Targeting the intestinal lymphatic system: a versatile path for enhanced oral bioavailability of drugs

References

• Cueni LN, Detmar M. The lymphatic system in health and disease. Lymphat Res Biol. 2008;6:109–122.
   PubMedGoogle Scholar
• Bouta EM, Bell RD, Rahimi H, et al. Targeting lymphatic function as a novel therapeutic intervention for rheumatoid arthritis. Nat Rev Rheumatol. 2018;14:94–106.
   PubMed Web of Science ®Google Scholar
• Scallan J, Huxley VH, Korthuis RJ. Chapter 3: the Lymphatic Vasculature. In: Scallan J, Huxley VH, Korthuis RJ, editor. Capillary fluid exchange: regulation, functions, and pathology. San Rafael (CA): Morgan & Claypool Life Sciences; 2010.
   Google Scholar
• Choi I, Lee S, Hong YK. The new era of the lymphatic system: no longer secondary to the blood vascular system. Cold Spring Harb Perspect Med. 2012;2:1–23.
   Web of Science ®Google Scholar
• Zimmermann KA Lymphatic System: facts, Functions & Diseases. Live Science. 2016. Available at http://www.livescience.com/26983-lymphatic-system.html.Accessed on 2017 Feb 18th.
   Google Scholar
• O’Driscoll CM. Chapter 1: anatomy and Physiology of the lymphatics. In: William NC, Stella VJ, Editors. Lymphatic transport of drugs. Boca Raton, FL, USA: CRC Press Inc 1992. p. 1–36.
   Google Scholar
• Miller MJ, McDole JR, Newberry RD. Microanatomy of the intestinal lymphatic system. Ann N Y Acad Sci. 2010;1207(Suppl 1):E21–8.
   PubMedGoogle Scholar
• Reddy LHV, Murthy RSR. Lymphatic transport of orally administered drugs. Indian J Exp Biol. 2002;40(1097–1):109.
   PubMedGoogle Scholar
• Ali Khan A, Mudassir J, Mohtar N, et al. Advanced drug delivery to the lymphatic system: lipid-based nanoformulations. Int J Nanomedicine. 2013;8:2733–2744.
   PubMed Web of Science ®Google Scholar
• Kim H, Kim Y, Lee J. Liposomal formulations for enhanced lymphatic drug delivery. Asian Journal of Pharmaceutical Sciences. 2013;8:96–103.
   Google Scholar
• Charman WNA, Stella VJ. Estimating the maximal potential for intestinal lymphatic transport of lipophilic drug molecules. Int J Pharm. 1986;34:175–178.
   Web of Science ®Google Scholar
• Trevaskis NL, Hu L, Caliph SM, et al. The mesenteric lymph duct cannulated rat model: application to the assessment of intestinal lymphatic drug transport. J Vis Exp. 2015; Epub 2015/ 04/14.
   PubMed Web of Science ®Google Scholar
• [cited 2017 Jun 6]. Available from: http://www.innerbody.com/image_digeov/dige10-new3.html
   Google Scholar
• Noah TK, Donahue B, Shroyer NF. Intestinal development and differentiation. Exp Cell Res. 2011;317:2702–2710.
   PubMed Web of Science ®Google Scholar
• Dixon JB. Mechanisms of chylomicron uptake into lacteals. Ann N Y Acad Sci. 2010;1207(Suppl 1):E52–7.
   PubMedGoogle Scholar
• Dixon JB. Lymphatic lipid transport: sewer or subway? Trends Endocrinol Metab. 2010;21:480–487.
   PubMed Web of Science ®Google Scholar
• Jung C, Hugot JP, Barreau F. Peyer’s patches: the immune sensors of the intestine. Int J Inflam. 2010;2010:823710.
   PubMedGoogle Scholar
• Delie F, Blanco-Príeto MJ. Polymeric particulates to improve oral bioavailability of peptide drugs. Molecules. 2005;10:65–80.
   PubMed Web of Science ®Google Scholar
• Po SP, Zuki ABZ, Zamri-Saad M, et al. Morphological study of the jejunal and ileal Peyer’s patches of three-month old calves. J Anim Vet Adv. 2005;4:579–589.
   Google Scholar
• Linden SK, Sutton P, Karlsson NG, et al. Mucins in the mucosal barrier to infection. Mucosal Immunol. 2008;1:183–197.
   PubMed Web of Science ®Google Scholar
• Egberts HJ, Koninkx JF, Van Dijk JE, et al. Biological and pathobiological aspects of the glycocalyx of the small intestinal epithelium. A Review. Vet Q. 1984;6:186–199.
