Modelling the impact of nucleolin expression level on the activity of F3 peptide-targeted pH-sensitive pegylated liposomes containing doxorubicin.
Ligand-mediated targeting
Modelling
Nanomedicine
Nucleolin expression
Protein homology
Journal
Drug delivery and translational research
ISSN: 2190-3948
Titre abrégé: Drug Deliv Transl Res
Pays: United States
ID NLM: 101540061
Informations de publication
Date de publication:
03 2022
03 2022
Historique:
accepted:
29
03
2021
pubmed:
17
4
2021
medline:
9
4
2022
entrez:
16
4
2021
Statut:
ppublish
Résumé
Strategies targeting nucleolin have enabled a significant improvement in intracellular bioavailability of their encapsulated payloads. In this respect, assessment of the impact of target cell heterogeneity and nucleolin homology across species (structurally and functionally) is of major importance. This work also aimed at mathematically modelling the nucleolin expression levels at the cell membrane, binding and internalization of pH-sensitive pegylated liposomes encapsulating doxorubicin and functionalized with the nucleolin-binding F3 peptide (PEGASEMP), and resulting cytotoxicity against cancer cells from mouse, rat, canine, and human origin. Herein, it was shown that nucleolin expression levels were not a limitation on the continuous internalization of F3 peptide-targeted liposomes, despite the saturable nature of the binding mechanism. Modeling enabled the prediction of nucleolin-mediated total doxorubicin exposure provided by the experimental settings of the assessment of PEGASEMP's impact on cell death. The former increased proportionally with nucleolin-binding sites, a measure relevant for patient stratification. This pattern of variation was observed for the resulting cell death in nonsaturating conditions, depending on the cancer cell sensitivity to doxorubicin. This approach differs from standard determination of cytotoxic concentrations, which normally report values of incubation doses rather than the actual intracellular bioactive drug exposure. Importantly, in the context of development of nucleolin-based targeted drug delivery, the structural nucleolin homology (higher than 84%) and functional similarity across species presented herein, emphasized the potential to use toxicological data and other metrics from lower species to infer the dose for a first-in-human trial.
Identifiants
pubmed: 33860446
doi: 10.1007/s13346-021-00972-z
pii: 10.1007/s13346-021-00972-z
doi:
Substances chimiques
Liposomes
0
Peptides
0
Phosphoproteins
0
RNA-Binding Proteins
0
Polyethylene Glycols
3WJQ0SDW1A
Doxorubicin
80168379AG
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
629-646Informations de copyright
© 2021. Controlled Release Society.
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