Mucus Penetrating Nanoparticles: Biophysical Tool and Method of Drug and Gene Delivery

Ensign, Laura M.; Schneider, Craig S.; Suk, Jung Soo; Cone, Richard A.; Hanes, Justin

doi:10.1002/adma.201201800

Cited by 232 publications

(138 citation statements)

References 57 publications

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“…Added to this, mucus provides a substantial barrier to the diffusion of large, charged and lipophilic entities, which can dramatically reduce diffusion rates [87][88][89]. Indeed, these issues have resulted in increasing interest in the development of muco-inert carrier systems in the form of mucus-penetrating particles that avoid interaction with mucus and thus experience a lower diffusion barrier [84,[90][91][92][93].…”

Section: Relevance For Mucoadhesionmentioning

confidence: 99%

Direct Determination of Chitosan–Mucin Interactions Using a Single-Molecule Strategy: Comparison to Alginate–Mucin Interactions

et al. 2015

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Aqueous chitosan possesses attractive interaction capacities with various molecular groups that can be involved in hydrogen bonds and electrostatic and hydrophobic interactions. In the present paper, we report on the direct determination of chitosan-mucin molecular pair interactions at various solvent conditions as compared to alginate-mucin interactions. Two chitosans of high molecular weight with different degrees of acetylation-thus possessing different solubility profiles in aqueous solution as a function of pH and two alginates with different fractions of α-guluronic acid were employed. The interaction properties were determined through a direct unbinding assay at the single-molecular pair level using an atomic force microscope. When probed against immobilized mucin, both chitosans and alginates revealed unbinding profiles characteristic of localized interactions along the polymers. The interaction capacities and estimated OPEN ACCESSPolymers 2015, 7 162 parameters of the energy landscapes of the pairwise chitosan-mucin and alginate-mucin interactions are discussed in view of possible contributions from various fundamental forces. Signatures arising both from an electrostatic mechanism and hydrophobic interaction are identified in the chitosan-mucin interaction properties. The molecular nature of the observed chitosan-mucin and alginate-mucin interactions indicates that force spectroscopy provides fundamental insights that can be useful in understanding the surface binding properties of other potentially mucoadhesive polymers.

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Section: Relevance For Mucoadhesionmentioning

confidence: 99%

Direct Determination of Chitosan–Mucin Interactions Using a Single-Molecule Strategy: Comparison to Alginate–Mucin Interactions

et al. 2015

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“…Thus, for efficient gene transfer to the airway epithelium in vivo, inhaled gene vectors must be small enough to diffuse through the mucus mesh while possessing a muco-inert surface to avoid adhesion to mucus constituents (20,22,(31)(32)(33). We have previously demonstrated that highly dense surface coatings of hydrophilic and neutrally charged polyethylene glycol (PEG) render therapeutic NPs resistant to mucoadhesion, thereby enabling rapid diffusion in airway mucus (20,22,(31)(32)(33). Of note, conventional (lower-density) PEG surface coatings do not provide muco-inert surfaces, resulting in immobilization of particles in CF mucus (26,27,33).…”

mentioning

confidence: 99%

Highly compacted biodegradable DNA nanoparticles capable of overcoming the mucus barrier for inhaled lung gene therapy

Mastorakos

Silva

Chisholm

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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166

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Gene therapy has emerged as an alternative for the treatment of diseases refractory to conventional therapeutics. Synthetic nanoparticle-based gene delivery systems offer highly tunable platforms for the delivery of therapeutic genes. However, the inability to achieve sustained, high-level transgene expression in vivo presents a significant hurdle. The respiratory system, although readily accessible, remains a challenging target, as effective gene therapy mandates colloidal stability in physiological fluids and the ability to overcome biological barriers found in the lung. We formulated highly stable DNA nanoparticles based on state-of-theart biodegradable polymers, poly(β-amino esters) (PBAEs), possessing a dense corona of polyethylene glycol. We found that these nanoparticles efficiently penetrated the nanoporous and highly adhesive human mucus gel layer that constitutes a primary barrier to reaching the underlying epithelium. We also discovered that these PBAE-based mucus-penetrating DNA nanoparticles (PBAE-MPPs) provided uniform and high-level transgene expression throughout the mouse lungs, superior to several gold standard gene delivery systems. PBAE-MPPs achieved robust transgene expression over at least 4 mo following a single administration, and their transfection efficiency was not attenuated by repeated administrations, underscoring their clinical relevance. Importantly, PBAE-MPPs demonstrated a favorable safety profile with no signs of toxicity following intratracheal administration.lung gene therapy | mucus-penetrating particles | nanotechnology | biodegradable polymer | nonviral gene delivery

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“…This shortcoming is circumvented in the newly published models, where simulated mucus is applied to cultured cell layers [14,39]. Furthermore, it has been argued that mucus secreted from cultured cells is unlikely to match the structural and adhesive characteristics of human mucus [44]. This could be supported by the finding that the mesh spacing of mucus secreted from the bronchial cell line Calu-3 is more homogenous and the scaffold thinner as compared to mucus from porcine small intestine [3].…”

Section: Mucus-containing In Vitro Modelsmentioning

confidence: 99%

Mucus as a Barrier to Drug Delivery – Understanding and Mimicking the Barrier Properties

Boegh

Nielsen

2014

Basic Clin Pharma Tox

254

170

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Viscoelastic mucus lines all mucosal surfaces of the body and forms a potential barrier to mucosal drug delivery. Mucus is mainly composed of water and mucins; high molecular weight glycoproteins forming an entangled network. Consequently, mucus forms a steric barrier, and due to its negative charge and hydrophobic domains, the overall hydrophilic mucus also presents an interactive barrier limiting the free diffusion of components within and through the mucus. Furthermore, mucus is a dynamic barrier due to its continuous secretion and shedding from the mucosal surfaces. Mucus is thus a highly complex gel barrier to drug delivery. Current knowledge of mucus characteristics and barrier properties, as achieved by state-of-the-art methodologies, is the topic of this MiniReview emphasizing the gastrointestinal mucus and an overall focus on oral drug delivery. Cell culture-based in vitro models are well-established as essential tools in drug research and development, but traditionally, mucus-containing models have only rarely been applied. However, a number of mucus-containing in vitro models have recently been described in the literature, and their properties and applications will be reviewed and discussed. Finally, studies of peptide and protein drug diffusion in and through mucus and studies of mucus-penetrating nanoparticles are included to illustrate the mucus as a potentially important barrier to obtain sufficient bioavailability of orally administered drugs, and thus an important parameter to address in the development of future oral drug delivery systems.

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Mucus Penetrating Nanoparticles: Biophysical Tool and Method of Drug and Gene Delivery

Cited by 232 publications

References 57 publications

Direct Determination of Chitosan–Mucin Interactions Using a Single-Molecule Strategy: Comparison to Alginate–Mucin Interactions

Direct Determination of Chitosan–Mucin Interactions Using a Single-Molecule Strategy: Comparison to Alginate–Mucin Interactions

Highly compacted biodegradable DNA nanoparticles capable of overcoming the mucus barrier for inhaled lung gene therapy

Mucus as a Barrier to Drug Delivery – Understanding and Mimicking the Barrier Properties

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