← Back to Search
Oral Drug Delivery With Polymeric Nanoparticles: The Gastrointestinal Mucus Barriers.
Laura M Ensign, R. Cone, J. Hanes
Published 2012 · Medicine
Download PDFAnalyze on Scholarcy
Oral delivery is the most common method for drug administration. However, poor solubility, stability, and bioavailability of many drugs make achieving therapeutic levels via the gastrointestinal (GI) tract challenging. Drug delivery must overcome numerous hurdles, including the acidic gastric environment and the continuous secretion of mucus that protects the GI tract. Nanoparticle drug carriers that can shield drugs from degradation and deliver them to intended sites within the GI tract may enable more efficient and sustained drug delivery. However, the rapid secretion and shedding of GI tract mucus can significantly limit the effectiveness of nanoparticle drug delivery systems. Many types of nanoparticles are efficiently trapped in and rapidly removed by mucus, making controlled release in the GI tract difficult. This review addresses the protective barrier properties of mucus secretions, how mucus affects the fate of orally administered nanoparticles, and recent developments in nanoparticles engineered to penetrate the mucus barrier.
This paper references
Effect of lipids and proteins on the viscosity of gastric mucus glycoprotein.
V. L. Murty (1984)
Common Gene Therapy Viral Vectors Do Not Efficiently Penetrate Sputum from Cystic Fibrosis Patients
Kaoru Hida (2011)
Gastric mucin hydrophobicity: effects of associated and covalently bound lipids, proteolysis, and reduction.
K. Gwożdziński (1988)
Wheat Germ Agglutinin
M. Burger (2002)
Interactions between Yersinia enterocolitica and rabbit ileal mucus: growth, adhesion, penetration, and subsequent changes in surface hydrophobicity and ability to adhere to ileal brush border membrane vesicles.
A. Paerregaard (1991)
New-concept chemotherapy by nanoparticles of biodegradable polymers: where are we now?
S. Feng (2006)
The Uptake and Translocation of Latex Nanospheres and Microspheres after Oral Administration to Rats
P. Jani (1989)
Utilizing Bacterial Mechanisms of Epithelial Cell Entry: Invasin-induced Oral Uptake of Latex Nanoparticles
N. Hussain (2004)
Histochemical alterations of mucin in normal colon, inflammatory bowel disease and colonic adenocarcinoma
D. Owen (1995)
Mucin structure, aggregation, physiological functions and biomedical applications
R. Bansil (2006)
Fluid mixing from viscous fingering.
B. Jha (2011)
Intestinal delivery of non-viral gene therapeutics: physiological barriers and preclinical models.
Martin O'Neill (2011)
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
I. Behrens (2004)
The lectin-cell interaction and its implications to intestinal lectin-mediated drug delivery.
F. Gabor (2004)
Mucoadhesion mechanism of chitosan and thiolated chitosan-poly(isobutyl cyanoacrylate) core-shell nanoparticles.
I. Bravo-Osuna (2007)
Lectin-mediated mucosal delivery of drugs and microparticles.
M. A. Clark (2000)
Biodegradable nanoparticles composed entirely of safe materials that rapidly penetrate human mucus.
Ming Yang (2011)
Rapid transport of large polymeric nanoparticles in fresh undiluted human mucus
S. Lai (2007)
Measurement of gastrointestinal pH profiles in normal ambulant human subjects.
D. F. Evans (1988)
Cell biology and active transport processes in the colon
J. Hastewell (1991)
Oral gene delivery with chitosan–DNA nanoparticles generates immunologic protection in a murine model of peanut allergy
K. Roy (1999)
Addressing the PEG mucoadhesivity paradox to engineer nanoparticles that "slip" through the human mucus barrier.
Y. Wang (2008)
Thickness of adherent mucus gel on colonic mucosa in humans and its relevance to colitis.
R. D. Pullan (1994)
The gastroduodenal mucus barrier and its role in protection against luminal pepsins: The effect of 16,16 dimethyl prostaglandin E2, carbopol‐polyacrylate, sucralfate and bismuth subsalicylate
M. Copeman (1994)
Hydrogen ion diffusion in dog gastric mucus glycoprotein: effect of associated lipids and covalently bound fatty acids.
