Emerging anticancer activity of candidal glucoseamine-6-phosphate synthase inhibitors upon nanoparticle-mediated delivery

Ahmet Kertmen; Julia Przysiecka; Emerson Coy; Łukasz Popenda; Ryszard Andruszkiewicz; Stefan Jurga; Sławomir Milewski

doi:10.1021/acs.langmuir.8b04250

Emerging anticancer activity of candidal glucoseamine-6-phosphate synthase inhibitors upon nanoparticle-mediated delivery

Abstract

Numerous glutamine analogues have been reported as irreversible inhibitors of the glucosamine-6-phosphate (GlcN-6-P) synthase in pathogenic Candida albicans in the last 3.5 decades. Among the reported inhibitors, the most effective N3-(4-methoxyfumaroyl)-L-2,3- diaminopropanoic acid (FMDP) has been extensively studied in order to develop its more active analogues. Several peptide−FMDP conjugates were tested to deliver FMDP to its subcellularly located GlcN-6-P synthase target. However, the rapid development of fungal resistance to FMDP−peptides required development of different therapeutic approaches to tackle antifungal resistance. In the current state of the global antifungal resistance, subcellular delivery of FMDP via free diffusion or endocytosis has become crucial. In this study, we report on in vitro nanomedical applications of FMDP and one of its ketoacid analogues, N3-trans-4-oxo-4-phenyl-2-butenoyl-L-2,3-diaminopropanoic acid (BADP). FMDP and BADP covalently attached to polyethylene glycol-coated iron oxide/silica core−shell nanoparticles are tested against intrinsically multidrug-resistant C. albicans. Three different human cancer cell lines potentially overexpressing the GlcN-6-P synthase enzyme are tested to demonstrate the immediate inhibitory effects of nanoparticle conjugates against mammalian cells. It is shown that nanoparticle-mediated delivery transforms FMDP and BADP into strong anticancer agents by inhibiting the growth of the tested cancer cells, whereas their anti-Candidal activity is decreased. This study discusses the emerging inhibitory effect of the FMDP/BADP−nanoparticle conjugates based on their cellular internalization efficiency and biocompatibility.

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Authors (7)

Ahmet Kertmen
Julia Przysiecka
- Uniwersytet Adama Mickiewicza Centrum NanoBioMedyczne
Emerson Coy
- Uniwersytet Adama Mickiewicza Centrum NanoBioMedyczne
Łukasz Popenda dr
- Uniwersytet Adama Mickiewicza Centrum NanoBioMedyczne
Ryszard Andruszkiewicz prof. dr hab. inż.
Stefan Jurga prof. dr hab.
- Uniwersytet Adama Mickiewicza Centrum NanoBioMedyczne
Sławomir Milewski prof. dr hab. inż.

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Category:

Articles

Type:

artykuł w czasopiśmie wyróżnionym w JCR

Published in:

LANGMUIR pages 5281 - 5293,
ISSN: 0743-7463

Language:

English

Publication year:

2019

Bibliographic description:

Kertmen A., Przysiecka J., Coy E., Popenda Ł., Andruszkiewicz R., Jurga S., Milewski S.: Emerging anticancer activity of candidal glucoseamine-6-phosphate synthase inhibitors upon nanoparticle-mediated delivery// LANGMUIR. -, iss. 15 (2019), s.5281-5293

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