   PubMed Web of Science ®Google Scholar
• Pelaseyed T, Bergstrom JH, Gustafsson JK, Ermund A, Birchenough GM, Schutte A, van der Post S, Svensson F, Rodriguez-Pineiro AM, Nystrom EE, Wising C, Johansson ME, Hansson GC. The mucus and mucins of the goblet cells and enterocytes provide the first defense line of the gastrointestinal tract and interact with the immune system. Immunol Rev. 2014;260:8–20.
   PubMed Web of Science ®Google Scholar
• Daneman R, Rescigno M. The gut immune barrier and the blood-brain barrier: are they so different? Immunity. 2009;31:722–735.
   PubMed Web of Science ®Google Scholar
• Iwasaki A, Linehan M, Welker R, et al. Immunofluorescence analysis of poliovirus receptor expression in Peyer’s patches of humans, primates, and CD155 transgenic mice: implications for poliovirus infection. J Infect Dis. 2002;186:585–592.
   PubMed Web of Science ®Google Scholar
• Ermund A, Gustafsson JK, Hansson GC, et al. Mucus properties and goblet cell quantification in mouse, rat and human ileal Peyer’s patches. PLoS One. 2013;8:e83688.
   PubMed Web of Science ®Google Scholar
• Gullberg E, Soderholm JD. Peyer’s patches and M cells as potential sites of the inflammatory onset in Crohn’s disease. Ann N Y Acad Sci. 2006;1072:218–232.
   PubMed Web of Science ®Google Scholar
• Neutra MR, Frey A, Kraehenbuhl J-P. Epithelial M cells: gateways for mucosal infection and immunization. Cell. 1996;86:345–348.
   PubMed Web of Science ®Google Scholar
• Anderson M, Omri A. The effect of different lipid components on the in vitro stability and release kinetics of liposome formulations. Drug Deliv. 2004;11:33–39.
   PubMed Web of Science ®Google Scholar
• Shah R, Eldridge D, Palombo E, et al. Lipid Nanoparticles: Production, Characterization and Stability. Switzerland: Springer International Publishing,  2015.
   Google Scholar
• Moss DM, Curley P, Kinvig H, et al. The biological challenges and pharmacological opportunities of orally administered nanomedicine delivery. Expert Rev Gastroenterol Hepatol. 2018;12:223–236.
   PubMed Web of Science ®Google Scholar
• Menard S, Cerf-Bensussan N, Heyman M. Multiple facets of intestinal permeability and epithelial handling of dietary antigens. Mucosal Immunol. 2010;3:247–259.
   PubMed Web of Science ®Google Scholar
• Lane ME, Corrigan OI. Paracellular and transcellular pathways facilitate insulin permeability in rat gut. J Pharm Pharmacol. 2006;58:271–275.
   PubMed Web of Science ®Google Scholar
• Camenisch G, Alsenz J, Van De Waterbeemd H, et al. Estimation of permeability by passive diffusion through caco-2 cell monolayers using the drugs’ lipophilicity and molecular weight. Eur J Pharm Sci. 1998;6:313–319.
   Web of Science ®Google Scholar
• 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;24:413–428.
   PubMed Web of Science ®Google Scholar
• Singh R, Singh S, Lillard JW Jr. Past, present, and future technologies for oral delivery of therapeutic proteins. J Pharm Sci. 2008;97:2497–2523.
   PubMed Web of Science ®Google Scholar
• Aungst BJ. Absorption enhancers: applications and advances. AAPS J. 2012;14:10–18.
   PubMed Web of Science ®Google Scholar
• Alai MS, Lin WJ, Pingale SS. Application of polymeric nanoparticles and micelles in insulin oral delivery. J Food Drug Anal. 2015;23:351–358.
   PubMed Web of Science ®Google Scholar
• Shaji J, Patole V. Protein and Peptide Drug Delivery: oral Approaches. Indian J Pharm Sci. 2008;70:269–277.
   PubMed Web of Science ®Google Scholar
• Anilkumar P, Badarinath AV, Naveen N, et al. A rationalized description on study of intestinal barrier, drug permeability and permeation enhancers. Journal of Global Trends in Pharmaceutical Sciences. 2011;2:431–449.
   Google Scholar
• Hochman J, Artursson P. Mechanisms of absorption enhancement and tight junction regulation. J Control Release. 1994;29:253–261.
   Web of Science ®Google Scholar
• Nielsen MJ, Rasmussen MR, Andersen CB, et al. Vitamin B12 transport from food to the body’s cells–a sophisticated, multistep pathway. Nat Rev Gastroenterol Hepatol. 2012;9:345–354.
   PubMed Web of Science ®Google Scholar
• Hamman JH, Demana PH, Olivier EI. Targeting receptors, transporters and site of absorption to improve oral drug delivery. Drug Target Insights. 2007;2:71–81.
   PubMedGoogle Scholar
• Clevers HC, Bevins CL. Paneth cells: maestros of the small intestinal crypts. Annu Rev Physiol. 2013;75:289–311.
