Mucoadhesion

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Mucoadhesion describes the attractive forces between a biological material and mucus or mucous membrane. [1] Mucous membranes adhere to epithelial surfaces such as the gastrointestinal tract (GI-tract), the vagina, the lung, the eye, etc. They are generally hydrophilic as they contain many hydrogen macromolecules due to the large amount of water (approximately 95%) within its composition. However, mucin also contains glycoproteins that enable the formation of a gel-like substance. [1] Understanding the hydrophilic bonding and adhesion mechanisms of mucus to biological material is of utmost importance in order to produce the most efficient applications. For example, in drug delivery systems, the mucus layer must be penetrated in order to effectively transport micro- or nanosized drug particles into the body. [2] Bioadhesion is the mechanism by which two biological materials are held together by interfacial forces. The mucoadhesive properties of polymers can be evaluated via rheological synergism studies with freshly isolated mucus, tensile studies and mucosal residence time studies. Results obtained with these in vitro methods show a high correlation with results obtained in humans. [3] [4]

Contents

Mucoadhesive bondings

Mucoadhesion involves several types of bonding mechanisms, and it is the interaction between each process that allows for the adhesive process. The major categories are wetting theory, adsorption theory, diffusion theory, electrostatic theory, and fracture theory. [5] Specific processes include mechanical interlocking, electrostatic, diffusion interpenetration, adsorption and fracture processes. [6]

Bonding mechanisms

Wetting theory: Wetting is the oldest and most prevalent theory of adhesion. The adhesive components in a liquid solution anchor themselves in irregularities on the substrate and eventually harden, providing sites on which to adhere. [6] Surface tension effects restrict the movement of the adhesive along the surface of the substrate, and is related to the thermodynamic work of adhesion by Dupre's Equation. [6] Measuring the affinity of the adhesive for the substrate is performed by determining the contact angle. Contact angles closer to zero indicate a more wettable interaction, and those interactions have a greater spreadability. [5]

Adsorption theory: Adsorption is another widely accepted theory, where adhesion between the substrate and adhesive is due to primary and secondary bonding. [5] The primary bonds are due to chemisorption, and result in comparatively long lasting covalent and non-covalent bonds. Among covalent bonds disulfide bonds are likely most important. Thiolated polymers – designated thiomers – are mucoadhesive polymers that can form disulfide bonds with cysteine-rich subdomains of mucus glycoproteins. [7] Recently several new classes of polymers have been developed that are capable of forming covalent bonds with mucosal surfaces similarly to thiomers. These polymers have acryloyl, methacryloyl, maleimide, boronate and N‐hydroxy (sulfo) succinimide ester groups in their structure. [8] Among non-covalent bonds likely ionic interactions such as interactions of mucoadhesive chitosans with the anionically charged mucus [9] and Hydrogen bonding are most important. [10] The secondary bonds include weak Van Der Waals forces, and interactions between hydrophobic substructure. [11]

Diffusion theory: The mechanism for diffusion involves polymer and mucin chains from the adhesive penetrating the matrix of the substrate and forming a semipermanent bond. [6] As the similarities between the adhesive and the substrate increase, so does the degree of mucoadhesion. [5] The bond strength increases with the degree of penetration, increasing the adhesion strength. [11] The penetration rate is determined by the diffusion coefficient, the degree of flexibility of the adsorbate chains, mobility and contact time. [10] The diffusion mechanism itself is affected by the length of the molecular chains being implanted and cross-linking density, and is driven by a concentration gradient. [5]

Electrostatic theory: is an electrostatic process involving the transfer of electrons across the interface between the substrate and adhesive. [6] The net result is the formation of a double layer of charges that are attracted to each other due to balancing of the Fermi layers, and therefore cause adhesion. [10] This theory only works given the assumption that the substrate and adhesive have different electrostatic surface characteristics. [11]

Places where fractures can occur when testing fracture theory. Fracture theory looks for force required to separate at the interface, but fractures can occur due to cohesive failure within either of the layers. Mucoadhesion Fracture Theory (fixed).png
Places where fractures can occur when testing fracture theory. Fracture theory looks for force required to separate at the interface, but fractures can occur due to cohesive failure within either of the layers.

