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Mahri, Sohaib (2021) Mechanisms of retention of PEGylated recombinant human deoxyribonuclease i (rhDNase) in the lungs. PhD thesis, Université Catholique de Louvain and University of Nottingham.

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Abstract

Conjugation of recombinant human deoxyribonuclease I (rhDNase) to large (≥ 20 kDa) polyethylene glycol (PEG) has been shown to prolong the lung residence time of the enzyme in mice. Here, we investigated the mechanisms of this extended retention of PEG-rhDNase conjugates.

PEG-rhDNase conjugates were detected in lung airspaces of mice for a longer time, at least 7 days post intratracheal instillation in the case of PEG30-rhDNase compared to ≤ 24 h for rhDNase. PEG30-rhDNase was significantly less absorbed than rhDNase in vivo from the lungs and in vitro across monolayers of lung epithelial cells. The uptake of PEGylated rhDNase by macrophages was delayed in vitro and in vivo whatever the PEG size. Moreover, local degradation in the lungs was observed for both proteins; however, more extensively for rhDNase. Finally, PEGylation did not seem to affect the mucociliary clearance of rhDNase significantly.

In conclusion, a decrease in cell uptake and systemic absorption play a significant role in the extended retention of PEGylated rhDNase in the lungs.

Item Type:	Thesis (University of Nottingham only) (PhD)
Supervisors:	Vanbever, Rita Bosquillon, Cynthia
Keywords:	Recombinant human deoxyribonuclease I, protein PEGylation, pulmonary drug delivery, alveolar macrophages, transport across Calu-3, diffusion in mucus, biodistribution, cystic fibrosis.
Subjects:	Q Science > QP Physiology > QP501 Animal biochemistry R Medicine > RM Therapeutics. Pharmacology
Faculties/Schools:	UK Campuses > Faculty of Science > School of Pharmacy
Item ID:	65811
Depositing User:	Mahri, Sohaib
Date Deposited:	12 Oct 2023 14:40
Last Modified:	12 Oct 2023 14:40
URI:	https://eprints.nottingham.ac.uk/id/eprint/65811

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