   PubMed Web of Science ®Google Scholar
• Lim JP, Gleeson PA. Macropinocytosis: an endocytic pathway for internalising large gulps. Immunol Cell Biol. 2011;89:836–843.
   PubMed Web of Science ®Google Scholar
• Maekawa M, Terasakaa S, Mochizuki Y, et al. Sequential breakdown of 3-phosphorylated phosphoinositides is essential for the completion of macropinocytosis. Proc Natl Acad Sci. 2014;111:E978–E87.
   PubMed Web of Science ®Google Scholar
• Mercer J, Helenius A. Virus entry by macropinocytosis. Nat Cell Biol. 2009;11:510–520.
   PubMed Web of Science ®Google Scholar
• McMahon HT, Boucrot E. Molecular mechanism and physiological functions of clathrin-mediated endocytosis. Nat Rev Mol Cell Biol. 2011;12:517–533.
   PubMed Web of Science ®Google Scholar
• Hirst J, Robinson MS. Clathrin and adaptors. Biochim Biophys Acta. 1998;1404:173–193.
   PubMed Web of Science ®Google Scholar
• Nabi IR, Le PU. Caveolae/raft-dependent endocytosis. J Cell Biol. 2003;161:673–677.
   PubMed Web of Science ®Google Scholar
• Herd H, Daum N, Jones AT, et al. Nanoparticle geometry and surface orientation influence mode of cellular uptake. ACS Nano. 2013;7:1961–1973.
   PubMed Web of Science ®Google Scholar
• Kuhn DA, Vanhecke D, Michen B, et al. Different endocytotic uptake mechanisms for nanoparticles in epithelial cells and macrophages. Beilstein J Nanotechnol. 2014;5:1625–1636.
   PubMed Web of Science ®Google Scholar
• Dos Santos T, Varela J, Lynch I, et al. Effects of transport inhibitors on the cellular uptake of carboxylated polystyrene nanoparticles in different cell lines. PLoS One. 2011;6:e24438.
   PubMed Web of Science ®Google Scholar
• Hu M, Zhang J, Ding R, et al. Improved oral bioavailability and therapeutic efficacy of dabigatran etexilate via Soluplus-TPGS binary mixed micelles system. Drug Dev Ind Pharm. 2017;43:687–697.
   PubMed Web of Science ®Google Scholar
• Salatin S, Yari Khosroushahi A. Overviews on the cellular uptake mechanism of polysaccharide colloidal nanoparticles. J Cell Mol Med. 2017;21:1668–1686.
   PubMed Web of Science ®Google Scholar
• Attili-Qadri S, Karra N, Nemirovski A, et al. Oral delivery system prolongs blood circulation of docetaxel nanocapsules via lymphatic absorption. Proc Natl Acad Sci U S A. 2013;110:17498–17503.
   PubMed Web of Science ®Google Scholar
• Wang T, Shen L, Zhang Z, et al. A novel core-shell lipid nanoparticle for improving oral administration of water soluble chemotherapeutic agents: inhibited intestinal hydrolysis and enhanced lymphatic absorption. Drug Deliv. 2017;24:1565–1573.
   PubMed Web of Science ®Google Scholar
• Alrushaid S, Sayre CL, Yanez JA, et al. Pharmacokinetic and toxicodynamic characterization of a novel doxorubicin derivative. Pharmaceutics. 2017;9:1–19.
   Web of Science ®Google Scholar
• Nishioka Y, Yoshino H. Lymphatic targeting with nanoparticulate system. Adv Drug Deliv Rev. 2001;47:55–64.
   PubMed Web of Science ®Google Scholar
• Chaudhri VK, Singh P, Hussain Z, et al. Lymphatic system and nanoparticulate carriers for lymphatic delivery. Int J Adv Res Biol Sci. 2016;3:142–152.
   Google Scholar
• Ghosh S, Roy T. Nanoparticulate drug-delivery systems: lymphatic uptake and its gastrointestinal applications. J Appl Pharm Sci. 2014;4:123–130.
   Google Scholar
• Zhang XY, Lu WY. Recent advances in lymphatic targeted drug delivery system for tumor metastasis. Cancer Biol Med. 2014;11:247–254.
   PubMedGoogle Scholar
• Chaudhary S, Garg T, Murthy RS, et al. Recent approaches of lipid-based delivery system for lymphatic targeting via oral route. J Drug Target. 2014;22:871–882.
   PubMed Web of Science ®Google Scholar
• Ahn H, Park JH. Liposomal delivery systems for intestinal lymphatic drug transport. Biomaterials Research. 2016;20:36.
   PubMedGoogle Scholar
• Cai S, Yang Q, Bagby TR, et al. Lymphatic drug delivery using engineered liposomes and solid lipid nanoparticles. Adv Drug Deliv Rev. 2011;63:901–908.