Fracture theory: Fracture theory is the major mechanism by which to determine the mechanical strength of a particular mucoadhesive, and describes the force necessary to separate the two materials after mucoadhesion has occurred. [10] Ultimate tensile strength is determined by the separating force and the total surface area of the adhesion, and failure generally occurs in one of the surfaces rather than at the interface. [5] Since the fracture theory only deals with the separation force, the diffusion and penetration of polymers is not accounted for in this mechanism. [5]

Stages of mucoadhesive process

The mucoadhesive process will differ greatly depending on the surface and properties of the adhesive. However, two general steps of the process have been identified: the contact stage and the consolidation stage. [1]

Contact stage

The contact stage is the initial wetting that occurs between the adhesive and membrane. This can occur mechanically by bringing together the two surfaces, or through the bodily systems, like when particles are deposited in the nasal cavity by inhalation. The principles of initial adsorption of small molecule adsorbates can be described by DLVO theory. [1]

Adsorption theory

According to DLVO theory, particles are held in suspension by a balance of attractive and repulsive forces. This theory can be applied to the adsorption of small molecules like mucoadhesive polymers, on surfaces, like mucus layers. Particles in general experience attractive van der Waals forces that promote coagulation; in the context of adsorption, the particle and mucus layers are naturally attracted. The attractive forces between particles increases with decreasing particle size due to increasing surface-area-to-volume ratio. This increases the strength of van der Waals interactions, so smaller particles should be easier to adsorb onto mucous membranes. [1]

DLVO theory also explains some of the challenges in establishing contact between particles and mucus layers in mucoadhesion due to their repulsive forces. Surfaces will develop an electrical double layer if they are in a solution containing ions, as is the case with many bodily systems, creating electrostatic repulsive forces between the adhesive and surface. Steric effects can also hinder particle adsorption to surfaces. Entropy or disorder of a system will decrease as polymeric mucoadhesives adsorb to surfaces, which makes establishing contact between the adhesive and membrane more difficult. Adhesives with large surface groups will also experience a decrease in entropy as they approach the surface, creating repulsion. [1]

Wettability theory

The initial adsorption of the molecule adhesive will also depend on the wetting between the adhesive and membrane. This can be described using Young's equation:

where is the interfacial tension between the membrane and gas or bodily environment, is the interfacial tension between the bioadhesive and membrane, is the interfacial tension between the bioadhesive and bodily environment, and is the contact angle of the bioadhesive on the membrane. The ideal contact angle is 0° meaning the bioadhesive perfectly wets the membrane and good contact is achieved. The interfacial tensions can be measured using common experimental techniques such as a Wilhelmy plate or the Du Noüy ring method to predict if the adhesive will make good contact with the membrane. [11]

Consolidation stage

Strong and prolonged adhesion

Mode of action of mucoadhesion. Dry mucus will not adhere to a mucoadhesive, but in the presence of moisture the mucus becomes plastic and can form intermolecular bonds. Mucoadhesion before and after hydrating mucus.png
Mode of action of mucoadhesion. Dry mucus will not adhere to a mucoadhesive, but in the presence of moisture the mucus becomes plastic and can form intermolecular bonds.

The consolidation stage of mucoadhesion involves the establishment of adhesive interactions to reinforce strong or prolonged adhesion. When moisture is present, mucoadhesive materials become activated and the system becomes plasticized. [10] This stimulus allows the mucoadhesive molecules to separate and break free while proceeding to link up by weak van der Waals and hydrogen bonds. [10] Consolidation factors are essential for the surface when exposed to significant dislodging stresses. [1] Multiple mucoadhesion theories exist that explain the consolidation stage, the main two which focus on macromolecular interpenetration and dehydration.

Macromolecular interpenetration theory

Interpenetration of a bioadhesive with mucus. In the contact stage, the two materials are brought into contact. In the consolidation stage the interpenetration of the polymers occurs. Mucoadhesion Interpenetration.png
Interpenetration of a bioadhesive with mucus. In the contact stage, the two materials are brought into contact. In the consolidation stage the interpenetration of the polymers occurs.

The Macromolecular Interpenetration theory, also known as the diffusion theory, states that the mucoadhesive molecules and mucus glycoproteins mutually interact by means of interpenetration of their chains and the forming of secondary semi-permanent adhesive bonds. [10] It is necessary that the mucoadhesive device has features or properties that favor both chemical and mechanical interactions for the macromolecular interpenetration theory to take place. [10] Molecules that can present mucoadhesive properties are molecules with hydrogen bond building groups, high molecular weight, flexible chains, and surface active properties. [10]

