The use of new quinazolinone derivative and doxorubicin loaded solid lipid nanoparticles in reversing drug resistance in experimental cancer cell lines: A systematic study

The aim of this research is to study the feasibility of using carnauba wax as a new carrier for anticancer agents to deliver doxorubicin (DOX) as a model drug and a novel quinazolinone derivative (QZO-DER) to different types of normal and resistant cancer cell lines. A Box-Behnken design was implemented to investigate the influence of high melting point carnauba wax stabilized with cell membrane lipid (lecithin) and non-ionic biocompatible surfactant (span 60) in different concentration on particle size, entrapment efficiency of each drug and percent drug release. The solid lipid nanoparticles (SLNPs) were produced via the hot-melting homogenization technique. SLNPS particle size was from 16.58 +/- 4 to 72.45 +/- 1.21 nm and from 7.93 +/- 1.67 to 174.31 +/- 4.86 nm for DOX and QZO-DER respectively. Entrapment efficiency was from 51.78 +/- 1.68% to 92.52 +/- 2.47% and from 50.21 +/- 1.8 to 82.95 +/- 3.56% for DOX and QZO-DER respectively. While the percentage of release after 36 h was from 29.28 +/- 3.89% to 78.08 +/- 3.78% and from 37.5 +/- 1.09 to 100 +/- 1.25% for DOX and QZO-DER respectively. Selected formulations for DOX (OFX1 and OFX4) and QZO-DER (OFR4 and OFR6) were generated after validation of design. The in vitro anticancer activity was tested against both a panel of wild type and DOX-resistant human cancer cell lines. Cancer cell lines included colorectal cancer (HCT-116), breast cancer (MCF-7 and MDA-231), and lung adenocarcinoma (A549). Most of the tested SLNPs improved the efficacy of QZO-DER and DOX against the different cancer cell lines and have extended the spectrum to cover those accruing resistance during chemotherapy. QZO-DER loaded SLNPs exhibited the highest ability to reverse the drug resistance of MDA-231 cells compared to MDA-231/ADR cells was 19.7-fold, while DOX loaded SLNPs that showed reversal power was 1.8 fold for the same cells. Additionally, SLNPs showed a broad safety margin in normal cells. This study presented the use of SLNPs with carnauba wax as a potential therapeutic strategy to improve anticancer activity and overcome cancer resistance for clinical use.