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Advanced Drug Delivery Reviews Jan 2018The viscoelastic mucus secretions coating exposed organs such as the lung airways and the female reproductive tract can trap and quickly eliminate not only foreign... (Review)
Review
The viscoelastic mucus secretions coating exposed organs such as the lung airways and the female reproductive tract can trap and quickly eliminate not only foreign pathogens and ultrafine particles but also particle-based drug delivery systems, thus limiting sustained and targeted drug delivery at mucosal surfaces. To improve particle distribution across the mucosa and enhance delivery to the underlying epithelium, many investigators have sought to develop nanoparticles capable of readily traversing mucus. The first synthetic nanoparticles shown capable of rapidly penetrating physiological mucus secretions utilized a dense coating of polyethylene glycol (PEG) covalently grafted onto the surface of preformed polymeric nanoparticles. In the decade since, PEG has become the gold standard in engineering mucus-penetrating drug carriers for sustained and targeted drug delivery to the lungs, gastrointestinal tract, eyes, and female reproductive tract. This review summarizes the history of the development of various PEG-based mucus-penetrating particles, and highlights the key physicochemical properties of PEG coatings and PEGylation strategies to achieve muco-inert PEG coatings on nanoparticle drug carriers for improved drug and gene delivery at mucosal surfaces.
Topics: Animals; Diffusion; Humans; Mucus; Nanoparticles; Polyethylene Glycols
PubMed: 28882703
DOI: 10.1016/j.addr.2017.08.010 -
International Journal of Pharmaceutics Aug 2013Mucus is a complex hydrogel, comprising glycoproteins, lipids, salts, DNA, enzymes and cellular debris, covering many epithelial surfaces in the human body. Once... (Review)
Review
Mucus is a complex hydrogel, comprising glycoproteins, lipids, salts, DNA, enzymes and cellular debris, covering many epithelial surfaces in the human body. Once secreted, mucin forms a barrier to protect the underlying tissues against the extracellular environment. Mucus can therefore adversely affect the absorption or action of drugs administered by the oral, pulmonary, vaginal, nasal or other routes. Solubility and lipophilicity are key factors determining drug absorption, as a drug has to be soluble in the body fluids at the site of absorption and must also possess enough lipophilicity to permeate the biological membrane. Evidence has accumulated over the past 40 years indicating that poorly soluble drugs will interact with mucus glycoprotein. Studies of the permeability of native or purified mucous gels are important when it comes to understanding the relative importance of hindered diffusion versus drug binding in mucous layers. This review highlights the current understanding of the drug-mucin interaction and also examines briefly the interaction of polymers and particles with the mucus matrix. While the concept of mucoadhesion was thought to provide an intensified and prolonged contact to mucosal absorption sites, mucopenetrating properties are nowadays being discussed for (nano)particulate carriers to overcome the mucus as a barrier and enhance drug delivery through mucus.
Topics: Absorption; Animals; Expectorants; Humans; Mucins; Mucus; Pharmaceutical Preparations; Solubility; Viscosity
PubMed: 23727593
DOI: 10.1016/j.ijpharm.2013.05.040 -
Mucus-Penetrating Particles and the Role of Ocular Mucus as a Barrier to Micro- and Nanosuspensions.Journal of Ocular Pharmacology and... 2020The ocular surface is naturally covered with a layer of mucus. Along with other functions, this mucus layer serves to trap and eliminate foreign substances, such as... (Review)
Review
The ocular surface is naturally covered with a layer of mucus. Along with other functions, this mucus layer serves to trap and eliminate foreign substances, such as allergens, pathogens, and debris. In playing this pivotal role, mucus can also hinder topical delivery of therapeutics to the eye. Recent studies provide evidence that drugs formulated as traditional micro- or nanoparticles are susceptible to entrapment and rapid clearance by ocular mucus. Mucus-penetrating particles (MPPs) is a nanoparticle technology that emerged over the past decade. With a muco-inert surface and a particle size smaller than the mucus mesh size, MPPs can diffuse in mucus essentially freely. Preclinical studies have shown that, compared with particles lacking the mucus-penetrating attributes, MPPs can improve the uniformity of drug particle distribution on mucosal surfaces and enhance drug delivery to ocular tissues.