   PubMed Web of Science ®Google Scholar
• Saraf S, Ghosh A, Kaur CD, et al. Novel modified nanosystem based lymphatic targeting. Research Journal of Nanoscience and Nanotechnology. 2011;1:60–74.
   Google Scholar
• [cited 2017 June 6]. Available from: http://www.vivo.colostate.edu/hbooks/pathphys/digestion/smallgut/absorb_lipids.html
   Google Scholar
• Mu H. The digestion of dietary triacylglycerols. Prog Lipid Res. 2004;43:105–133.
   PubMed Web of Science ®Google Scholar
• Phan CT, Tso P. Intestinal lipid absorption and transport. Front Biosci. 2001;6:D299–319.
   PubMed Web of Science ®Google Scholar
• Ramaldes GA, Pereira MA, De Castro PT, et al. Liposome uptake by the Peyer’s patches of mice after oral administration. Rev Bras Cienc Farm. 2002;38:173–182.
   Google Scholar
• Bargoni A, Cavalli R, Caputo O, et al. Solid lipid nanoparticles in lymph and plasma after duodenal administration to rats. Pharm Res. 1998;15:745–750.
   PubMed Web of Science ®Google Scholar
• Tomizawa H, Aramaki Y, Fujii Y, et al. Uptake of phosphatidylserine liposomes by rat Peyer’s patches following intraluminal administration. Pharm Res. 1993;10:549–552.
   PubMed Web of Science ®Google Scholar
• Harde H, Das M, Jain S. Solid lipid nanoparticles: an oral bioavailability enhancer vehicle. Expert Opin Drug Deliv. 2011;8:1407–1424.
   PubMed Web of Science ®Google Scholar
• Aramaki Y, Tomizawa H, Hara T, et al. Stability of liposomes in vitro and their uptake by rat Peyer’s patches following oral administration. Pharmaceutical Research. 1993;10:1228–1231.
   PubMed Web of Science ®Google Scholar
• Prajapati JB, Verma SD, Patel AA. Oral bioavailability enhancement of agomelatine by loading into nanostructured lipid carriers: peyer’s patch targeting approach. Int J Nanomedicine. 2018;13:35–38.
   PubMedGoogle Scholar
• Yun Y, Cho YW, Park K. Nanoparticles for oral delivery: targeted nanoparticles with peptidic ligands for oral protein delivery. Adv Drug Deliv Rev. 2013;65:822–832.
   PubMed Web of Science ®Google Scholar
• Joshi G, Kumar A, Sawant K. Enhanced bioavailability and intestinal uptake of Gemcitabine HCl loaded PLGA nanoparticles after oral delivery. Eur J Pharm Sci. 2014;60:80–89.
   PubMed Web of Science ®Google Scholar
• Van Der Lubben IM, Verhoef JC, Van Aelst AC, et al. Chitosan microparticles for oral vaccination: preparation, characterization and preliminary in vivo uptake studies in murine Peyer’s patches. Biomaterials. 2001;22:687–694.
   PubMed Web of Science ®Google Scholar
• Janeway CAJ, Travers P, Mea W. Immunobiology: the immune system in health and disease. ed. 5th edition. New York: Garland Science; 2001. The mucosal immune system. Available from https://www.ncbi.nlm.nih.gov/books/NBK27169/
   Google Scholar
• Miller H, Zhang J, KuoLee R, et al. Intestinal M cells: the fallible sentinels? World J Gastroenterol. 2007;13:1477–1486.
   PubMed Web of Science ®Google Scholar
• De Jesus M, Ostroff GR, Levitz SM, et al. A population of Langerin-positive dendritic cells in murine Peyer’s patches involved in sampling beta-glucan microparticles. PLoS One. 2014;9:e91002.
   PubMed Web of Science ®Google Scholar
• Pridgen EM, Alexis F, Farokhzad OC. Polymeric nanoparticle technologies for oral drug delivery. Clin Gastroenterol Hepatol. 2014;12:1605–1610.
   PubMed Web of Science ®Google Scholar
• 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;11:205–214.
   Web of Science ®Google Scholar
• Des Rieux A, Fievez V, Garinot M, et al. Nanoparticles as potential oral delivery systems of proteins and vaccines: a mechanistic approach. J Control Release. 2006;116:1–27.
   PubMed Web of Science ®Google Scholar
• Gullberg E, Leonard M, Karlsson J, et al. Expression of specific markers and particle transport in a new human intestinal M-cell model. Biochem Biophys Res Commun. 2000;279:808–813.
   PubMed Web of Science ®Google Scholar
• Jani P, Halbert GW, Langridge J, et al. The uptake and translocation of latex nanospheres and microspheres after oral administration to rats. J Pharm Pharmacol. 1989;41:809–812.
