Preclinical evaluation of topically-administered PEGylated Fab’ lung toxicity

Freches, Danielle; Rocks, Natacha; Patil, Harshad P.; Perin, Fabienne; Snick, Jacques Van; Vanbever, Rita; Cataldo, Didier

doi:10.1016/j.ijpx.2019.100019

Cited by 4 publications

(10 citation statements)

References 39 publications

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“…This uptake was shown to affect large proteins more efficiently than small proteins and peptides purportedly due to the longer presence of the formers within the airspaces [25]. Uptake of PEG and PEGylated proteins by alveolar macrophages in vivo has also been demonstrated previously [7,12,16,26,27].…”

Section: Introductionsupporting

confidence: 52%

“…Figure 3B). This observation could be attributed to (i) the prolonged presence of PEG30-rhDNase in lungs airspaces and, therefore, more availability for macrophage uptake, and (ii) potentially, the higher resistance of PEGylated rhDNase to degradation within macrophages [18,27]. The former suggestion was confirmed in vitro where the uptake of rhDNase at 24 h was higher than that of PEG30-rhDNase in MHS cells.…”

Section: Discussionmentioning

confidence: 84%

“…The former suggestion was confirmed in vitro where the uptake of rhDNase at 24 h was higher than that of PEG30-rhDNase in MHS cells. Similarly, higher amounts of PEGylated rhDNase and Fab' fragments were detected in alveolar macrophages in vivo 24 h post-delivery compared to their corresponding non-PEGylated counterparts [7,27].…”

Section: Discussionmentioning

confidence: 99%

“…Preceding reports have highlighted the role of alveolar macrophages in the sequestration and clearance of proteins, PEGylated or not, after pulmonary delivery [12,23,27]. The contribution of alveolar macrophages in the uptake of native and PEGylated rhDNase was also suggested in vivo in our laboratory [7,16].…”

Section: Influence Of Pegylation and Peg Size On The Uptake Of Rhdnasmentioning

confidence: 97%

“…Direct quantification of proteins (PEGylated or not) in alveolar macrophages recovered by BAL following pulmonary delivery did not exceed 3% of the administered doses[7,23,27]. However, this percentage is probably largely underestimated because BAL only recovers a small fraction (10%) of alveolar macrophages[27].…”

mentioning

confidence: 99%

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PEGylation of recombinant human deoxyribonuclease I decreases its transport across lung epithelial cells and uptake by macrophages

Mahri

Hardy

Wilms

et al. 2021

International Journal of Pharmaceutics

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Conjugation to high molecular weight (MW) polyethylene glycol (PEG) was previously shown to largely prolong the lung residence time of recombinant human deoxyribonuclease I (rhDNase) and improve its therapeutic efficacy following pulmonary delivery in mice. In this paper, we investigated the mechanisms promoting the extended lung retention of PEG-rhDNase conjugates using cell culture models and lung biological media. Uptake by alveolar macrophages was also assessed in vivo. Transport experiments showed that PEGylation reduced the uptake and transport of rhDNase across monolayers of Calu-3 cells cultured at an air-liquid interface. PEGylation also decreased the uptake of rhDNase by macrophages in vitro whatever the PEG size as well as in vivo 4 h following intratracheal instillation in mice. However, the reverse was observed in vivo at 24 h. The uptake of rhDNase by macrophages was dependent on energy, time, and concentration and occurred at rates indicative of adsorptive endocytosis. The diffusion of PEGylated rhDNase in porcine tracheal mucus and cystic fibrosis sputa was slower compared with that of rhDNase. Nevertheless, no significant binding of PEGylated rhDNase to both media was observed. In conclusion, decreased transport across lung epithelial cells and uptake by macrophages appear to contribute to the longer retention of PEGylated rhDNase in the lungs.

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Section: Introductionsupporting

confidence: 52%

Section: Discussionmentioning

confidence: 84%

Section: Discussionmentioning

confidence: 99%

Section: Influence Of Pegylation and Peg Size On The Uptake Of Rhdnasmentioning

confidence: 97%

mentioning

confidence: 99%

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PEGylation of recombinant human deoxyribonuclease I decreases its transport across lung epithelial cells and uptake by macrophages

Mahri

Hardy

Wilms

et al. 2021

International Journal of Pharmaceutics

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

Mahri

Rondon

Wilms

et al. 2021

Journal of Controlled Release

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Pegylation, a Successful Strategy to Address the Storage and Instability Problems of Blood Products: Review 2011-2021

Alam

Varshney

Kaur

et al. 2024

CPB

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Depression is one of the most challenging diseases for society to treat. It is a highly prevalent and disabling illness in the general population. Affective disorders are characterised by depressed mood, diminished interest and pleasure, feelings of guilt or poor self-worth, sleep or food difficulties, decreased energy, and impaired attention. This manuscript will look at depression from a behavioural analytic perspective. The pathogenesis of major depressive disorder is poorly understood. Several lines of experimental and clinical evidence, however, show that the therapeutic effect of most antidepressant drugs is related to an increase in 5-HT-mediated neurotransmission. Alternative techniques, however, are employed to obtain this net effect. A better understanding of the neurological mechanism underpinning antidepressant drugs' delayed onset of action has resulted in the development of ways to accelerate antidepressant responses, which are discussed further below. Many antidepressant medications on the market today are beneficial, but they come with many downsides, including unpleasant side effects, potential interactions, and a low response rate. Natural drugs, on the other hand, are extremely effective, have a low risk, and a limited amount of side effects, which are covered briefly in this paper. Alternative modalities of administration have received a lot of attention in recent decades as a complement to approved prescription pharmaceuticals, especially for people who cannot tolerate oral or parenteral methods. The most promising non-invasive systemic delivery techniques are transdermal and transbronchial administration, and these are the focus of this research.

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Preclinical evaluation of topically-administered PEGylated Fab’ lung toxicity

Abstract: Graphical abstract

Cited by 4 publications

References 39 publications

PEGylation of recombinant human deoxyribonuclease I decreases its transport across lung epithelial cells and uptake by macrophages

PEGylation of recombinant human deoxyribonuclease I decreases its transport across lung epithelial cells and uptake by macrophages

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

Pegylation, a Successful Strategy to Address the Storage and Instability Problems of Blood Products: Review 2011-2021

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