Topics: Administration, Topical; Animals; Drug Compounding; Drug Delivery Systems; Humans; Mice; Models, Animal; Mucus; Nanoparticles; Ocular Physiological Phenomena; Surface Properties
PubMed: 32667250
DOI: 10.1089/jop.2020.0022 -
Advanced Drug Delivery Reviews Jan 2018A layer of mucus covers the surface of all wet epithelia throughout the human body. Mucus is a hydrogel mainly composed of water, mucins (glycoproteins), DNA, proteins,... (Review)
Review
A layer of mucus covers the surface of all wet epithelia throughout the human body. Mucus is a hydrogel mainly composed of water, mucins (glycoproteins), DNA, proteins, lipids, and cell debris. This complex composition yields a tenacious viscoelastic hydrogel that lubricates and protects the exposed epithelia from external threats and enzymatic degradation. The natural protective role of mucus is nowadays acknowledged as a major barrier to be overcome in non-invasive drug delivery. The heterogeneity of mucus components offers a wide range of potential chemical interaction sites for macromolecules, while the mesh-like architecture given to mucus by the intermolecular cross-linking of mucin molecules results in a dense network that physically, and in a size-dependent manner, hinders the diffusion of nanoparticles through mucus. Consequently, drug diffusion, epithelial absorption, drug bioavailability, and ultimately therapeutic outcomes of mucosal drug delivery can be attenuated.
Topics: Animals; Biological Transport; Drug Delivery Systems; Humans; Mucus; Pharmaceutical Preparations
PubMed: 29106910
DOI: 10.1016/j.addr.2017.10.009 -
Advanced Drug Delivery Reviews Jan 2018In this review we discuss mucus, the viscoelastic secretion from goblet or mucous producing cells that lines the epithelial surfaces of all organs exposed to the... (Review)
Review
In this review we discuss mucus, the viscoelastic secretion from goblet or mucous producing cells that lines the epithelial surfaces of all organs exposed to the external world. Mucus is a complex aqueous fluid that owes its viscoelastic, lubricating and hydration properties to the glycoprotein mucin combined with electrolytes, lipids and other smaller proteins. Electron microscopy of mucosal surfaces reveals a highly convoluted surface with a network of fibers and pores of varying sizes. The major structural and functional component, mucin is a complex glycoprotein coded by about 20 mucin genes which produce a protein backbone having multiple tandem repeats of Serine, Threonine (ST repeats) where oligosaccharides are covalently O-linked. The N- and C-terminals of this apoprotein contain other domains with little or no glycosylation but rich in cysteines leading to dimerization and further multimerization via SS bonds. The synthesis of this complex protein starts in the endoplasmic reticulum with the formation of the apoprotein and is further modified via glycosylation in the cis and medial Golgi and packaged into mucin granules via Ca bridging of the negative charges on the oligosaccharide brush in the trans Golgi. The mucin granules fuse with the plasma membrane of the secretory cells and following activation by signaling molecules release Ca and undergo a dramatic change in volume due to hydration of the highly negatively charged polymer brush leading to exocytosis from the cells and forming the mucus layer. The rheological properties of mucus and its active component mucin and its mucoadhesivity are briefly discussed in light of their importance to mucosal drug delivery.
Topics: Animals; Humans; Mucus
PubMed: 28970050
DOI: 10.1016/j.addr.2017.09.023 -
International Journal of Pharmaceutics Oct 2017Mucus is a selective barrier to particles and molecules, preventing penetration to the epithelial surface of mucosal tissues. Significant advances in transmucosal drug... (Review)
Review
Mucus is a selective barrier to particles and molecules, preventing penetration to the epithelial surface of mucosal tissues. Significant advances in transmucosal drug delivery have recently been made and have emphasized that an understanding of the basic structure, viscoelastic properties, and interactions of mucus is of great value in the design of efficient drug delivery systems. Mucins, the primary non-aqueous component of mucus, are polymers carrying a complex and heterogeneous structure with domains that undergo a variety of molecular interactions, such as hydrophilic/hydrophobic, hydrogen bonds and electrostatic interactions. These properties are directly relevant to the numerous mucin-associated diseases, as well as delivering drugs across the mucus barrier. Therefore, in this review we discuss regional differences in mucus composition, mucus physicochemical properties, such as pore size, viscoelasticity, pH, and ionic strength. These factors are also discussed with respect to changes in mucus properties as a function of disease state. Collectively, the review seeks to provide a state of the art roadmap for researchers who must contend with this critical barrier to drug delivery.
Topics: Drug Delivery Systems; Humans; Hydrophobic and Hydrophilic Interactions; Mucins; Mucus; Viscosity
PubMed: 28917986
DOI: 10.1016/j.ijpharm.2017.09.018 -
Advanced Drug Delivery Reviews Feb 2009Mucus is tenacious. It sticks to most particles, preventing their penetration to the epithelial surface. Multiple low-affinity hydrophobic interactions play a major role... (Review)
Review
Mucus is tenacious. It sticks to most particles, preventing their penetration to the epithelial surface. Multiple low-affinity hydrophobic interactions play a major role in these adhesive interactions. Mucus gel is also shear-thinning, making it an excellent lubricant that ensures an unstirred layer of mucus remains adherent to the epithelial surface. Thus nanoparticles (NP) must diffuse readily through the unstirred adherent layer if they are to contact epithelial cells efficiently. This article reviews some of the physiological and biochemical properties that form the mucus barrier. Capsid viruses can diffuse through mucus as rapidly as through water and thereby penetrate to the epithelium even though they have to diffuse 'upstream' through mucus that is being continuously secreted. These viruses are smaller than the mucus mesh spacing, and have surfaces that do not stick to mucus. They form a useful model for developing NP for mucosal drug delivery.
