Gemcitabine Lipid Prodrugs: The Key Role of the Lipid Moiety on the Self-Assembly into Nanoparticles

A small library of amphiphilic prodrugs has been synthesized by conjugation of gemcitabine (Gem) (a hydrophilic nucleoside analogue) to a series of lipid moieties and investigated for their capacity to spontaneously self-assemble into nanosized objects by simple nanoprecipitation. Four of these conj...

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Veröffentlicht in:Bioconjugate chemistry 2021-04, Vol.32 (4), p.782-793
Hauptverfasser: Coppens, Eleonore, Desmaële, Didier, Mougin, Julie, Tusseau-Nenez, Sandrine, Couvreur, Patrick, Mura, Simona
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container_title Bioconjugate chemistry
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creator Coppens, Eleonore
Desmaële, Didier
Mougin, Julie
Tusseau-Nenez, Sandrine
Couvreur, Patrick
Mura, Simona
description A small library of amphiphilic prodrugs has been synthesized by conjugation of gemcitabine (Gem) (a hydrophilic nucleoside analogue) to a series of lipid moieties and investigated for their capacity to spontaneously self-assemble into nanosized objects by simple nanoprecipitation. Four of these conjugates formed stable nanoparticles (NPs), while with the others, immediate aggregation occurred, whatever the tested experimental conditions. Whether such capacity could have been predicted based on the prodrug physicochemical features was a matter of question. Among various parameters, the hydrophilic–lipophilic balance (HLB) value seemed to hold a predictive character. Indeed, we identified a threshold value which well correlated with the tendency (or not) of the synthesized prodrugs to form stable nanoparticles. Such a hypothesis was further confirmed by broadening the analysis to Gem and other nucleoside prodrugs already described in the literature. We also observed that, in the case of Gem prodrugs, the lipid moiety affected not only the colloidal properties but also the in vitro anticancer efficacy of the resulting nanoparticles. Overall, this study provides a useful demonstration of the predictive potential of the HLB value for lipid prodrug NP formulation and highlights the need of their opportune in vitro screening, as optimal drug loading does not always translate in an efficient biological activity.
doi_str_mv 10.1021/acs.bioconjchem.1c00051
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ispartof Bioconjugate chemistry, 2021-04, Vol.32 (4), p.782-793
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source American Chemical Society Journals
subjects Anticancer properties
Biological activity
Chemical Sciences
Conjugation
Drugs
Gemcitabine
Hydrophilicity
Lipids
Lipophilic
Nanoparticles
Nucleoside analogs
Nucleosides
Organic chemistry
Prodrugs
Self-assembly
Synthesis
title Gemcitabine Lipid Prodrugs: The Key Role of the Lipid Moiety on the Self-Assembly into Nanoparticles
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