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Self-Assembled Supramolecular Nanoparticles Improve the Cytotoxic Efficacy of CK2 Inhibitor THN7

Faculté de Pharmacie—ISPB, EA 4446 Bioactive Molecules and Medicinal Chemistry, SFR Santé Lyon-Est CNRS UMS3453—INSERM US7, Université de Lyon, Université Claude Bernard Lyon 1, 8 Avenue Rockefeller, F-69373 Lyon CEDEX 8, France
Institute of Pharmaceutical and Medicinal Chemistry, PharmaCampus, Westfälische Wilhelms-Universität Münster, Corrensstr. 48, 48149 Münster, Germany
Department of Pharmaceutical Technology, Faculty of Pharmacy, University of Debrecen, Nagyerdei körút 98, H-4032 Debrecen, Hungary
CSAp, Institut de Chimie et Biochimie Moléculaires et Supramoléculaires, Bâtiment Raulin, Université de Lyon, Université Lyon 1, 43 Bd du 11 novembre 1918, 69622 Villeurbanne CEDEX, France
Authors to whom correspondence should be addressed.
Pharmaceuticals 2018, 11(1), 10;
Received: 16 December 2017 / Revised: 24 January 2018 / Accepted: 25 January 2018 / Published: 26 January 2018
(This article belongs to the Special Issue Choices of the Journal)
Since the approval of imatinib in 2001, kinase inhibitors have revolutionized cancer therapies. Inside this family of phosphotransferases, casein kinase 2 (CK2) is of great interest and numerous scaffolds have been investigated to design CK2 inhibitors. Recently, functionalized indeno[1,2-b]indoles have been revealed to have high potency against human cancer cell lines such as MCF-7 breast carcinoma and A-427 lung carcinoma. 4-Methoxy-5-isopropyl-5,6,7,8-tetrahydroindeno[1,2-b]indole-9,10-dione (THN7), identified as a potent inhibitor of CK2 (IC50 = 71 nM), was selected for an encapsulation study in order to evaluate its antiproliferative activity as THN7-loaded cyclodextrin nanoparticles. Four α-cyclodextrins (α-CDs) were selected to encapsulate THN7 and all experiments indicated that the nanoencapsulation of this CK2 inhibitor in α-CDs was successful. No additional surface-active agent was used during the nanoformulation process. Nanoparticles formed between THN7 and α-C6H13 amphiphilic derivative gave the best results in terms of encapsulation rate (% of associated drug = 35%), with a stability constant (K11) of 298 mol·L−1 and a size of 132 nm. Hemolytic activity of the four α-CDs was determined before the in cellulo evaluation and the α-C6H13 derivative gave the lowest value of hemolytic potency (HC50 = 1.93 mol·L−1). Only the THN7-loaded cyclodextrin nanoparticles showing less toxicity on human erythrocytes (α-C6H13, α-C8H17 and α-C4H9) were tested against A-427 cells. All drug-loaded nanoparticles caused more cytotoxicity against A-427 cells than THN7 alone. Based on these results, the use of amphiphilic CD nanoparticles could be considered as a drug delivery system for indeno[1,2-b]indoles, allowing an optimized bioavailability and offering perspectives for the in vivo development of CK2 inhibitors. View Full-Text
Keywords: indeno[1,2-b]indole; CK2 inhibitor; cyclodextrin; nanoparticles; in cellulo; human erythrocytes; A427 cells indeno[1,2-b]indole; CK2 inhibitor; cyclodextrin; nanoparticles; in cellulo; human erythrocytes; A427 cells
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Nacereddine, A.; Bollacke, A.; Róka, E.; Marminon, C.; Bouaziz, Z.; Fenyvesi, F.; Bácskay, I.K.; Jose, J.; Perret, F.; Le Borgne, M. Self-Assembled Supramolecular Nanoparticles Improve the Cytotoxic Efficacy of CK2 Inhibitor THN7. Pharmaceuticals 2018, 11, 10.

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