J. Sarosiek (1984)
Gastrointestinal distribution and in vivo gene transfection studies with nanoparticles-in-microsphere oral system (NiMOS).
M. Bhavsar (2007)
pH-Responsive nanoparticles for drug delivery.
W. Gao (2010)
Biopharmaceutical parameters to consider in order to alter the fate of nanocarriers after oral delivery.
E. Roger (2010)
Diffusion of macromolecules and virus-like particles in human cervical mucus.
S. S. Olmsted (2001)
Novel mucoadhesion tests for polymers and polymer-coated particles to design optimal mucoadhesive drug delivery systems.
H. Takeuchi (2005)
Traffic of poly(lactic acid) nanoparticulate vaccine vehicle from intestinal mucus to sub-epithelial immune competent cells.
C. Primard (2010)
Interplay Between Intestinal pH, Transit Time and Feed Status on the In Vivo Performance of pH Responsive Ileo-Colonic Release Systems
V. C. Ibekwe (2008)
Glycoprotein mucin molecular brush on cancer cell surface acting as mechanical barrier against drug delivery
X. Wang (2010)
Formulation of lipid-based delivery systems for oral administration: materials, methods and strategies.
C. Pouton (2008)
The effect of physical barriers and properties on the oral absorption of particulates.
Increased oxidative stress and decreased antioxidant defenses in mucosa of inflammatory bowel disease
L. Lih-Brody (2005)
Some biological issues in oral, controlled drug delivery
P. Gruber (1987)
In vitro and cell uptake studies for targeting of ligand anchored nanoparticles for colon tumors.
A. Jain (2008)
Preparation and characterization of lectin-latex conjugates for specific bioadhesion.
J. M. Irache (1994)
Migration of adhesive and nonadhesive particles in the rat intestine under altered mucus secretion conditions.
B. Tirosh (1998)
Micro- and macrorheology of mucus.
S. Lai (2009)
Barrier properties of mucus.
Richard A. Cone (2009)
Design of biodegradable particles for protein delivery.
A. Vila (2002)
The penetration of fresh undiluted sputum expectorated by cystic fibrosis patients by non-adhesive polymer nanoparticles.
J. Suk (2009)
Structure and macromolecular properties of mucus glycoproteins.
I. Carlstedt (1988)
Barrier properties of gastrointestinal mucus to nanoparticle transport.
Jason S. Crater (2010)
Viscous fingering of HCI through gastric mucin
K. Ramakrishnan Bhaskar (1992)
Mucins in the gastrointestinal tract in health and disease.
A. Corfield (2001)
Biodistribution, pharmacodynamics and pharmacokinetics of insulin analogues in a rat model: Oral delivery using pH-responsive nanoparticles vs. subcutaneous injection.
K. Sonaje (2010)
Stealth liposomes: review of the basic science, rationale, and clinical applications, existing and potential
M. Immordino (2006)
Nanoparticles reveal that human cervicovaginal mucus is riddled with pores larger than viruses
S. Lai (2009)
The role of PEG on the stability in digestive fluids and in vivo fate of PEG-PLA nanoparticles following oral administration.
Calcitonin and Insulin in Isobutylcyanoacrylate Nanocapsules: Protection Against Proteases and Effect on Intestinal Absorption in Rats
P. J. Lowe (1994)
Bioadhesion: new possibilities for drug administration?
J. Woodley (2001)
The effect of gastro-intestinal mucus on drug absorption
A. Macadam (1993)
Bioadhesive microspheres: III. An in vivo transit and bioavailability study of drug-loaded alginate and poly(fumaric-co-sebacic anhydride) microspheres
Donald E. Chickering (1997)
Size-Dependent Bioadhesion of Micro- and Nanoparticulate Carriers to the Inflamed Colonic Mucosa
A. Lamprecht (2004)
Chemiluminescence assay of mucosal reactive oxygen species in gastric cancer, ulcer and antral mucosa.
Y. Peng (2008)
The adherent gastrointestinal mucus gel layer: thickness and physical state in vivo.
C. Atuma (2001)
The Transfer of Polystyrene Microspheres from the Gastrointestinal Tract to the Circulation after Oral Administration in the Rat
J. Eyles (1995)
Role of intestinal mucus in transepithelial passage of bacteria across the intact ileum in vitro.
