Nanoparticles that do not adhere to mucus provide uniform and long-lasting drug delivery to airways following inhalation

Schneider, Craig S.; Xu, Qingguo; Boylan, Nicholas J.; Chisholm, Jane; Tang, Benjamin C.; Schuster, Benjamin S.; Henning, Andreas; Ensign, Laura M.; Lee, Ethan; Adstamongkonkul, Pichet; Simons, Brian W.; Wang, Sho Yu S.; Gong, Xiaoqun; Yu, Tao; Boyle, Michael; Suk, Jung Soo; Hanes, Justin

doi:10.1126/sciadv.1601556

Cited by 251 publications

(188 citation statements)

References 72 publications

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“…We note similar sample mixing and preparation techniques have been employed by other researchers studying nanoparticle transport in mucus [17,24]. Furthermore, previous studies from our group have confirmed that mucus samples subjected to these manipulations retain their expected bulk rheological properties and recapitulate ex vivo the in vivo barrier properties of mucus gels to nanoparticles [35,37,48,49]. After the particles were introduced into the sputum, the slide was sealed with a glass coverslip and then incubated at room temperature for 1–2 h to prevent advection during imaging.…”

Section: Methodssupporting

confidence: 64%

Photoactivatable fluorescent probes reveal heterogeneous nanoparticle permeation through biological gels at multiple scales

Schuster

Allan

Kays

et al. 2017

Journal of Controlled Release

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Diffusion through biological gels is crucial for effective drug delivery using nanoparticles. Here, we demonstrate a new method to measure diffusivity over a large range of length scales – from tens of nanometers to tens of micrometers – using photoactivatable fluorescent nanoparticle probes. We have applied this method to investigate the length-scale dependent mobility of nanoparticles in fibrin gels and in sputum from patients with cystic fibrosis (CF). Nanoparticles composed of poly(lactic-co-glycolic acid), with polyethylene glycol coatings to resist bioadhesion, were internally labeled with caged rhodamine to make the particles photoactivatable. We activated particles within a region of sample using brief, targeted exposure to UV light, uncaging the rhodamine and causing the particles in that region to become fluorescent. We imaged the subsequent spatiotemporal evolution in fluorescence intensity and observed the collective particle diffusion over tens of minutes and tens of micrometers. We also performed complementary multiple particle tracking experiments on the same particles, extending significantly the range over which particle motion and its heterogeneity can be observed. In fibrin gels, both methods showed an immobile fraction of particles and a mobile fraction that diffused over all measured length scales. In the CF sputum, particle diffusion was spatially heterogeneous and locally anisotropic but nevertheless typically led to unbounded transport extending tens of micrometers within tens of minutes. These findings provide insight into the mesoscale architecture of these gels and its role in setting their permeability on physiologically relevant length scales, pointing toward strategies for improving nanoparticle drug delivery.

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Section: Methodssupporting

confidence: 64%

Photoactivatable fluorescent probes reveal heterogeneous nanoparticle permeation through biological gels at multiple scales

Schuster

Allan

Kays

et al. 2017

Journal of Controlled Release

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“…The advantages of these materials reside primarily in their size (at least one dimension should be at the nanometer level), since many biological systems such as viruses and proteins are nano-sized (25). Nanoparticles can be administered via sub-cutaneous and intramuscular injections, or can be delivered through the mucosal sites (oral and intranasal), and penetrate capillaries as well as mucosal surfaces (26,27). Recent progresses have allowed the preparation of nanoparticles with unique physicochemical properties.…”

Section: Nanoparticles An Alternative Approach To Conventional Vaccinesmentioning

confidence: 99%

Nanoparticle-Based Vaccines Against Respiratory Viruses

et al. 2019

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The respiratory mucosa is the primary portal of entry for numerous viruses such as the respiratory syncytial virus, the influenza virus and the parainfluenza virus. These pathogens initially infect the upper respiratory tract and then reach the lower respiratory tract, leading to diseases. Vaccination is an affordable way to control the pathogenicity of viruses and constitutes the strategy of choice to fight against infections, including those leading to pulmonary diseases. Conventional vaccines based on live-attenuated pathogens present a risk of reversion to pathogenic virulence while inactivated pathogen vaccines often lead to a weak immune response. Subunit vaccines were developed to overcome these issues. However, these vaccines may suffer from a limited immunogenicity and, in most cases, the protection induced is only partial. A new generation of vaccines based on nanoparticles has shown great potential to address most of the limitations of conventional and subunit vaccines. This is due to recent advances in chemical and biological engineering, which allow the design of nanoparticles with a precise control over the size, shape, functionality and surface properties, leading to enhanced antigen presentation and strong immunogenicity. This short review provides an overview of the advantages associated with the use of nanoparticles as vaccine delivery platforms to immunize against respiratory viruses and highlights relevant examples demonstrating their potential as safe, effective and affordable vaccines.

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“…These assays do not provide quantitative measurements of diffusion parameters, but nonetheless serve as a valuable bridge between in vitro studies and translation to the clinic. 47,52,88,89 …”

Section: Size-dependent Filtrationmentioning

confidence: 99%

“…51 Second, high-density surface-grafted PEG forms a brush that physically resists the adsorption of gel components, 153 while the low PEG molecular weight precludes adhesion to gel components due to chain entanglement. 51 Neither of these reasons is gel-specific, which explains why PEGylation seems to be fairly universally applicable to promoting diffusion in biological hydrogels: PEGylated particles effectively penetrate many types of mucus, 51–53,89,154,155 biofilms, 44 and ECM. 47,156,157 In addition, recently Maisel et al (2016) recently showed that PEG molecular weights as high as 40 kDa can be used for mucus penetration, with higher molecular weights requiring extremely high PEGylation density to reduce entanglements.…”

Section: Selective Transport Of Objects On the Order Of Mesh Sizementioning

confidence: 99%

The particle in the spider's web: transport through biological hydrogels

2017

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Biological hydrogels such as mucus, extracellular matrix, biofilms, and the nuclear pore have diverse functions and compositions, but all act as selectively permeable barriers to the diffusion of particles. Each barrier has a crosslinked polymeric mesh that blocks penetration of large particles such as pathogens, nanotherapeutics, or macromolecules. These polymeric meshes also employ interactive filtering, in which affinity between solutes and the gel matrix controls permeability. Interactive filtering affects the transport of particles of all sizes including peptides, antibiotics, and nanoparticles and in many cases this filtering can be described in terms of the effects of charge and hydrophobicity. The concepts described in this review can guide strategies to exploit or overcome gel barriers, particularly for applications in diagnostics, pharmacology, biomaterials, and drug delivery.

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Nanoparticles that do not adhere to mucus provide uniform and long-lasting drug delivery to airways following inhalation

Abstract: Debunking the mucoadhesion myth: Nonsticky particles for enhanced pulmonary drug delivery.

Cited by 251 publications

References 72 publications

Photoactivatable fluorescent probes reveal heterogeneous nanoparticle permeation through biological gels at multiple scales

Photoactivatable fluorescent probes reveal heterogeneous nanoparticle permeation through biological gels at multiple scales

Nanoparticle-Based Vaccines Against Respiratory Viruses

The particle in the spider's web: transport through biological hydrogels

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