Utilization of endogenous albumin trafficking pathways in the lungs has potential to modestly increase the lung interstitial access and absorption of drug delivery systems after inhaled administration

ABSTRACT

Objectives

Drug delivery systems typically show limited access to the lung interstitium and absorption after pulmonary delivery. The aim of this work was to undertake a proof-of-concept investigation into the potential of employing endogenous albumin and albumin absorption mechanisms in the lungs to improve lung interstitial access and absorption of inhaled drug delivery systems that bind albumin.

Methods

The permeability of human albumin (HSA) through monolayers of primary human alveolar epithelia, small airway epithelia, and microvascular endothelium were investigated. The pulmonary pharmacokinetics of bovine serum albumin (BSA) was also investigated in efferent caudal mediastinal lymph duct-cannulated sheep after inhaled aerosol administration.

Results

Membrane permeability coefficient values (P_app) of HSA increased in the order alveolar epithelia<small airway epithelia<microvascular endothelium, where the permeability of HSA through small airway and microvascular endothelia were approximately 4- and 28-fold higher than alveolar epithelia, respectively. Only 6.5% of the delivered BSA aerosol dose was absorbed from the lungs of sheep over 5 days, although half of the absorbed dose was absorbed via the lung lymph.

Conclusion

Drug delivery systems that bind endogenous albumin may show a modest increase in lung permeability and absorption after inhaled delivery compared to systems that do not efficiently bind albumin.

KEYWORDS:

• Albumin
• inhaled
• lung permeability
• nebulized
• pharmacokinetics
• sheep

Author disclosures

L Kaminskas, A Whittaker and M Whittaker were responsible for development of the concept. L Kaminskas, J Ibrahim, N Butcher, C Subasic, A Kothapalli and J Blanchfield were responsible for the project design. All authors were responsible for data analysis and interpretation of the results. L Kaminskas, J Ibrahim and N Butcher were responsible for drafting the paper. All other authors were responsible for revising the paper draft. All authors agree to be accountable for all aspects of the work.

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.

Acknowledgments

The authors would like to acknowledge the assistance of David Ascher in establishing the stability of BSA to nebulization and Rob Bischof for his help with sheep surgery and dosing.

SUPPLEMENTARY MATERIAL

Supplemental data for this article can be accessed online at https://doi.org/10.1080/17425247.2023.2244881

Additional information

Funding

This work was funded by a National Health and Medical Research Council (NHMRC) grant. L Kaminskas was funded by an NHMRC CDF2.