C. Albanese (1994)
Diffusion of drugs in native and purified gastrointestinal mucus.
A. Larhed (1997)
Barrier Properties of Gastrointestinal Mucus to Nanoparticle Transport
Jason S. Crater and (2010)
Effect of diet on mucin kinetics and composition: nutrition and health implications.
L. Montagné (2004)
Quantitative and microautoradiographic study on mouse intestinal distribution of polycyanoacrylate nanoparticles
J. Kreuter (1989)
Responsive polymers in controlled drug delivery
A. Bajpai (2008)
Wheat germ agglutinin. Molecular characteristics and specificity for sugar binding.
Y. Nagata (1974)
Enhanced Oral Uptake of Tomato Lectin-Conjugated Nanoparticles in the Rat
N. Hussain (2004)
Lipid Based Therapy for Ulcerative Colitis—Modulation of Intestinal Mucus Membrane Phospholipids as a Tool to Influence Inflammation
Hannah Schneider (2010)
Recent advances in the understanding of uptake of microparticulates across the gastrointestinal lymphatics.
N. Hussain (2001)
Drug transfer through mucus.
K. Khanvilkar (2001)
The Influence of Intestinal Mucus Components on the Diffusion of Drugs
A. Larhed (2004)
Chitosans as absorption enhancers of poorly absorbable drugs. 3: Influence of mucus on absorption enhancement.
N. G. Schipper (1999)
Mucins in cancer: protection and control of the cell surface
M. Hollingsworth (2004)
Mucins and inflammatory bowel disease.
T. Shirazi (2000)
Lectin-mediated drug targeting: history and applications.
C. Bies (2004)
Biologically erodable microspheres as potential oral drug delivery systems
E. Mathiowitz (1997)
Aggregation behavior of methacrylic acid/ethyl acrylate copolymer in dilute solutions
S. Dai (2000)
Light microscopical observations on luminally administered dyes, dextrans, nanospheres and microspheres in the pre-epithelial mucus gel layer of the rat distal colon
L. Szentkuti (1997)
Polymeric nano- and microparticle technologies for oral gene delivery
M. Bhavsar (2007)
Salmonella-like bioadhesive nanoparticles.
Hesham H. Salman (2005)
Preparation and evaluation of lectin-conjugated PLGA nanoparticles for oral delivery of thymopentin.
Yashu Yin (2006)
Lectin-conjugated PLGA nanoparticles loaded with thymopentin: ex vivo bioadhesion and in vivo biodistribution.
Yashu Yin (2007)
Alterations in the Composition of the Supramucosal Defense Barrier in Relation to Disease Severity of Ulcerative Colitis
R. Longman (2006)
Microemulsions as drug delivery systems to improve the solubility and the bioavailability of poorly water-soluble drugs
Cai-Xia He (2010)
Rapid transport of muco-inert nanoparticles in cystic fibrosis sputum treated with N-acetyl cysteine.
J. Suk (2011)
Poly(alkyl cyanoacrylate) nanospheres for oral administration of insulin.
C. Damgé (1997)
Cytochemical analysis of alkaline phosphatase and esterase activities and of lectin-binding and anionic sites in rat and mouse Peyer's patch M cells.
R. L. Owen (1983)
Lipids associated with rat small-intestinal mucus glycoprotein.
H. Witas (1983)
Characterization of particle translocation through mucin hydrogels.
O. Lieleg (2010)
Vitamin B12-mediated transport of nanoparticles across Caco-2 cells.
G. J. Russell-Jones (1999)
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
A. Frey (1996)
Mucoadhesive DL-Lactide/Glycolide Copolymer Nanospheres Coated with Chitosan to Improve Oral Delivery of Elcatonin
Y. Kawashima (2000)
Role of intestinal mucus on the uptake of latex beads by Peyer's patches and on their transport to mesenteric lymph nodes in rats.
J. Khan (1999)
Mucus-penetrating nanoparticles for drug and gene delivery to mucosal tissues.
S. Lai (2009)
Mucin dynamics and enteric pathogens
M. McGuckin (2011)
Nanoparticles as potential oral delivery systems of proteins and vaccines: a mechanistic approach.
A. des Rieux (2006)
Altering Mucus Rheology to “Solidify” Human Mucus at the Nanoscale
S. Lai (2009)
The secretion and function of intestinal mucus.
H. Florey (1962)
A simple method for measuring thickness of the mucus gel layer adherent to rat, frog and human gastric mucosa: influence of feeding, prostaglandin, N-acetylcysteine and other agents.
S. Kerss (1982)
Polymeric nanoparticles for oral delivery of drugs and vaccines: a critical evaluation of in vivo studies.
S. Galindo-Rodriguez (2005)
Phospholipids and Lipid-Based Formulations in Oral Drug Delivery
G. Fricker (2010)
Oral IL-10 gene delivery in a microsphere-based formulation for local transfection and therapeutic efficacy in inflammatory bowel disease
M. Bhavsar (2008)
Handbook of mucosal immunology
C. Fiocchi (1994)
The hydrophobic barrier properties of gastrointestinal mucus.
L. Lichtenberger (1995)
Mucins in cancer: function, prognosis and therapy
D. Kufe (2009)
Biodegradable polymer nanoparticles that rapidly penetrate the human mucus barrier
Benjamin C Tang (2009)
Nanoparticulate delivery of novel drug combination regimens for the chemoprevention of colon cancer.
Naveen Kanthamneni (2010)
The in Vitro Cell Association of Invasin Coated Polylactide-Co-glycolide Nanoparticles
G. Dawson (2004)
Reactive oxygen metabolites and upper gastrointestinal diseases.
J. Kountouras (2001)
Transport of nanoparticles across an in vitro model of the human intestinal follicle associated epithelium.
A. des Rieux (2005)
Gastric mucus gel layer thickness measured by direct light microscopy. An experimental study in the rat.
B. Sandzén (1988)
Mucin depletion in inflammatory bowel disease.
D. Mccormick (1990)
Delayed Release Phosphatidylcholine in Chronic-active Ulcerative Colitis: A Randomized, Double-blinded, Dose Finding Study
W. Stremmel (2010)
The mucosal immune system at the gastrointestinal barrier.
M. Schenk (2008)
Helicobacter pylori infection produces reversible glycosylation changes to gastric mucins
H. Ota (1998)
Targeted delivery of low molecular drugs using chitosan and its derivatives.
J. H. Park (2010)
Bioadhesion by Means of Specific Binding of Tomato Lectin
C. Lehr (2004)
A review of stimuli-responsive nanocarriers for drug and gene delivery.
Srinivas Ganta (2008)
Alterations of phospholipid concentration and species composition of the intestinal mucus barrier in ulcerative colitis: A clue to pathogenesis
A. Braun (2009)
Multi-ion-crosslinked nanoparticles with pH-responsive characteristics for oral delivery of protein drugs.
Y. Lin (2008)
Phosphatidylcholine and lysophosphatidylcholine in intestinal mucus of ulcerative colitis patients. A quantitative approach by nanoelectrospray‐tandem mass spectrometry
R. Ehehalt (2004)
Drug delivery to the gastrointestinal tract
J. G. Hardy (1989)
Effectiveness of Liposomes Possessing Surface-Linked Recombinant B Subunit of Cholera Toxin as an Oral Antigen Delivery System
E. Harokopakis (1998)
Biodegradable nanoparticles for targeted drug delivery in treatment of inflammatory bowel disease.
A. Lamprecht (2001)
An in vivo comparison of intestinal pH and bacteria as physiological trigger mechanisms for colonic targeting in man.
E. McConnell (2008)
Comparison of the gastrointestinal anatomy, physiology, and biochemistry of humans and commonly used laboratory animals
T. Kararli (1995)
Human Immunodeficiency Virus Type 1 Is Trapped by Acidic but Not by Neutralized Human Cervicovaginal Mucus
S. Lai (2009)
Orally delivered thioketal nanoparticles loaded with TNF-α-siRNA target inflammation and inhibit gene expression in the intestines.
