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Int J Mol Sci. 2019 Oct 9;20(20). pii: E4998. doi: 10.3390/ijms20204998.

Mixed-Generation PAMAM G3-G0 Megamer as a Drug Delivery System for Nimesulide: Antitumor Activity of the Conjugate Against Human Squamous Carcinoma and Glioblastoma Cells.

Author information

1
Faculty of Chemistry, Rzeszów University of Technology, 35-939 Rzeszów, Poland. magzar@prz.edu.pl.
2
Department of Biomedical Engineering, Wrocław University of Science and Technology, 50-370 Wrocław, Poland. przemyslaw.sarelo@pwr.edu.pl.
3
Department of Biomedical Engineering, Wrocław University of Science and Technology, 50-370 Wrocław, Poland. marta.kopaczynska@pwr.edu.pl.
4
Faculty of Chemistry, University of Wrocław, 50-383 Wrocław, Poland. agata.bialonska@gmail.com.
5
Faculty of Chemistry, Rzeszów University of Technology, 35-939 Rzeszów, Poland. luram@prz.edu.pl.
6
Faculty of Chemistry, Rzeszów University of Technology, 35-939 Rzeszów, Poland. mwalczak@prz.edu.pl.
7
Centre for Innovative Research in Medical and Natural Sciences, Faculty of Medicine, University of Rzeszów, 35-310 Rzeszów, Poland. daebisher@ur.edu.pl.
8
Centre for Innovative Research in Medical and Natural Sciences, Faculty of Medicine, University of Rzeszów, 35-310 Rzeszów, Poland. swolowiec@ur.edu.pl.

Abstract

Polyhydroxylated dendrimer was synthesized from poly(amidoamine) (PAMAM) dendrimer generation 3 by addition of glycidol (G3gl). G3gl megamer was further modified by binding PAMAM G0 dendrimers by activation of G3gl with p-nitrophenylchloroformate, followed by the addition of excess PAMAM G0 and purification using dialysis. The maximum G0 binding capacity of G3gl was 12 in the case when G0 was equipped with two covalently attached nimesulide equivalents. Nimesulide (N) was converted into N-(p-nitrophenyl) carbonate derivative and fully characterized using X-ray crystallography and spectral methods. Nimesulide was then attached to G0 via a urea bond to yield G02N. The mixed generation G3gl-G02N megamer was characterized using 1H NMR spectroscopy, and its molecular weight was estimated to be 22.4 kDa. The AFM image of G3gl-G02N deposited on mica demonstrated aggregation of nimesulide-covered megamer. The height of the deposited megamer was 8.5 nm. The megameric conjugate with nimesulide was tested in vitro on three human cell lines: squamous cell carcinoma (SCC-15) and glioblastoma (U-118 MG) overexpressing cyclooxygenase-2 (COX-2), and normal skin fibroblasts (BJ). The conjugate efficiently penetrated into all cells and was more cytotoxic against SCC-15 than against BJ. Moreover, the conjugate produced a strong and selective antiproliferative effect on both cancer cell lines (IC50 < 7.5 µM).

KEYWORDS:

PAMAM megamer; anticancer activity; drug delivery system; nimesulide conjugate

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