Fabrication of all-trans-retinoic acid-loaded biocompatible precirol: A strategy for escaping dose-dependent side effects of doxorubicin.

Abstract

Drug delivery-based nanoparticles have been emerged to be an alternative and efficient approach to cancer therapy compared to conventional systems. Here, we investigated the role of all-trans retinoic acid (ATRA) formulated with precirol in increasing doxorubicin (Dox) induced apoptosis and cell cycle arrest in MDA-MB-231 breast cancer cells.ATRA-loaded Nano structured lipid carriers (NLCs) were evaluated in terms of particle size, zeta potential, Fourier transforms infrared spectroscopy (FTIR), cell internalization, and scanning electron microscope (SEM). To understand molecular mechanism of apoptosis and cell cycle progression flow cytometric assay, MTT and DAPI staining was applied. Real time (RT)-PCR analysis was employed to investigate the expression of apoptosis related genes, including Survivin, Bcl-2 and Bax.The optimized ATRA formulation exhibited average particle size of 95آ±5nm with nearly narrow size distribution. The IC50 values for ATRA and doxorubicin were 48آ±0.4?M and 0.81آ±0.02?M, respectively. ATRA-loaded NLCs decreased percentage of cell proliferation from 51آ±7.2% to 36آ±4.1% (p <0.05). Co-treatment of the MDA-MB-231 cells with ATRA formulation and doxorubicin caused two-fold increase in the percentage of apoptosis (p<0.05). The results from gene expression exhibited a significant decrease in survivin along with increase at Bax mRNA levels accompanied by a slight increase in Bax/Bcl-2 ratio.Our results propose that ATRA encapsulated in precirol as a biocompatible compound augments the efficacy of Dox in cancer therapy.