   PubMed Web of Science ®Google Scholar
• Des Rieux A, Ragnarsson EG, Gullberg E, et al. Transport of nanoparticles across an in vitro model of the human intestinal follicle associated epithelium. Eur J Pharm Sci. 2005;25:455–465.
   PubMed Web of Science ®Google Scholar
• Shakweh M, Ponchel G, Fattal E. Particle uptake by Peyer’s patches: a pathway for drug and vaccine delivery. Expert Opin Drug Deliv. 2004;1:141–163.
   PubMedGoogle Scholar
• Florence AT. Nanoparticle uptake by the oral route: fulfilling its potential? Drug Discov Today Technol. 2005;2:75–81.
   PubMedGoogle Scholar
• Garinot M, Fievez V, Pourcelle V, et al. PEGylated PLGA-based nanoparticles targeting M cells for oral vaccination. J Control Release 2007;120:195–204.
   PubMed Web of Science ®Google Scholar
• Jepson MA, Simmons NL, Savidge TC, et al. Selective binding and transcytosis of latex microspheres by rabbit intestinal M cells. Cell Tissue Res. 1993;271:399–405.
   PubMed Web of Science ®Google Scholar
• Jepson MA, Simmons NL, O’hagan DT, et al. Comparison of Poly(DL-Lactide-co-Glycolide) and polystyrene microsphere targeting to intestinal M cells. J Drug Target. 1993;1:245–249.
   PubMed Web of Science ®Google Scholar
• Clark MA, Jepson MA, Hirst BH. Exploiting M cells for drug and vaccine delivery. Adv Drug Deliv Rev. 2001;50:81–106.
   PubMed Web of Science ®Google Scholar
• Eldridge JH, Meulbroek JA, Staas JK, et al. Vaccine-containingbiodegradable microspheresspecifically enter the gut-associated lymphoid tissue following oral administration and induce a disseminated mucosal immune response. Adv Exp Med Biol. 1989;251:191–202.
   PubMedGoogle Scholar
• Ermak TH, Dougherty EP, Bhagat HR, et al. Uptake and transport of copolymer biodegradable microspheres by rabbit Peyer’s patch M cells. Cell Tissue Res. 1995;279:433–436.
   PubMed Web of Science ®Google Scholar
• Torche A-M, Jouan H, Corre PL, et al. Ex vivo and in situ PLGA microspheres uptake by pig ileal Peyer’s patch segment. Int J Pharm. 2000;201:15–27.
   PubMed Web of Science ®Google Scholar
• Margaris KN, Black RA. Modelling the lymphatic system: challenges and opportunities. Journal of the Royal Society, Interface. 2012;9:601–612.
   PubMed Web of Science ®Google Scholar
• Zhao J, Li X, Luo Q, et al. Screening of surface markers on rat intestinal mucosa microfold cells by using laser capture microdissection combined with protein chip technology. Int J Clin Exp Med. 2014;7:932–939.
   PubMed Web of Science ®Google Scholar
• Hase K, Kawano K, Nochi T, et al. Uptake through glycoprotein 2 of FimH(+) bacteria by M cells initiates mucosal immune response. Nature. 2009;462:226–230.
   PubMed Web of Science ®Google Scholar
• Peek RM, Fiske C, Wilson KT. Role of innate immunity in Helicobacter pylori-induced gastric malignancy. Physiol Rev. 2010;90:831–858.
   PubMed Web of Science ®Google Scholar
• Datta N, Mukherjee S, Das L, et al. Targeting of immunostimulatory DNA cures experimental visceral leishmaniasis through nitric oxide up-regulation and T cell activation. Eur J Immunol. 2003;33:1508–1518.
   PubMed Web of Science ®Google Scholar
• Medda S, Jaisankar P, Manna RK, et al. Phospholipid microspheres: a novel delivery mode for targeting antileishmanial agent in experimental leishmaniasis. J Drug Target. 2003;11:123–128.
   PubMed Web of Science ®Google Scholar
• Fievez V, Plapied L, Des Rieux A, et al. Targeting nanoparticles to M Cells with non-peptidic ligands for oral vaccination. Eur J Pharm Biopharm 2009;73:16–24.
   PubMed Web of Science ®Google Scholar
• Singodia D, Verma A, Verma RK, et al. Investigations into an alternate approach to target mannose receptors on macrophages using 4-sulfated N-acetyl galactosamine more efficiently in comparison with mannose-decorated liposomes: an application in drug delivery. Nanomedicine. 2012;8:468–477.
   PubMed Web of Science ®Google Scholar
• Youngren SR, Mulik R, Jun B, et al. Freeze-dried targeted mannosylated selenium-loaded nanoliposomes: development and evaluation. AAPS PharmSciTech. 2013;14:1012–1024.