It is perceived that increase in adhesion force is associated with the degree of penetration of polymer chains. [10] Literature states that the degree of penetration required for efficient bioadhesive bonds lies in the range of 0.2-0.5μm. [10] The following equation can be used to estimate the degree of penetration of polymer and mucus chains:

with as contact time and as the diffusion coefficient of the mucoadhesive material in the mucus. [10] Maximum adhesion strength is reached when penetration depth is approximately equal to polymer chain size. [10] Properties of mutual solubility and structural similarity will improve the mucoadhesive bond. [1]

Dehydration theory

The dehydration theory explains why mucoadhesion can arise rapidly. When two gels capable of rapid gelation in an aqueous environment are brought into contact, movement occurs between the two gels until a state of equilibrium is reached. [1] Gels associated with a strong affinity for water will have high osmotic pressures and large swelling forces. [1] The difference in osmotic pressure when these gels contact mucus gels will draw water into the formulation and quickly dehydrate the mucus gel, forcing intermixing and consolidation until equilibrium results. [12]

This mixture of formulation and mucus can increase contact time with the mucous membrane, leading to the consolidation of the adhesive bond. [12] However, the dehydration theory does not apply to solid formulations or highly hydrated forms. [1]

Mucoadhesives in drug delivery

Depending on the dosage form and route of administration, mucoadhesives may be used for either local or systemic drug delivery. An overview on the mucoadhesive properties of mucoadhesives is provided by Vjera Grabovac and Andreas Bernkop-Schnürch. [13] The bioavailability of such drugs is affected by many factors unique to each route of application. In general, mucoadhesives work to increase the contact time at these sites, prolonging the residence time and maintaining an effective release rate. These polymeric coatings may be applied to a wide variety of liquid and solid dosages, each specially suited for the route of administration.

Dosage Forms

Disk-shaped tablets FlattenedRoundPills.jpg
Disk-shaped tablets
Common Patch System Contraceptivepatch.jpg
Common Patch System

Tablets

Tablets are small, solid dosages suitable for the use of mucoadhesive coatings. The coating may be formulated to adhere to a specific mucosa, enabling both systemic and targeted local administration. Tablets are generally taken enterally, as the size and stiffness of the form results in poor patient compliance when administered through other routes. [10]

Patches

In general, patches consist of three separate layers that contribute and control the release of medicine. The outer impermeable backing layer controls the direction of release and reduces drug loss away from the site of contact. It also protects the other layers and acts as a mechanical support. The middle reservoir layer holds the drug and is tailored to provide the specified dosage. The final inner layer consists of the mucoadhesive, allowing the patch to adhere to the specified mucosa. [10]

Gels

As a liquid or semisolid dosage, gels are typically used where a solid form would affect the patient’s comfort. As a trade-off, conventional gels have poor retention rates. This results in unpredictable losses of the drug, as the non-solid dosage is unable to maintain its position at the site of administration. Mucoadhesives increase retention by dynamically increasing the viscosity of the gel after application. This allows the gel to effectively administer the drug at the local site while maintaining the comfort of the patient. [10]

Solutions

These dosage forms are commonly used to deliver drugs to the eye and nasal cavity. They often include mucoadhesive polymers to improve retention on dynamic mucosal surfaces. Some advanced eye drop formulations may also turn from a liquid to a gel (so called in situ gelling systems) upon drug administration. For example, gel-forming solutions containing Pluronics could be used to improve the efficiency of eye drops and provide better retention on ocular surfaces. [14]

Routes of Administration

Oromucosal

With a 0.1-0.7 mm thick mucus layer, the oral cavity serves as an important route of administration for mucoadhesive dosages. Permeation sites can be separated into two groups: sublingual and buccal, in which the former is much more permeable than the latter. However, the sublingual mucosa also produces more saliva, resulting in relatively low retention rates. Thus, sublingual mucosa is preferable for rapid onset and short duration treatments, while the buccal mucosa is more appropriate for longer dosage and onset times. Because of this dichotomy, the oral cavity is suitable for both local and systemic administration. Some common dosage forms for the oral cavity include gels, ointments, patches, and tablets. Depending on the dosage form, some drug loss can occur due to swallowing of saliva. This can be minimized by layering the side of the dosage facing the oral cavity with an impermeable coating(,) commonly seen in patches. [15]

Nasal

With an active surface area of 160 cm2, the nasal cavity is another noteworthy route of mucoadhesive administration. Due to the sweeping motion of the cilia that lines the mucosa, nasal mucus has a quick turnover of 10 to 15 minutes. Because of this, the nasal cavity is most suitable for rapid, local medicinal dosages. Additionally, its close proximity to the blood–brain barrier makes it a convenient route for administering specialized drugs to the central nervous system. Gels, solutions, and aerosols are common dosage forms in the nasal cavity. However, recent research into particles and microspheres have shown increased bioavailability over non-solid forms of medicine largely due to the use of mucoadhesives. [16]

