Biodistribution and elimination pathways of PEGylated recombinant human deoxyribonuclease I after pulmonary delivery in mice

Mahri, Sohaib; Rondon, Aur�lie; Wilms, Tobias; Bosquillon, Cynthia; Vanbever, Rita

Abstract

Conjugation of recombinant human deoxyribonuclease I (rhDNase) to polyethylene glycol (PEG) of 20 to 40 kDa was previously shown to prolong the residence time of rhDNase in the lungs of mice after pulmonary delivery while preserving its full enzymatic activity. This work aimed to study the fate of native and PEGylated rhDNase in the lungs and to elucidate their biodistribution and elimination pathways after intratracheal instillation in mice. In vivo fluorescence imaging revealed that PEG30 kDa-conjugated rhDNase (PEG30-rhDNase) was retained in mouse lungs for a significantly longer period of time than native rhDNase (12 days vs 5 days). Confocal microscopy confirmed the presence of PEGylated rhDNase in lung airspaces for at least 7 days. In contrast, the unconjugated rhDNase was cleared from the lung lumina within 24 h and was only found in lung parenchyma and alveolar macrophages thereafter. Systemic absorption of intact rhDNase and PEG30-rhDNase was observed. However, this was significantly lower for the latter. Catabolism, primarily in the lungs and secondarily systemically followed by renal excretion of byproducts were the predominant elimination pathways for both native and PEGylated rhDNase. Catabolism was nevertheless more extensive for the native protein. On the other hand, mucociliary clearance appeared to play a less prominent role in the clearance of those proteins after pulmonary delivery. The prolonged presence of PEGylated rhDNase in lung airspaces appears ideal for its mucolytic action in patients with cystic fibrosis.

• Journal Article Type: Article
• Acceptance Date: Oct 17, 2020
• Online Publication Date: Oct 20, 2020
• Publication Date: Jan 10, 2021
• Deposit Date: Nov 3, 2020
• Publicly Available Date: Oct 21, 2021
• Journal: Journal of Controlled Release
• Print ISSN: 0168-3659
• Electronic ISSN: 1873-4995
• Publisher: Elsevier
• Peer Reviewed: Peer Reviewed
• Volume: 329
• Pages: 1054-1065
• DOI: https://doi.org/10.1016/j.jconrel.2020.10.034
• Keywords: Pharmaceutical Science
• Public URL: https://nottingham-repository.worktribe.com/output/5014398
• Publisher URL: https://www.sciencedirect.com/science/article/pii/S016836592030612X?via%3Dihub