A free-floating mucin layer to investigate the effect of the local microenvironment in lungs on mucin-nanoparticle interactions

Hydrogels made of crosslinked macromolecules used in regenerative medicine technologies can be designed to affect the fate of surrounding cells and tissues in defined ways. Their function typically depends on the type and number of bioactive moieties such as receptor ligands present in the hydrogel. However, the detail in how such moieties are presented to cells can also be instrumental. In this work, how the crosslinking architecture of a hydrogel can affect its bioactivity is explored. It is shown that bovine submaxillary mucins, a highly glycosylated and immune‐modulating protein, exhibit strikingly different bioactivities whether they are crosslinked through their glycans or their protein domains. Both the susceptibility to enzymatic degradation and macrophage response are affected, while rheological properties and barrier to diffusion are mostly unaffected. The results suggest that crosslinking architecture affects the accessibility of the substrate to proteases and the pattern of sialic acid residues exposed to the macrophages. Thus, modulating the accessibility of binding sites through the choice of the crosslinking strategy appears as a useful parameter to tune the bioactivity of hydrogel‐based systems.

show abstract

“…This was also recently shown for surface‐bound mucins and their binding to dextrans, antibodies, [ 58 ] and nanoparticles. [ 59 ]…”

Section: Resultsmentioning

confidence: 99%

Modulating the Bioactivity of Mucin Hydrogels with Crosslinking Architecture

Jiang

Yan

Rickert

et al. 2021

Adv Funct Materials

View full text Add to dashboard Cite

show abstract

“…Due to pulmonary infections, changes in pH and ionic strength may occur. Data from quartz crystal microbalance with dissipation in mucus-coated sensors showed that a decrease in pH and increase in ionic strength induced softer mucus with more hydrophobic areas [ 120 ]. These changes may affect the permeation.…”

Section: Overcoming Non-cellular Barriersmentioning

confidence: 99%

Non-Cellular Layers of the Respiratory Tract: Protection against Pathogens and Target for Drug Delivery

Frőhlich

2022

Pharmaceutics

View full text Add to dashboard Cite

Epithelial barriers separate the human body from the environment to maintain homeostasis. Compared to the skin and gastrointestinal tract, the respiratory barrier is the thinnest and least protective. The properties of the epithelial cells (height, number of layers, intercellular junctions) and non-cellular layers, mucus in the conducting airways and surfactant in the respiratory parts determine the permeability of the barrier. The review focuses on the non-cellular layers and describes the architecture of the mucus and surfactant followed by interaction with gases and pathogens. While the penetration of gases into the respiratory tract is mainly determined by their hydrophobicity, pathogens use different mechanisms to invade the respiratory tract. Often, the combination of mucus adhesion and subsequent permeation of the mucus mesh is used. Similar mechanisms are also employed to improve drug delivery across the respiratory barrier. Depending on the payload and target region, various mucus-targeting delivery systems have been developed. It appears that the mucus-targeting strategy has to be selected according to the planned application.

show abstract

“…For example, the pH value of lung lining fluid in the proximal part (on the surface of the mucus matrix) as well as the distal part of the respiratory tract under normal conditions is close to neutral. However, it will decrease to pH 6.0-6.5 under pathological conditions in, e.g., CF and COPD patients due to the chronic bacterial infections [41][42][43], which consequently significantly influence the conformational structure of the mucin molecules [44][45][46], and thereby affects the mucus-nanoparticle interaction [47]. In addition, the respiratory tract diseases induce overproduction and dehydration of mucus with important impact on the interaction between mucus and the drug molecule or the drug delivery system administered to the lungs [38].…”

Section: Lung Lining Fluidmentioning

confidence: 99%

“…TPGS is an FDA-approved pharmaceutical excipient consisting of a lipophilic moiety (vitamin E) and a hydrophilic moiety (PEG) [138,139] and is documented to be cleaved into vitamin E and PEG by enzymes secreted by bacteria [140][141][142]. Our recent study showed that the mucus-inert, enzymatically cleavable TPGS shell can reduce non-specific interactions of the nanoparticles with pulmonary surfactant and mucin [47,52], and allow accumulation of the nanoparticles deep in the biofilms [93].…”

Section: Plga-based Nanoparticlesmentioning

confidence: 99%

Nanoparticle-mediated pulmonary drug delivery: state of the art towards efficient treatment of recalcitrant respiratory tract bacterial infections

Huang

Kłodzińska

Wan

et al. 2021

Drug Deliv. and Transl. Res.

Self Cite

View full text Add to dashboard Cite

Graphical abstract Recalcitrant respiratory tract infections caused by bacteria have emerged as one of the greatest health challenges worldwide. Aerosolized antimicrobial therapy is becoming increasingly attractive to combat such infections, as it allows targeted delivery of high drug concentrations to the infected organ while limiting systemic exposure. However, successful aerosolized antimicrobial therapy is still challenged by the diverse biological barriers in infected lungs. Nanoparticle-mediated pulmonary drug delivery is gaining increasing attention as a means to overcome the biological barriers and accomplish site-specific drug delivery by controlling release of the loaded drug(s) at the target site. With the aim to summarize emerging efforts in combating respiratory tract infections by using nanoparticle-mediated pulmonary delivery strategies, this review provides a brief introduction to the bacterial infection-related pulmonary diseases and the biological barriers for effective treatment of recalcitrant respiratory tract infections. This is followed by a summary of recent advances in design of inhalable nanoparticle-based drug delivery systems that overcome the biological barriers and increase drug bioavailability. Finally, challenges for the translation from exploratory laboratory research to clinical application are also discussed and potential solutions proposed.

show abstract

A free-floating mucin layer to investigate the effect of the local microenvironment in lungs on mucin-nanoparticle interactions

Cited by 22 publications

References 37 publications

Modulating the Bioactivity of Mucin Hydrogels with Crosslinking Architecture

Modulating the Bioactivity of Mucin Hydrogels with Crosslinking Architecture

Non-Cellular Layers of the Respiratory Tract: Protection against Pathogens and Target for Drug Delivery

Nanoparticle-mediated pulmonary drug delivery: state of the art towards efficient treatment of recalcitrant respiratory tract bacterial infections

Contact Info

Product

Resources

About