   PubMed Web of Science ®Google Scholar
• De Coen R, Vanparijs N, Risseeuw MD, et al. pH-degradable mannosylated nanogels for dendritic cell targeting. Biomacromolecules. 2016;17:2479–2488.
   PubMed Web of Science ®Google Scholar
• Muller CD, Schuber F. Neo-mannosylated liposomes: synthesis and interaction with mouse Kupffer cells and resident pelitoneal macrophages. Biochim Biophys Acta. 1989;986:97–105.
   PubMed Web of Science ®Google Scholar
• Barratt GM, Nolibe D, Yapo A, et al. Use of mannosylated liposomes for in vivo targeting of a macrophage activator and control of artificial pulmonary metastases. Ann Inst Pasteur Immunol. 1987;138:437–450.
   PubMedGoogle Scholar
• Garcon N, Gregoriadis G, Taylor M, et al. Mannose-mediated targeted immunoadjuvant action of liposomes. Immunology. 1988;64:743–745.
   PubMed Web of Science ®Google Scholar
• Kaur A, Jain S, Tiwary AK. Mannan-coated gelatin nanoparticles for sustained and targeted delivery of didanosine: in vitro and in vivo evaluation. Acta Pharm. 2008;58:61–74.
   PubMed Web of Science ®Google Scholar
• Stimac A, Segota S, Dutour Sikiric M, et al. Surface modified liposomes by mannosylated conjugates anchored via the adamantyl moiety in the lipid bilayer. Biochim Biophys Acta. 2012;1818:2252–2259.
   PubMed Web of Science ®Google Scholar
• Mcg A-C, Hernandez MJM, Camanas RMV, et al. Formation and instability of o-phthalaldehyde derivatives of amino acids. Anal Biochem. 1989;178:1–7.
   PubMed Web of Science ®Google Scholar
• Zuman P. Reactions of orthophthalaldehyde with nucleophiles. Chem Rev. 2004;104:3217–3238.
   PubMed Web of Science ®Google Scholar
• Wang X, Kochetkova I, Haddad A, et al. Transgene vaccination using Ulex europaeus agglutinin I (UEA-1) for targeted mucosal immunization against HIV-1 envelope. Vaccine. 2005;23:3836–3842.
   PubMed Web of Science ®Google Scholar
• Clark MA, Blair H, Liang L, et al. Targeting polymerised liposome vaccine carriers to intestinal M cells. Vaccine. 2001;20:208–217.
   PubMed Web of Science ®Google Scholar
• Foster N, Clark MA, Jepson MA, et al. Ulex europaeus 1 lectin targets microspheres to mouse Peyer’s patch M-cells in vivo. Vaccine. 1998;16:536–541.
   PubMed Web of Science ®Google Scholar
• Manocha M, Pal PC, Chitralekha KT, et al. Enhanced mucosal and systemic immune response with intranasal immunization of mice with HIV peptides entrapped in PLG microparticles in combination with Ulex Europaeus-I lectin as M cell target. Vaccine. 2005;23:5599–5617.
   PubMed Web of Science ®Google Scholar
• Chionh YT, Wee JL, Every AL, et al. M-cell targeting of whole killed bacteria induces protective immunity against gastrointestinal pathogens. Infect Immun. 2009;77:2962–2970.
   PubMed Web of Science ®Google Scholar
• Choudhry N, Bajaj-Elliott M, McDonald V. The terminal sialic acid of glycoconjugates on the surface of intestinal epithelial cells activates excystation of Cryptosporidium parvum. Infect Immun. 2008;76:3735–3741.
   PubMed Web of Science ®Google Scholar
• Wood KM, Stone GM, Peppas NA. Wheat germ agglutinin functionalized complexation hydrogels for oral insulin delivery. Biomacromolecules. 2008;9:1293–1298.
   PubMed Web of Science ®Google Scholar
• Romano PR, Mackay A, Vong M, et al. Development of recombinant Aleuria aurantia lectins with altered binding specificities to fucosylated glycans. Biochem Biophys Res Commun. 2011;414:84–89.
   PubMed Web of Science ®Google Scholar
• Roth-Walter F, Scholl I, Untersmayr E, et al. M cell targeting with Aleuria aurantia lectin as a novel approach for oral allergen immunotherapy. J Allergy Clin Immunol. 2004;114:1362–1368.
   PubMed Web of Science ®Google Scholar
• Cornick S, Tawiah A, Chadee K. Roles and regulation of the mucus barrier in the gut. Tissue Barriers. 2015;3:e982426.
   PubMed Web of Science ®Google Scholar
• Jepson MA, Clark MA, Hirst BH. M cell targeting by lectins: a strategy for mucosal vaccination and drug delivery. Adv Drug Deliv Rev. 2004;56:511–525.
   PubMed Web of Science ®Google Scholar
• Irache JM, Durrer C, Duchêne D, et al. In vitro study of lectin-latex conjugates for specific bioadhesion. J Control Release. 1994;31:181–188.
