Enhancing nanoparticle penetration through airway mucus to improve drug delivery efficacy in the lung

ABSTRACT

Introduction: Airway mucus gel layer serves as a key delivery barrier that limits the performance of inhaled drug delivery nanoparticles. Conventional nanoparticles are readily trapped by the airway mucus and rapidly cleared from the lung via mucus clearance mechanisms. These nanoparticles cannot distribute throughout the lung airways, long-reside in the lung and/or reach the airway epithelium. To address this challenge, strategies to enhance particle penetration through the airway mucus have been developed and proof-of-concept has been established using mucus model systems..

Areas covered: In this review, we first overview the biochemical and biophysical characteristics that render the airway mucus a challenging delivery barrier. We then introduce strategies to improve particle penetration through the airway mucus. Specifically, we walk through two classes of approaches, including modification of physicochemical properties of nanoparticles and modulation of barrier properties of airway mucus.

Expert opinion: State-of-the-art strategies to overcome the airway mucus barrier have been introduced and experimentally validated. However, data should be interpreted in the comprehensive context of therapeutic delivery from the site of administration to the final destination to determine clinically-relevant approaches. Further, safety should be carefully monitored, particularly when it comes to mucus-altering strategies that may perturb physiological functions of airway mucus.

KEYWORDS:

• Airway mucus
• mucoadhesion
• nanoparticle
• drug delivery
• inhaled therapy

Article highlights

• Airway mucus serves as an adhesive and steric barrier to inhaled nanoparticle-based therapeutic delivery.

• The barrier properties of airway mucus is enhanced and/or altered in disease conditions.

• The airway mucus barrier can be overcome by manipulating nanoparticle properties and/or transiently modulating the airway mucus barrier.

• Strategies to overcome the airway mucus barrier should be validated using pathophysiologically relevant and complementary experimental settings and with safety consideration.

• The airway mucus, while critical and challenging, is not the only hurdle and thus other delivery barriers should be taken into account for clinical development of inhaled nanoparticle-based therapies.

This box summarizes key points contained in the article.

Declaration of interest

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Additional information

Funding

Funding was provided by the National Institute of Health (R01HL125169, R01HL127413 and R01HL136617) and the Cystic Fibrosis Foundation (SUK18I0). The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH.