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Eur J Pharm Sci. 2018 Nov 1;124:1-9. doi: 10.1016/j.ejps.2018.08.019. Epub 2018 Aug 15.

Biotinylated PAMAM G3 dendrimer conjugated with celecoxib and/or Fmoc-l-Leucine and its cytotoxicity for normal and cancer human cell lines.

Author information

1
Faculty of Chemistry, Rzeszów University of Technology, 6 Powstańców Warszawy Ave, 35-959 Rzeszów, Poland. Electronic address: luram@prz.edu.pl.
2
Faculty of Medical Sciences, Rzeszów University of Information Technology and Management, 2 Sucharskiego Str, 35-225 Rzeszów, Poland.
3
Faculty of Chemistry, Rzeszów University of Technology, 6 Powstańców Warszawy Ave, 35-959 Rzeszów, Poland.
4
Department of Drug Technology and Biotechnology, Faculty of Chemistry, Warsaw University of Technology,75 Koszykowa Str, 00-664 Warsaw, Poland.
5
Centre for Innovative Research in Medical and Natural Sciences, Faculty of Medicine, University of Rzeszów, Warzywna 1a, 35-310 Rzeszów, Poland.

Abstract

Tumors still remain one of the main causes of mortality due to the lack of effective anti-cancer therapy. Recently it has been shown, that overexpression of inducible cyclooxygenase-2 (COX-2) and decrease of peroxisome proliferator-activated receptor γ (PPARγ) expression accompany many malignances, therefore, it has been proposed, that COX-2 inhibitors and PPARγ agonists are potential candidates for anticancer therapy and their synergistic, antineoplastic action has been described. In the present study a COX-2 inhibitor (celecoxib) and/or PPARγ agonist (Fmoc-l-Leucine) were conjugated with the biotinylated G3 PAMAM dendrimer to form a three different constructs targeted to cells with increased biotin uptake. All conjugates were characterized by the NMR spectroscopy. Investigation of three types of human cells: normal skin fibroblasts (BJ), immortalized keratinocytes (HaCaT) and cancer lines: glioblastoma (U-118 MG) and squamous cell carcinoma (SCC-15) revealed similar biotin labeled ATTO590 accumulation (after 24 h), except for SCC-15 with significantly lower loading. Constitutive expression of COX-2 protein was confirmed in all tested cells with significantly higher levels (2-2.5 times) in both cancer lines. Comparison of cytotoxicity of the new synthetized dendrimers clearly documented the highest cytotoxicity of the G31B16C15L dendrimer conjugated with both drugs (1: 1) as compared with drugs alone and single conjugates. Additive effects of construct with both compounds were shown for fibroblasts and both cancer cell lines in the order BJ > U-118 MG > SCC-15 with IC50 in the range: 0.69, 1.44 and 2.22 μM, respectively and lowest cytotoxicity in HaCaT cells (IC50 = 2.88). Our results showed, that biotinylated G3 PAMAM dendrimers substituted with COX-2 inhibitor, celecoxib, and PPARγ agonist, Fmoc-l-Leucine (1:1) may be a good candidate for local therapy of glioblastoma but not a skin cancer. Since the effect of PPARγ agonists on COX-2 expression vary depending upon the cell type, specificity of used agonist and the presence of other environmental factors, it is necessary to carefully evaluate the response of chosen drugs on the target cells.

KEYWORDS:

Biotin uptake; Biotinylated PAMAM G3 dendrimer; COX-2 expression; Conjugates with celecoxib and/or Fmoc-l-Leucine; Cytotoxicity; Normal and cancer human cell lines

PMID:
30118847
DOI:
10.1016/j.ejps.2018.08.019
[Indexed for MEDLINE]

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