   Web of Science ®Google Scholar
• Deryugina EI, Ratnikov BI, Postnova TI, et al. Processing of integrin alpha(v) subunit by membrane type 1 matrix metalloproteinase stimulates migration of breast carcinoma cells on vitronectin and enhances tyrosine phosphorylation of focal adhesion kinase. J Biol Chem. 2002;277:9749–9756.
   PubMed Web of Science ®Google Scholar
• Campbell ID, Humphries MJ. Integrin structure, activation, and interactions. Cold Spring Harb Perspect Biol. 2011;3:1–14.
   Web of Science ®Google Scholar
• Pimton P, Sarkar S, Sheth N, et al. Fibronectin-mediated upregulation of α5β1 integrin and cell adhesion during differentiation of mouse embryonic stem cells. Cell Adh Migr. 2014;5:73–82.
   Google Scholar
• Tyrer PC, Ruth Foxwell A, Kyd JM, et al. Receptor mediated targeting of M-cells. Vaccine. 2007;25:3204–3209.
   PubMed Web of Science ®Google Scholar
• Humphries JD, Byron A, Humphries MJ. Integrin ligands at a glance. Journal of Cell Science. 2006;119:3901–3903.
   PubMed Web of Science ®Google Scholar
• Frey A, Giannasca KT, Weltzin R, et al. Role of the glycocalyx in regulating access of microparticles to apical plasma membranes of intestinal epithelial cells: implications for microbial attachment and oral vaccine targeting. J Exp Med. 1996;184:1045–1059.
   PubMed Web of Science ®Google Scholar
• Salphati L, Childers K, Pan L, et al. Evaluation of a single-pass intestinal-perfusion method in rat for the prediction of absorption in man. J Pharm Pharmacol. 2001;53:1007–1013.
   PubMed Web of Science ®Google Scholar
• Patel JR, Barve KH. Intestinal permeability of Lamivudine using single pass intestinal perfusion. Indian J Pharm Sci. 2012;74:478–481.
   PubMed Web of Science ®Google Scholar
• Lozoya-Agullo I, Gonzalez-Alvarez I, Gonzalez-Alvarez M, et al. In situ perfusion model in rat colon for drug absorption studies: comparison with small intestine and caco-2 cell model. J Pharm Sci. 2015;104:3136–3145.
   PubMed Web of Science ®Google Scholar
• Tsai YJ, Tsai TH. Mesenteric lymphatic absorption and the pharmacokinetics of naringin and naringenin in the rat. J Agric Food Chem. 2012;60:12435–12442.
   PubMed Web of Science ®Google Scholar
• Porter CJH, Charman WN. Model systems for intestinal lymphatic transport studies. In: Borchardt RT, Smith PL, Wilson G. Eds., Models for assessing drug absorption and metabolism. New York: Springer Science & Business Media; 1996. Vol. 8. 85–102.
   Google Scholar
• Warshaw AL. A simplified method of cannulating the intestinal lymphatic of the rat. Gut. 1972;13:66–67.
   PubMed Web of Science ®Google Scholar
• Griffin B, O’Driscoll C. 0. In: Ehrhardt C, Kim K-J, Eds. Drug absorption studies. US: Springer; 2008. p. 34–76.
   Google Scholar
• Gershkovich P, Qadri B, Yacovan A, et al. Different impacts of intestinal lymphatic transport on the oral bioavailability of structurally similar synthetic lipophilic cannabinoids: dexanabinol and PRS-211,220. Eur J Pharm Sci. 2007;31:298–305.
   PubMed Web of Science ®Google Scholar
• Caliph SM, Charman WN, Porter CJH. Effect of short-, medium-, and long-chain fatty acid-based vehicles on the absolute oral bioavailability and intestinal lymphatic transport of halofantrine and assessment of mass balance in lymph-cannulated and non-cannulated rats. J Pharm Sci. 2000;89:1073–1084.
   PubMed Web of Science ®Google Scholar
• Manowitz NR, Tso P, Drake DS, et al. Dietary supplementation with Pluronic L-81 modifies hepatic secretion of very low density lipoproteins in the rat. J Lipid Res. 1986;26:196–207.
   Google Scholar
• Lu WJ, Yang Q, Yang L, et al. Chylomicron formation and secretion is required for lipid-stimulated release of incretins GLP-1 and GIP. Lipids. 2012;47:571–580.
   PubMed Web of Science ®Google Scholar
• Ghoshal S, Witta J, Zhong J, et al. Chylomicrons promote intestinal absorption of lipopolysaccharides. J Lipid Res. 2009;50:90–97.
   PubMed Web of Science ®Google Scholar
• Dahan A, Hoffman A. Evaluation of a chylomicron flow blocking approach to investigate the intestinal lymphatic transport of lipophilic drugs. Eur J Pharm Sci. 2005;24:381–388.