Topics: Adhesiveness; Animals; Elasticity; Humans; Mucins; Mucous Membrane; Mucus; Viscosity
PubMed: 19135107
DOI: 10.1016/j.addr.2008.09.008 -
Drugs Jul 2014Airway mucus has a key role in protective innate immune responses, but excessive mucus production and secretion in proximal and in distal airways are associated with... (Review)
Review
Airway mucus has a key role in protective innate immune responses, but excessive mucus production and secretion in proximal and in distal airways are associated with disabling symptoms (cough and sputum), lung function decline, exacerbations and mortality in patients with chronic obstructive pulmonary disease (COPD). Cellular and molecular mechanisms leading to mucin production and secretion have largely been identified using cultured epithelial cells and animal models. Cigarette smoke and microbial products are potent triggers of mucin production, which involves recognition of specific molecular patterns by cognate receptors and activation of metalloproteases at the epithelial cell surface, leading to epidermal growth factor receptor activation and mucin mRNA and protein synthesis. After mucin synthesis has occurred, mucins are tightly packed into intracytoplasmic granules. Many stimuli induce secretion of mucin granules from epithelial cells, but neutrophil serine proteases are the most potent inducers of mucin secretion. Neutrophils recruited to the airway epithelium also promote mucin production via neutrophil proteases and oxidative stress. Several drugs currently available for the treatment of COPD patients reduced mucus hypersecretion in preclinical models relevant to COPD, but their effects on mucus hypersecretion in humans have not been assessed. Testing the effects of these drugs and of novel molecules designed for reducing mucus production and/or secretion will require performing specifically designed clinical trials. These trials will be necessary to explore the hypothesis that reducing mucus hypersecretion is beneficial in COPD patients.
Topics: Humans; Mucus; Pulmonary Disease, Chronic Obstructive; Respiratory System
PubMed: 24890395
DOI: 10.1007/s40265-014-0235-3 -
Cold Spring Harbor Perspectives in... Nov 2012Our purpose here is not to address specific issues of mucus pathology, but to illustrate how polymer networks theory and its remarkable predictive power can be applied... (Review)
Review
Our purpose here is not to address specific issues of mucus pathology, but to illustrate how polymer networks theory and its remarkable predictive power can be applied to study the supramolecular dynamics of mucus. Avoiding unnecessary mathematical formalization, in the light of available theory, we focus on the rather slow progress and the still large number of missing gaps in the complex topology and supramolecular dynamics of airway mucus. We start with the limited information on the polymer physics of respiratory mucins to then converge on the supramolecular organization and resulting physical properties of the mucus gel. In each section, we briefly discuss progress on the subject, the uncertainties associated with the established knowledge, and the many riddles that still remain.
Topics: Gels; Humans; Hydrophobic and Hydrophilic Interactions; Kinetics; Molecular Conformation; Mucins; Mucus; Phase Transition; Polymers; Respiratory System
PubMed: 23125200
DOI: 10.1101/cshperspect.a009597 -
Cell Host & Microbe Feb 2016The interaction between respiratory pathogens and their hosts is complex and incompletely understood. This is particularly true when pathogens encounter the mucus layer... (Review)
Review
The interaction between respiratory pathogens and their hosts is complex and incompletely understood. This is particularly true when pathogens encounter the mucus layer covering the respiratory tract. The mucus layer provides an essential first host barrier to inhaled pathogens that can prevent pathogen invasion and subsequent infection. Respiratory mucus has numerous functions and interactions, both with the host and with pathogens. This review summarizes the current understanding of respiratory mucus and its interactions with the respiratory pathogens Pseudomonas aeruginosa, respiratory syncytial virus and influenza viruses, with particular focus on influenza virus transmissibility and host-range specificity. Based on current findings we propose that respiratory mucus represents an understudied host-restriction factor for influenza virus.
Topics: Animals; Host-Pathogen Interactions; Humans; Mucus; Pseudomonas aeruginosa; Respiratory Tract Infections; Virus Physiological Phenomena
PubMed: 26867175
DOI: 10.1016/j.chom.2016.01.001