Ocular

Within the eye, it is difficult to achieve therapeutic concentrations through systemic administration. Often, other parts of the body will reach toxic levels of the medication before the eye reaches the treatment concentration. Consequently, direct administration through the fibrous tunic is common. This is made difficult due to the numerous defense mechanisms in place, such as blinking, tear production, and the tightness of the corneal epithelium. Estimates put tear turnover rates at 5 minutes, meaning most conventional drugs are not retained for long periods of time. Mucoadhesives increase retention rates, either by enhancing the viscosity or bonding directly to one of the mucosae surrounding the eye. [15] [17]

Intravesical

Intravesical drug administration is the delivery of pharmaceuticals to the urinary bladder through a catheter. [18] This route of administration is used for the therapy of bladder cancer and interstitial cystitis. The retention of dosage forms in the bladder is relatively poor, which is related to the need for a periodical urine voiding. Some mucoadhesive materials are able to stick to mucosal lining in the bladder, resist urine wash out effects and provide a sustained drug delivery. [19] [20]

See also

Related Research Articles

<span class="mw-page-title-main">Adhesive</span> Non-metallic material used to bond various materials together

Adhesive, also known as glue, cement, mucilage, or paste, is any non-metallic substance applied to one or both surfaces of two separate items that binds them together and resists their separation.

<span class="mw-page-title-main">Biopolymer</span> Polymer produced by a living organism

Biopolymers are natural polymers produced by the cells of living organisms. Like other polymers, biopolymers consist of monomeric units that are covalently bonded in chains to form larger molecules. There are three main classes of biopolymers, classified according to the monomers used and the structure of the biopolymer formed: polynucleotides, polypeptides, and polysaccharides. The Polynucleotides, RNA and DNA, are long polymers of nucleotides. Polypeptides include proteins and shorter polymers of amino acids; some major examples include collagen, actin, and fibrin. Polysaccharides are linear or branched chains of sugar carbohydrates; examples include starch, cellulose, and alginate. Other examples of biopolymers include natural rubbers, suberin and lignin, cutin and cutan, melanin, and polyhydroxyalkanoates (PHAs).

<span class="mw-page-title-main">Mucus</span> Secretion produced by mucous membranes

Mucus is a slippery aqueous secretion produced by, and covering, mucous membranes. It is typically produced from cells found in mucous glands, although it may also originate from mixed glands, which contain both serous and mucous cells. It is a viscous colloid containing inorganic salts, antimicrobial enzymes, immunoglobulins, and glycoproteins such as lactoferrin and mucins, which are produced by goblet cells in the mucous membranes and submucosal glands. Mucus serves to protect epithelial cells in the linings of the respiratory, digestive, and urogenital systems, and structures in the visual and auditory systems from pathogenic fungi, bacteria and viruses. Most of the mucus in the body is produced in the gastrointestinal tract.

<span class="mw-page-title-main">Adhesion</span> Molecular property

Adhesion is the tendency of dissimilar particles or surfaces to cling to one another.

<span class="mw-page-title-main">Hydrogel</span> Soft water-rich polymer gel

A hydrogel is a biphasic material, a mixture of porous, permeable solids and at least 10% by weight or volume of interstitial fluid composed completely or mainly by water. In hydrogels the porous permeable solid is a water insoluble three dimensional network of natural or synthetic polymers and a fluid, having absorbed a large amount of water or biological fluids. These properties underpin several applications, especially in the biomedical area. Many hydrogels are synthetic, but some are derived from nature. The term 'hydrogel' was coined in 1894.

<span class="mw-page-title-main">Topical medication</span> Medication applied to body surfaces

A topical medication is a medication that is applied to a particular place on or in the body. Most often topical medication means application to body surfaces such as the skin or mucous membranes to treat ailments via a large range of classes including creams, foams, gels, lotions, and ointments. Many topical medications are epicutaneous, meaning that they are applied directly to the skin. Topical medications may also be inhalational, such as asthma medications, or applied to the surface of tissues other than the skin, such as eye drops applied to the conjunctiva, or ear drops placed in the ear, or medications applied to the surface of a tooth. The word topical derives from Greek τοπικόςtopikos, "of a place".

