Computational study of DMPC liposomes loaded with the N-(2-Hydroxyphenyl)-2-propylpentanamide (HO-AAVPA) and determination of its antiproliferative activity in vitro in NIH-3T3 cells

Abstract

N-(2-Hydroxyphenyl)-2-propylpentanamide (HO-AAVPA) is a valproic acid (VPA) derivative that has shown promising antiproliferative effects in different cancer cell lines, such as A204, HeLa, and MDA-MB-231. However, its low water solubility could reduce its therapeutic effectiveness. To solve this problem, in this work, we incorporated HO-AAVPA into dimyristoyl-phosphatidylcholine (DMPC) liposomes in the presence or absence of cholesterol (CHOL). Using differential scanning calorimetry (DSC), we found that the transition enthalpy (ΔH_tr) of DMPC liposomes is reduced in the presence of CHOL and/or HO-AAVPA, indicating the favorable interactions between CHOL and/or HO-AAVPA and DMPC. Further, by molecular dynamics simulations it was possible to observed that HO-AAVPA migrates from the center of the bilayer toward the water and lipid interface of the DPMC bilayer systems exposing the amine group to water and the aliphatic chain toward the interior of the bilayer. As a consequence, we observed an ordering of the lipid bilayer. Moreover, CHOL harbors into the inner bilayer membrane, increasing the order parameter of the system. The liposomal solutions loaded with HO-AAVPA were tested in the NIH3T3 cell line, showing a reduction in cell proliferation compared to those cells presented without liposomes.

Communicated by Ramaswamy H. Sarma

Keywords:

• N-(2-hydroxyphenyl)-2-propylpentanamide
• DMPC liposomes
• liposome-drug interaction
• CHARMM-GUI membrane
• molecular dynamic simulation

Acknowledgements

Xelhua Marcos acknowledges CONACYT México, for a postdoctoral fellowship. Yudibeth Sixto-Lopez thanks to CONACYT for PhD scholarship and for the ‘Beca para mujeres índigenas’. We gratefully acknowledge to CONACYT (Grants: CB-254600, APN-782 and SEP-CONACYT-ANUIES-ECOS Francia: 296636), to Instituto Politécnico Nacional (Grant: Proyectos Insignia IPN-2015), COFAA-SIP/IPN.

Disclosure statement

No potential conflict of interest was reported by the authors.