D. S. Wilson (2010)
Fate of polymeric nanocarriers for oral drug delivery
L. Plapied (2011)
Controlled vaccine release in the gut-associated lymphoid tissues. I. Orally administered biodegradable microspheres target the peyer's patches
J. Eldridge (1990)
This paper is referenced by
Mechanistic insight into the interaction of gastrointestinal mucus with oral diblock copolymers synthesized via ATRP method
Jiao Liu (2018)
Enzyme-Functionalized PLGA Nanoparticles with Enhanced Mucus Permeation Rate
E. Samaridou (2014)
Controlling the Stability of Colloidal Drug Aggregates for Chemotherapeutic Delivery
Ahil N. Ganesh (2019)
FORMULATION AND EVALUATION OF NIFEDIPINE LOADED CHITOSAN MICROSPHERS FOR MUCOADHESIVE DRUG DELIVERY
P. Sudheer (2014)
Pseudomonas aeruginosa pyocyanin production reduced by quorum‐sensing inhibiting nanocarriers
H. Lu (2018)
Engineering Tumor-Targeting Nanoparticles as Vehicles for Precision Nanomedicine
Amber Gonda (2019)
Thiolated polymers as mucoadhesive drug delivery systems
Sarah Duggan (2017)
Polypeptide-based polyelectrolyte complexes overcoming the biological barriers of oral insulin delivery
Yongjun Jeong (2017)
Polymeric micelles in mucosal drug delivery: Challenges towards clinical translation.
A. Sosnik (2015)
Plant protein-based hydrophobic fine and ultrafine carrier particles in drug delivery systems
Hedieh Malekzad (2018)
Polymer-lipid hybrid systems: merging the benefits of polymeric and lipid-based nanocarriers to improve oral drug delivery
Shasha Rao (2016)
VP6-SUMO self-assembly as nanocarriers for gastrointestinal delivery
V. Palmieri (2015)
Enhancing vitamin E bioaccessibility: factors impacting solubilization and hydrolysis of α-tocopherol acetate encapsulated in emulsion-based delivery systems.
Ying Yang (2015)
Chitosan hybrid microgels for oral drug delivery.
Michelly Cristina Galdioli Pellá (2020)
Oral delivery of protein-based therapeutics: Gastroprotective strategies, physiological barriers and in vitro permeability prediction.
L. Wright (2020)
Influence of nanoparticles on liver tissue and hepatic functions: a review.
R. Cornu (2019)
Biocompatible polymeric nanoparticles with exceptional gastrointestinal stability as oral delivery vehicles for lipophilic bioactives
Qiaobin Hu (2019)
Controlled release of Doxycycline from gum acacia/poly(sodium acrylate) microparticles for oral drug delivery.
S. K. Bajpai (2017)
Mucus penetration enhanced lipid polymer nanoparticles improve the eradication rate of Helicobacter pylori biofilm.
Pengyu Li (2019)
Modified nanoparticles with cell-penetrating peptide and amphipathic chitosan derivative for enhanced oral colon absorption of insulin: preparation and evaluation
F. Guo (2016)
Mucus models to evaluate nanomedicines for diffusion.
A. Groo (2014)
Scientific and Regulatory Considerations for Generic Complex Drug Products Containing Nanomaterials
Nan Zheng (2017)
Correction to: A systematic review of nano formulation of natural products for the treatment of inflammatory bowel disease: drug delivery and pharmacological targets
Yasamin Davatgaran Taghipour (2018)
Application of Nanotechnology in Functional Foods
R. Singh (2019)
Hierarchically targetable polysaccharide-coated solid lipid nanoparticles as an oral chemo/thermotherapy delivery system for local treatment of colon cancer.
Ming-Yin Shen (2019)
Functional Chitosan Carriers for Oral Colon-Specific Drug Delivery
N. Musa (2019)
Hydrogel/polymer micelles composites derived from polymerization of microemulsions for oral drug delivery
Li Chen (2013)
Characterization of gemini nanoparticle assembly by fluorescence correlation spectroscopy
Chilbert Dong (2014)
Formulation and advantages of furazolidone in spray dried and liposomal drug delivery systems
Muhammad Irfan Alam (2017)
Biodistribution, excretion, and toxicity of mesoporous silica nanoparticles after oral administration depend on their shape.
L. Li (2015)
Carboxymethyl chitosan/phospholipid bilayer-capped mesoporous carbon nanoparticles with pH-responsive and prolonged release properties for oral delivery of the antitumor drug, Docetaxel.
Yonglong Zhang (2017)
A new approach for analyzing an adhesive bacterial protein in the mouse gastrointestinal tract using optical tissue clearing
K. Nishiyama (2019)See more