enteric-coated capsules filled with mono-disperse micro-particles containing PLGA-lipid-PEG nanoparticles for oral delivery of insulin. Int J Pharm. 2015;484(1–2):181–191.
  • Li H, Zhang Z, Bao X, et al. Fatty acid and quaternary ammonium modified chitosan nanoparticles for insulin delivery. Colloids Surf B Biointerfaces. 2018;170:136–143.
  • Zhang Z, Cai H, Liu Z, et al. Effective enhancement of hypoglycemic effect of insulin by liver-targeted nanoparticles containing cholic acid-modified chitosan derivative. Mol Pharm. 2016;13(7):2433–2442.
  • Thompson C, Cheng WP, Gadad P, et al. Uptake and transport of novel amphiphilic polyelectrolyte-insulin nanocomplexes by Caco-2 cells–towards oral insulin. Pharm Res. 2011;28(4):886–896.
  • Boulenc X, Breul T, Gautier J-C, et al. Sodium lauryl sulphate increases tiludronate paracellular transport using human epithelial Caco-2 monolayers. Int J Pharm. 1995;123(1):71–83.
  • Ganeshkumar M, Ponrasu T, Sathishkumar M, et al. Preparation of amphiphilic hollow carbon nanosphere loaded insulin for oral delivery. Colloids Surf B Biointerfaces. 2013;103:238–243.
  • Zhang X, Sun M, Zheng A, et al. Preparation and characterization of insulin-loaded bioadhesive PLGA nanoparticles for oral administration. Eur J Pharm Sci. 2012;45(5):632–638.
  • Boushra M, Tous S, Fetih G, et al. Development and evaluation of viscosity-enhanced nanocarrier (ven) for oral insulin delivery. Int J Pharm. 2016;511(1):462–472.
  • Bai X, Kong M, Xia G, et al. Systematic investigation of fabrication conditions of nanocarrier based on carboxymethyl chitosan for sustained release of insulin. Int J Biol Macromol. 2017;102:468–474.
  • Wang Y, Huang F, Sun Y, et al. Development of shell cross-linked nanoparticles based on boronic acid-related reactions for self-regulated insulin delivery. J Biomater Sci Polym Ed. 2017;28(1):93–106.
  • Mahjub R, Radmehr M, Dorkoosh FA, et al. Lyophilized insulin nanoparticles prepared from quaternized n-aryl derivatives of chitosan as a new strategy for oral delivery of insulin: In vitro, ex vivo and in vivo characterizations. Drug Dev Ind Pharm. 2014;40(12):1645–1659.
  • Shamsa ES, Mahjub R, Mansoorpour M, et al. Nanoparticles prepared from n,n-dimethyl-n-octyl chitosan as the novel approach for oral delivery of insulin: preparation, statistical optimization and in-vitro characterization. Iran J Pharm Res. 2018;17(2):442–459.
  • Wu Z, Zhang S, Zhang X, et al. Phenylboronic acid grafted chitosan as a glucose-sensitive vehicle for controlled insulin release. J Pharm Sci. 2011;100(6):2278–2286.
  • Araujo F, Shrestha N, Shahbazi MA, et al. The impact of nanoparticles on the mucosal translocation and transport of glp-1 across the intestinal epithelium. Biomaterials. 2014;35(33):9199–9207.
  • Georgantzopoulou A, Serchi T, Cambier S, et al. Effects of silver nanoparticles and ions on a co-culture model for the gastrointestinal epithelium. Part Fibre Toxicol. 2015;13(1):9.
  • Antoine D, Pellequer Y, Tempesta C, et al. Biorelevant media resistant co-culture model mimicking permeability of human intestine. Int J Pharm. 2015;481(1–2):27–36.
  • Cho HJ, Oh J, Choo MK, et al. Chondroitin sulfate-capped gold nanoparticles for the oral delivery of insulin. Int J Biol Macromol. 2014;63:15–20.
  • Yu Z, Yu M, Zhang Z, et al. Bovine serum albumin nanoparticles as controlled release carrier for local drug delivery to the inner ear. Nanoscale Res Lett. 2014;9(1):343.
  • Hu K, Li J, Shen Y, et al. Lactoferrin-conjugated peg–pla nanoparticles with improved brain delivery: in vitro and in vivo evaluations. J Control Release. 2009;134(1):55–61.
  • Salamat-Miller N, Johnston TP. Current strategies used to enhance the paracellular transport of therapeutic polypeptides across the intestinal epithelium. Int J Pharm. 2005;294(1–2):201–216.
  • Evans DF, Pye G, Bramley R, et al. Measurement of gastrointestinal ph profiles in normal ambulant human subjects. Gut. 1988;29(8):1035–1041. Aug
  • Chuang EY, Lin KJ, Su FY, et al. Calcium depletion-mediated protease inhibition and apical-junctional-complex disassembly via an egta-conjugated carrier for oral insulin delivery. J Control Release. 2013;169(3):296–305.
  • Su FY, Lin KJ, Sonaje K, et al. Protease inhibition and absorption enhancement by functional nanoparticles for effective oral insulin delivery. Biomaterials. 2012;33(9):2801–2811.
  • Sonaje K, Chen YJ, Chen HL, et al. Enteric-coated capsules filled with freeze-dried chitosan/poly(gamma-glutamic acid) nanoparticles for oral insulin delivery. Biomaterials. 2010;31(12):3384–3394.
  • Lopes MA, Abrahim BA, Seica R, et al. Intestinal uptake of insulin nanoparticles: facts or myths? CPB. 2014;15(7):629–638.
  • Sajeesh S, Bouchemal K, Sharma CP, et al. Surface-functionalized polymethacrylic acid based hydrogel microparticles for oral drug delivery. Eur J Pharm Biopharm. 2010;74(2):209–218.