<span class="mw-page-title-main">Alginic acid</span> Polysaccharide found in brown algae

Alginic acid, also called algin, is a naturally occurring, edible polysaccharide found in brown algae. It is hydrophilic and forms a viscous gum when hydrated. With metals such as sodium and calcium, its salts are known as alginates. Its colour ranges from white to yellowish-brown. It is sold in filamentous, granular, or powdered forms.

A drug carrier or drug vehicle is a substrate used in the process of drug delivery which serves to improve the selectivity, effectiveness, and/or safety of drug administration. Drug carriers are primarily used to control the release of drugs into systemic circulation. This can be accomplished either by slow release of a particular drug over a long period of time or by triggered release at the drug's target by some stimulus, such as changes in pH, application of heat, and activation by light. Drug carriers are also used to improve the pharmacokinetic properties, specifically the bioavailability, of many drugs with poor water solubility and/or membrane permeability.

Modified-release dosage is a mechanism that delivers a drug with a delay after its administration or for a prolonged period of time or to a specific target in the body.

Thiolated polymers – designated thiomers – are functional polymers used in biotechnology product development with the intention to prolong mucosal drug residence time and to enhance absorption of drugs. The name thiomer was coined by Andreas Bernkop-Schnürch in 2000. Thiomers have thiol bearing side chains. Sulfhydryl ligands of low molecular mass are covalently bound to a polymeric backbone consisting of mainly biodegradable polymers, such as chitosan, hyaluronic acid, cellulose derivatives, pullulan, starch, gelatin, polyacrylates, cyclodextrins, or silicones.

Bioadhesives are natural polymeric materials that act as adhesives. The term is sometimes used more loosely to describe a glue formed synthetically from biological monomers such as sugars, or to mean a synthetic material designed to adhere to biological tissue.

A nanogel is a polymer-based, crosslinked hydrogel particle on the sub-micron scale. These complex networks of polymers present a unique opportunity in the field of drug delivery at the intersection of nanoparticles and hydrogel synthesis. Nanogels can be natural, synthetic, or a combination of the two and have a high degree of tunability in terms of their size, shape, surface functionalization, and degradation mechanisms. Given these inherent characteristics in addition to their biocompatibility and capacity to encapsulate small drugs and molecules, nanogels are a promising strategy to treat disease and dysfunction by serving as delivery vehicles capable of navigating across challenging physiological barriers within the body. 

Adsorption is the accumulation and adhesion of molecules, atoms, ions, or larger particles to a surface, but without surface penetration occurring. The adsorption of larger biomolecules such as proteins is of high physiological relevance, and as such they adsorb with different mechanisms than their molecular or atomic analogs. Some of the major driving forces behind protein adsorption include: surface energy, intermolecular forces, hydrophobicity, and ionic or electrostatic interaction. By knowing how these factors affect protein adsorption, they can then be manipulated by machining, alloying, and other engineering techniques to select for the most optimal performance in biomedical or physiological applications.

Adsorption of polyelectrolytes on solid substrates is a surface phenomenon where long-chained polymer molecules with charged groups bind to a surface that is charged in the opposite polarity. On the molecular level, the polymers do not actually bond to the surface, but tend to "stick" to the surface via intermolecular forces and the charges created by the dissociation of various side groups of the polymer. Because the polymer molecules are so long, they have a large amount of surface area with which to contact the surface and thus do not desorb as small molecules are likely to do. This means that adsorbed layers of polyelectrolytes form a very durable coating. Due to this important characteristic of polyelectrolyte layers they are used extensively in industry as flocculants, for solubilization, as supersorbers, antistatic agents, as oil recovery aids, as gelling aids in nutrition, additives in concrete, or for blood compatibility enhancement to name a few.

Buccal administration is a topical route of administration by which drugs held or applied in the buccal area diffuse through the oral mucosa and enter directly into the bloodstream. Buccal administration may provide better bioavailability of some drugs and a more rapid onset of action compared to oral administration because the medication does not pass through the digestive system and thereby avoids first pass metabolism.

<span class="mw-page-title-main">Bovine submaxillary mucin coatings</span> Surface treatment for biomaterials

Bovine submaxillary mucin (BSM) coatings are a surface treatment provided to biomaterials intended to reduce the growth of disadvantageous bacteria and fungi such as S. epidermidis, E. coli, and Candida albicans. BSM is a substance extracted from the fresh salivary glands of cows. It exhibits unique physical properties, such as high molecular weight and amphiphilicity, that allow it to be used for many biomedical applications.

