{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,18]],"date-time":"2026-08-18T04:57:22Z","timestamp":1787029042743,"version":"build-2736575974"},"reference-count":100,"publisher":"MDPI AG","issue":"20","license":[{"start":{"date-parts":[[2019,10,22]],"date-time":"2019-10-22T00:00:00Z","timestamp":1571702400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100004281","name":"Narodowe Centrum Nauki","doi-asserted-by":"publisher","award":["2014\/13\/D\/NZ3\/02825"],"award-info":[{"award-number":["2014\/13\/D\/NZ3\/02825"]}],"id":[{"id":"10.13039\/501100004281","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Molecules"],"abstract":"<jats:p>Glioblastoma multiforme (GBM) is the most malignant type of central nervous system tumor that is resistant to all currently used forms of therapy. Thus, more effective GBM treatment strategies are being investigated, including combined therapies with drugs that may cross the blood brain barrier (BBB). Another important issue considers the decrease of deleterious side effects of therapy. It has been shown that nanocarrier conjugates with biotin can penetrate BBB. In this study, biotinylated PAMAM G3 dendrimers substituted with the recognized anticancer agents cyclooxygenase-2 (COX-2) inhibitor celecoxib and peroxisome proliferator-activated receptor \u03b3 (PPAR\u03b3) agonist Fmoc-L-Leucine (G3-BCL) were tested in vitro on human cell lines with different p53 status: glioblastoma (U-118 MG), normal fibroblasts (BJ) and immortalized keratinocytes (HaCaT). G3-BCL penetrated efficiently into the lysosomal and mitochondrial compartments of U-118 MG cells and induced death of U-118 MG cells via apoptosis and inhibited proliferation and migration at low IC50 = 1.25 \u00b5M concentration, considerably lower than either drug applied alone. Comparison of the effects of G3-BCL on expression of COX-2 and PPAR\u03b3 protein and PGE2 production of three different investigated cell line phenotypes revealed that the anti-glioma effect of the conjugate was realized by other mechanisms other than influencing PPAR-\u03b3 expression and regardless of p53 cell status, it was dependent on COX-2 protein level and high PGE2 production. Similar G3-BCL cytotoxicity was seen in normal fibroblasts (IC50 = 1.29 \u00b5M) and higher resistance in HaCaT cells (IC50 = 4.49 \u00b5M). Thus, G3-BCL might be a good candidate for the targeted, local glioma therapy with limited site effects.<\/jats:p>","DOI":"10.3390\/molecules24203801","type":"journal-article","created":{"date-parts":[[2019,10,23]],"date-time":"2019-10-23T11:46:59Z","timestamp":1571831219000},"page":"3801","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":25,"title":["The Effect of Biotinylated PAMAM G3 Dendrimers Conjugated with COX-2 Inhibitor (celecoxib) and PPAR\u03b3 Agonist (Fmoc-L-Leucine) on Human Normal Fibroblasts, Immortalized Keratinocytes and Glioma Cells in Vitro"],"prefix":"10.3390","volume":"24","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-7964-0777","authenticated-orcid":false,"given":"\u0141ukasz","family":"Uram","sequence":"first","affiliation":[{"name":"Faculty of Chemistry, Rzesz\u00f3w University of Technology, 6 Powsta\u0144c\u00f3w Warszawy Ave, 35-959 Rzesz\u00f3w, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maria","family":"Misiorek","sequence":"additional","affiliation":[{"name":"Faculty of Chemistry, Rzesz\u00f3w University of Technology, 6 Powsta\u0144c\u00f3w Warszawy Ave, 35-959 Rzesz\u00f3w, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Monika","family":"Pichla","sequence":"additional","affiliation":[{"name":"Faculty of Chemistry, Rzesz\u00f3w University of Technology, 6 Powsta\u0144c\u00f3w Warszawy Ave, 35-959 Rzesz\u00f3w, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Aleksandra","family":"Filipowicz-Rachwa\u0142","sequence":"additional","affiliation":[{"name":"Department of Cosmetics and Pharmaceutical Products Technology, Rzesz\u00f3w University of Information Technology and Management, 2 Sucharskiego Str, 35-225 Rzesz\u00f3w, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0263-2621","authenticated-orcid":false,"given":"Joanna","family":"Markowicz","sequence":"additional","affiliation":[{"name":"Faculty of Chemistry, Rzesz\u00f3w University of Technology, 6 Powsta\u0144c\u00f3w Warszawy Ave, 35-959 Rzesz\u00f3w, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3215-9350","authenticated-orcid":false,"given":"Stanis\u0142aw","family":"Wo\u0142owiec","sequence":"additional","affiliation":[{"name":"Faculty of Medicine, University of Rzesz\u00f3w, Warzywna 1a, 35-310 Rzeszow, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"El\u017cbieta","family":"Wa\u0142ajtys-Rode","sequence":"additional","affiliation":[{"name":"Department of Drug Technology and Biotechnology, Faculty of Chemistry, Warsaw University of Technology,75 Koszykowa Str, 00-664 Warsaw, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2019,10,22]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"93","DOI":"10.1007\/s00401-005-0991-y","article-title":"Epidemiology and etiology of gliomas","volume":"109","author":"Ohgaki","year":"2005","journal-title":"Acta Neuropathol."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"896","DOI":"10.1093\/neuonc\/nou087","article-title":"The epidemiology of glioma in adults: A \u201cstate of the science\u201d review","volume":"16","author":"Ostrom","year":"2014","journal-title":"Neuro Oncol."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"217","DOI":"10.1007\/s11060-004-2751-6","article-title":"Molecular Mechanisms of Glioma Cell Migration and Invasion","volume":"70","author":"Demuth","year":"2004","journal-title":"J. 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