  • Brown RC, Davis Thomas P. Calcium modulation of adherens and tight junction function. Stroke. 2002;33(6):1706–1711.
  • Shan W, Zhu X, Tao W, et al. Enhanced oral delivery of protein drugs using zwitterion-functionalized nanoparticles to overcome both the diffusion and absorption barriers. ACS Appl Mater Interfaces. 2016;8(38):25444–25453.
  • Shaklai M, Tavassoli M. Lanthanum as an electron microscopic stain. J Histochem Cytochem. 1982;30(12):1325–1330.
  • He X, Sugawara M, Takekuma Y, et al. Absorption of ester prodrugs in Caco-2 and rat intestine models. Antimicrob Agents Ch. 2004;48(7):2604–2609.
  • Ma Z, Lim TM, Lim LY. Pharmacological activity of peroral chitosan-insulin nanoparticles in diabetic rats. Int J Pharm. 2005;293(1–2):271–280.
  • Yang M, Lai SK, Wang YY, et al. Biodegradable nanoparticles composed entirely of safe materials that rapidly penetrate human mucus. Angew Chem Int Ed Engl. 2011;50(11):2597–2600.
  • Zhang ZH, Zhang YL, Zhou JP, et al. Solid lipid nanoparticles modified with stearic acid-octaarginine for oral administration of insulin. Int J Nanomedicine. 2012;7:3333–3339.
  • Panyam J, Zhou WZ, Prabha S, et al. Rapid endo-lysosomal escape of poly(dl-lactide-co-glycolide) nanoparticles: implications for drug and gene delivery. FASEB J. 2002;16(10):1217–1226.
  • Deng W, Xie Q, Wang H, et al. Selenium nanoparticles as versatile carriers for oral delivery of insulin: insight into the synergic antidiabetic effect and mechanism. Nanomedicine. 2017;13(6):1965–1974.
  • Andreani T, Miziara L, Lorenzon EN, et al. Effect of mucoadhesive polymers on the in vitro performance of insulin-loaded silica nanoparticles: interactions with mucin and biomembrane models. Eur J Pharm Biopharm. 2015;93:118–126.
  • Sarmento B, Ribeiro A, Veiga F, et al. Alginate/chitosan nanoparticles are effective for oral insulin delivery. Pharm Res. 2007;24(12):2198–2206.
  • Des Rieux A, Fievez V, Theate I, et al. An improved in vitro model of human intestinal follicle-associated epithelium to study nanoparticle transport by M cells. Eur J Pharm Sci. 2007;30(5):380–391.
  • Eldridge JH, Hammond CJ, Meulbroek JA, et al. Controlled vaccine release in the gut-associated lymphoid tissues. I. Orally administered biodegradable microspheres target the Peyer’s patches. J Control Release. 1990;11(1–3):205–214.
  • Fasano A. Innovative strategies for the oral delivery of drugs and peptides. Trends Biotechnol. 1998;16(4):152–157.
  • Grabowski N, Hillaireau H, Vergnaud J, et al. Toxicity of surface-modified PLGA nanoparticles toward lung alveolar epithelial cells. Int J Pharm. 2013;454(2):686–694.
  • Ma Z, Lim LY. Uptake of chitosan and associated insulin in Caco-2 cell monolayers: a comparison between chitosan molecules and chitosan nanoparticles. Pharm Res. 2003;20(11):1812–1819.
  • Mao S, Germershaus O, Fischer D, et al. Uptake and transport of PEG-graft-trimethyl-chitosan copolymer-insulin nanocomplexes by epithelial cells. Pharm Res. 2005;22(12):2058–2068.
  • Bannunah AM, Vllasaliu D, Lord J, et al. Mechanisms of nanoparticle internalization and transport across an intestinal epithelial cell model: effect of size and surface charge. Mol Pharm. 2014;11(12):4363–4373.
  • Cui Y, Shan W, Zhou R, et al. The combination of endolysosomal escape and basolateral stimulation to overcome the difficulties of “easy uptake hard transcytosis” of ligand-modified nanoparticles in oral drug delivery. Nanoscale. 2018;10(3):1494–1507.
  • Rho JG, Han HS, Han JH, et al. Self-assembled hyaluronic acid nanoparticles: Implications as a nanomedicine for treatment of type 2 diabetes. J Control Release. 2018;279:89–98.
  • Rodal SK, Skretting G, Garred O, et al. Extraction of cholesterol with methyl-beta-cyclodextrin perturbs formation of clathrin-coated endocytic vesicles. MBoC. 1999;10(4):961–974.
  • Chiu YL, Ho YC, Chen YM, et al. The characteristics, cellular uptake and intracellular trafficking of nanoparticles made of hydrophobically-modified chitosan. J Control Release. 2010;146(1):152–159.
  • Perumal OP, Inapagolla R, Kannan S, et al. The effect of surface functionality on cellular trafficking of dendrimers. Biomaterials. 2008;29(24–25):3469–3476.
  • Kruth HS, Jones NL, Huang W, et al. Macropinocytosis is the endocytic pathway that mediates macrophage foam cell formation with native low density lipoprotein. J Biol Chem. 2005;280(3):2352–2360.
  • Du W, Fan Y, Zheng N, et al. Transferrin receptor specific nanocarriers conjugated with functional 7peptide for oral drug delivery. Biomaterials. 2013;34(3):794–806.
  • Zhang Q, Liu Q, Wu J, et al. Pept1 involved in the uptake and transepithelial transport of cefditoren in vivo and in vitro. Eur J Pharmacol. 2009;612(1–3):9–14.

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