<span class="mw-page-title-main">Andreas Bernkop-Schnürch</span> Austrian university teacher (born 1965)

Andreas Bernkop-Schnürch is an Austrian scientist and entrepreneur. He is Head of the Department of Pharmaceutical Technology, Institute of Pharmacy, University of Innsbruck. His research centers on the areas of drug delivery, dosage forms, controlled release, bionanotechnology, polymer engineering and tissue engineering. He is the inventor of several technologies such as thiolated polymers for that he coined the name thiomers in 2000 and phosphatase triggered charge-converting nanoparticles for mucosal drug delivery. Since 2014 he is on the scientific advisory board of the Nicotine Science Center, Denmark. From 2016 to 2018 he served as a member of the Scientific Committee of the Innovative Medicines Initiative (IMI) of the European Union in Brussels giving advice on scientific priorities to be included in the Strategic Research Agenda for Horizon 2020. He is member of the editorial board of numerous pharmaceutical journals including International Journal of Pharmaceutics, Journal of Drug Delivery Science and Technology, Scientia Pharmaceutica, Drug Development and Industrial Pharmacy and European Journal of Pharmaceutics and Biopharmaceutis. Andreas Bernkop-Schnürch is the founder of Thiomatrix Forschungs- und Beratungs GmbH, Mucobiomer Biotechnologische Forschungs- und Entwicklungs GmbH and Green River Polymers Forschungs und Entwicklungs GmbH. Since 2022 he is listed as a Highly Cited Researcher of the Institute of Scientific Information.

Vitaliy Khutoryanskiy FRSC is a British and Kazakhstani scientist, a Professor of Formulation Science and a Royal Society Industry Fellow at the University of Reading. His research focuses on polymers, biomaterials, nanomaterials, drug delivery, and pharmaceutical sciences. Khutoryanskiy has published over 200 original research articles, book chapters, and reviews. His publications have attracted > 11000 citations and his current h-index is 50. He received several prestigious awards in recognition for his research in polymers, colloids and drug delivery as well as for contributions to research peer-review and mentoring of early career researchers. He holds several honorary professorship titles from different universities.

Topical gels are a topical drug delivery dosage form commonly used in cosmetics and treatments for skin diseases because of their advantages over cream and ointment. They are formed from a mixture of gelator, solvent, active drug, and other excipients, and can be classified into organogels and hydrogels. Drug formulation and preparation methods depend on the properties of the gelators, solvents, drug and excipients used.

<span class="mw-page-title-main">Intravesical drug delivery</span> Intravesical drug delivery, drug delivery to the bladder

Intravesical drug delivery is the delivery of medications directly into the bladder by urinary catheter. This method of drug delivery is used to directly target diseases of the bladder such as interstitial cystitis and bladder cancer, but currently faces obstacles such as low drug retention time due to washing out with urine and issues with the low permeability of the bladder wall itself. Due to the advantages of directly targeting the bladder, as well as the effectiveness of permeability enhancers, advances in intravesical drug carriers, and mucoadhesive, intravesical drug delivery is becoming more effective and of increased interest in the medical community.

References

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  18. ↑ Kolawole, Oluwadamilola M.; Lau, Wing Man; Mostafid, Hugh; Khutoryanskiy, Vitaliy V. (October 2017). "Advances in intravesical drug delivery systems to treat bladder cancer". International Journal of Pharmaceutics. 532 (1): 105–117. doi:10.1016/j.ijpharm.2017.08.120. ISSN   0378-5173. PMID   28867449.
  19. ↑ Cook, M. T.; Schmidt, S. A.; Lee, E.; Samprasit, W.; Opanasopit, P.; Khutoryanskiy, V. V. (2015). "Synthesis of mucoadhesive thiol-bearing microgels from 2-(acetylthio)ethylacrylate and 2-hydroxyethylmethacrylate: novel drug delivery systems for chemotherapeutic agents to the bladder". Journal of Materials Chemistry B. 3 (32): 6599–6604. doi: 10.1039/C5TB00834D . hdl: 2299/16268 . PMID   32262796.
  20. ↑ Barthelmes, J; Dünnhaupt, S; Unterhofer, S; Perera, G; Schlocker, W; Bernkop-Schnürch, A (January 2013). "Thiolated particles as effective intravesical drug delivery systems for treatment of bladder-related diseases". Nanomedicine (Lond). 8 (1): 65–75. doi:10.2217/nnm.12.76. PMID   22812707.
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