RESUMO
LPSF/AC04 (5Z)-[5-acridin-9-ylmethylene-3-(4-methyl-benzyl)-thiazolidine-2,4-dione] is an acridine-based derivative, part of a series of new anticancer agents synthesized for the purpose of developing more effective and less toxic anticancer drugs. However, the use of LPSF/AC04 is limited due to its low solubility in aqueous solutions. To overcome this problem, we investigated the interaction of LPSF/AC04 with hydroxypropyl-ß-cyclodextrin (HP-ß-CyD) and hydroxypropyl-γ-cyclodextrin (HP-γ-CyD) in inclusion complexes and determine which of the complexes formed presents the most significant interactions. In this paper, we report the physical characterization of the LPSF/AC04-HP-CyD inclusion complexes by thermogravimetric analysis, differential scanning calorimetry, infrared spectroscopy absorption, Raman spectroscopy, (1)HNMR, scanning electron microscopy, and by molecular modeling approaches. In addition, we verified that HP-ß-CyD complexation enhances the aqueous solubility of LPSF/AC04, and a significant increase in the antiproliferative activity of LPSF/AC04 against cell lines can be achieved by the encapsulation into liposomes. These findings showed that the nanoencapsulation of LPSF/AC04 and LPSF/AC04-HP-CyD inclusion complexes in liposomes leads to improved drug penetration into the cells and, as a result, an enhancement of cytotoxic activity. Further in vivo studies comparing free and encapsulated LPSF/AC04 will be undertaken to support this investigation.
Assuntos
Acridinas/química , Acridinas/farmacologia , Antineoplásicos/química , Antineoplásicos/farmacologia , Lipossomos/química , Tiazolidinedionas/química , Tiazolidinedionas/farmacologia , beta-Ciclodextrinas/química , gama-Ciclodextrinas/química , 2-Hidroxipropil-beta-Ciclodextrina , Absorção , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Estabilidade de Medicamentos , Excipientes/química , Humanos , Solubilidade , Água/químicaRESUMO
The aim of this study was to encapsulate lapachone (ß-lap) or inclusion complex (ß-lap:HPß-CD) in liposomes and to evaluate their physicochemical characteristics. In addition, the investigation of the main aspects of the interaction between ß-lap and 2-hydroxypropyl-ß-cyclodextrin (HPß-CD), using both experimental and molecular modeling approaches was discussed. Furthermore, the in vitro drug release kinetics was evaluated. First, a phase solubility study of ß-lap in HPß-CD was performed and the ß-lap:HPß-CD was prepared by the freeze-drying technique. A 302-fold increase of solubility was achieved for ß-lap in HPß-CD solution with a constant of association K(1:1) of 961 M(-1) and a complexation efficiency of ß-lap of 0.1538. (1)H NMR, TG, DSC, IR, Raman and SEM indicated a change in the molecular environment of ß-lap in the inclusion complex. Molecular modeling confirms these results suggesting that ß-lap was included in the cavity of HPß-CD, with an intermolecular interaction energy of -23.67 kJ mol(-1). ß-lap:HPß-CD and ß-lap-loaded liposomes presented encapsulation efficiencies of 93% and 97%, respectively. The kinetic rate constants of 183.95±1.82 µg/h and 216.25±2.34 µg/h were calculated for ß-lap and ß-lap:HPß-CD-loaded liposomes, respectively. In conclusion, molecular modeling elucidates the formation of the inclusion complex, stabilized through hydrogen bonds, and the encapsulation of ß-lap and ß-lap:HPß-CD into liposomes could provide an alternative means leading eventually to its use in cancer research.