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

ABSTRACT: 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 ?-cyclodextrins (?-CDs) were selected to encapsulate THN7 and all experiments indicated that the nanoencapsulation of this CK2 inhibitor in ?-CDs was successful. No additional surface-active agent was used during the nanoformulation process. Nanoparticles formed between THN7 and ?-C?H₁₃ 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 ?-CDs was determined before the in cellulo evaluation and the ?-C?H₁₃ 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 (?-C?H₁₃, ?-C?H₁₇ and ?-C?H?) 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.

SUBMITTER: Nacereddine A 

PROVIDER: S-EPMC5874706 | biostudies-literature | 2018 Jan

REPOSITORIES: biostudies-literature