   PubMed Web of Science ®Google Scholar
• Glickman RM, Kirsch K. Lymph chylomicron formation during the inhibition of protein synthesis .Studies of Chylomicron Apoproteins. J Clin Invest. 1973;52:2910–2920.
   PubMed Web of Science ®Google Scholar
• Elsheikh MA, Elnaggar YSR, Otify DY, et al. Bioactive-chylomicrons for oral lymphatic targeting of berberine chloride: novel flow-blockage assay in tissue-based and caco-2 cell line models. Pharm Res. 2018;35:18.
   PubMed Web of Science ®Google Scholar
• Elsheikh MA, Elnaggar YSR, Hamdy DA, et al. Novel cremochylomicrons for improved oral bioavailability of the antineoplastic phytomedicine berberine chloride: optimization and pharmacokinetics. Int J Pharm. 2018;535:316–324.
   PubMed Web of Science ®Google Scholar
• Green PHR, Glickman RM. Intestinal lipoprotein metabolism. J Lipid Res. 1981;22:1153–1173.
   PubMed Web of Science ®Google Scholar
• Rosenbloom SJ, Ferguson FC. Fatty change in organs of the rat treated with colchicine. Toxicol Appl Pharmacol. 1968;13:50–61.
   Web of Science ®Google Scholar
• Simon-Assmann P, Turck N, Sidhoum-Jenny M, et al. In vitro models of intestinal epithelial cell differentiation. Cell Biol Toxicol. 2007;23:241–256.
   PubMed Web of Science ®Google Scholar
• Ogawa N, Satsu H, Watanabe H, et al. Acetic acid suppresses the increase in disaccharidase activity that occurs during culture of caco-2 cells. J Nutr. 2000;130:507–513.
   PubMed Web of Science ®Google Scholar
• Grasset E, Pinto M, Dussaulx E, et al. Epithelial properties of human colonic carcinoma cell line caco-2: electrical parameters. Am J Physiol. 1984;247:C260–7.
   PubMed Web of Science ®Google Scholar
• Meunier V, Bourrie M, Berger Y, et al. The human intestinal epithelial cell line caco-2; pharmacological and pharmacokinetic applications. Cell Biol Toxicol. 1995;11:187–194.
   PubMed Web of Science ®Google Scholar
• Kerneis S, Bogdanova A, Kraehenbuhl JP, et al. Conversion by Peyer’s patch lymphocytes of human enterocytes into M cells that transport bacteria. Science. 1997;277:949–952.
   PubMed Web of Science ®Google Scholar
• 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;30:380–391.
   PubMed Web of Science ®Google Scholar
• Vazquez M, Velez D, Devesa V. In vitro characterization of the intestinal absorption of methylmercury using a caco-2 cell model. Chem Res Toxicol. 2014;27:254–264.
   PubMed Web of Science ®Google Scholar
• Gullberg E, Keita AV, Salim SY, et al. Identification of cell adhesion molecules in the human follicle-associated epithelium that improve nanoparticle uptake into the Peyer’s patches. J Pharmacol Exp Ther. 2006;319:632–639.
   PubMed Web of Science ®Google Scholar
• Balamuralidhara V, Pramodkumar TM, Srujana N, et al. pH sensitive drug delivery systems: a review.. Am J Drug Discov Dev. 2011;1:24–48.
   Google Scholar
• Tummala S, Satish Kumar MN, Prakash A. Formulation and characterization of 5-Fluorouracil enteric coated nanoparticles for sustained and localized release in treating colorectal cancer. Saudi Pharm J. 2015;23:308–314.
   PubMed Web of Science ®Google Scholar
• Eskandari S, Varamini P, Toth I. Formulation, characterization and permeability study of nano particles of lipo-endomorphin-1 for oral delivery. J Liposome Res. 2013;23:311–317.
   PubMed Web of Science ®Google Scholar
• Hosny KM, Ahmed OAA, Al-Abdali RT. Enteric-coated alendronate sodium nanoliposomes: a novel formula to overcome barriers for the treatment of osteoporosis. Expert Opin Drug Deliv. 2013;10:741–746.
   PubMed Web of Science ®Google Scholar
• Sun H, Liu D, Li Y, et al. Preparation and in vitro/in vivo characterization of enteric-coated nanoparticles loaded with the antihypertensive peptide VLPVPR. Int J Nanomedicine. 2014;9:1709–1716.
   PubMed Web of Science ®Google Scholar
• Trevaskis NL, Kaminskas LM, Porter CJ. From sewer to saviour - targeting the lymphatic system to promote drug exposure and activity. Nat Rev Drug Discov. 2015;14:781–803.
   PubMed Web of Science ®Google Scholar