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Emerging Anticancer Activity of Candidal Glucoseamine-6-Phosphate Synthase Inhibitors upon Nanoparticle-mediated Delivery

Publish Year: 2019
Publisher:  ACS Publications - Langmuir, 2019, 35 (15), 5281-5293
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A. Kertmen, Ł. Przysiecka, L. E. Coy, Ł. Popenda, Ryszard Andruszkiewicz, S. Jurga, Sławomir Milewski
Numerous glutamine analogs have been reported as irreversible inhibitors of Glucosamine-6-phosphate (GlcN-6-P) synthase in pathogenic Candida albicans in last three-and-half 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 analogs. A number of peptide-FMDP conjugates were tested to deliver FMDP to its subcellularly located GlcN-6-P synthase target. However, rapid development of fungal resistance to FMDP-peptides required development of different therapeutic approaches to tackle antifungal resistance. In the current state of the 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 analogs, 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 Candida albicans. Three (3) different human cancer cell lines potentially overexpressing 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 a strong anticancer agent by inhibiting the growth of tested cancer cells, while 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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