Liposomal encapsulation of trans-crocetin enhances oxygenation in patients with COVID-19-related ARDS receiving mechanical ventilation.
COVID-19
Clinical trial
Drug delivery
Nanomedicine
Sepsis
Journal
Journal of controlled release : official journal of the Controlled Release Society
ISSN: 1873-4995
Titre abrégé: J Control Release
Pays: Netherlands
ID NLM: 8607908
Informations de publication
Date de publication:
10 08 2021
10 08 2021
Historique:
received:
18
06
2021
accepted:
21
06
2021
pubmed:
28
6
2021
medline:
19
8
2021
entrez:
27
6
2021
Statut:
ppublish
Résumé
Current therapeutic treatments improving the impaired transportation of oxygen in acute respiratory distress syndrome (ARDS) have been found to be relevant and beneficial for the therapeutic treatment of COVID-19 patients suffering from severe respiratory complications. Hence, we report the preclinical and the preliminary results of the Phase I/II clinical trial of LEAF-4L6715, a liposomal nanocarrier encapsulating the kosmotropic agent trans-crocetin (TC), which, once injected, enhance the oxygenation of vascular tissue and therefore has the potential to improve the clinical outcomes of ARDS and COVID-19 in severely impacted patients. We demonstrated that the liposomal formulation enabled to increase from 30 min to 48 h the reoxygenation properties of free TCs in vitro in endothelial cells, but also to improve the half-life of TC by 6-fold in healthy mice. Furthermore, we identified 25 mg/kg as the maximum tolerated dose in mice. This determined concentration led to the validation of the therapeutic efficacy of LEAF-4 L6715 in a sepsis mouse model. Finally, we report the preliminary outcomes of an open-label multicenter Phase I/II clinical trial (EudraCT 2020-001393-30; NCT04378920), which was aimed to define the appropriate schedule and dosage of LEAF-4L6715 and to confirm its tolerability profile and preliminary clinical activity in COVID-19 patients treated in intensive care unit.
Identifiants
pubmed: 34175365
pii: S0168-3659(21)00320-5
doi: 10.1016/j.jconrel.2021.06.033
pmc: PMC8225316
pii:
doi:
Substances chimiques
trans-sodium crocetinate
0
Vitamin A
11103-57-4
Carotenoids
36-88-4
Types de publication
Journal Article
Multicenter Study
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
252-261Informations de copyright
Copyright © 2021 The Author(s). Published by Elsevier B.V. All rights reserved.
Références
N Engl J Med. 2000 Jun 1;342(22):1638-43
pubmed: 10836875
N Engl J Med. 2013 Jun 6;368(23):2159-68
pubmed: 23688302
Sci Rep. 2020 Feb 27;10(1):3654
pubmed: 32107408
Lancet Respir Med. 2020 Aug;8(8):816-821
pubmed: 32645311
N Engl J Med. 2017 Nov 9;377(19):1904-1905
pubmed: 29117492
J Thromb Haemost. 2020 Apr;18(4):844-847
pubmed: 32073213
Inflamm Res. 2020 Mar;69(3):267-278
pubmed: 31925528
Radiology. 2020 Nov;297(2):E252-E262
pubmed: 32614258
N Engl J Med. 2011 Feb 17;364(7):656-65
pubmed: 21323543
Nat Rev Dis Primers. 2019 Mar 14;5(1):18
pubmed: 30872586
J Phys Chem B. 2006 Sep 21;110(37):18078-80
pubmed: 16970413
JAMA Intern Med. 2020 Jul 1;180(7):934-943
pubmed: 32167524
Trends Biotechnol. 2014 Sep;32(9):466-73
pubmed: 24929580
Pulm Pharmacol Ther. 2005;18(3):213-6
pubmed: 15707856
N Engl J Med. 1999 Feb 11;340(6):438-47
pubmed: 9971869
Expert Opin Investig Drugs. 2008 Jun;17(6):917-24
pubmed: 18491992