Intra-vaginal gemcitabine-hybrid nanoparticles for effective cervical cancer treatment

Abstract

Aim: This study aims to develop and evaluate hybrid nanoparticles for the effective intravaginal delivery of the anticancer gemcitabine in cervical cancer rat model. Methodology: Gemcitabine loaded hybrid nanoparticles (GEM-HNPs) were prepared by ionic gelation method using chitosan, lecithin, and a surfactant. The effect of different variables (chitosan/lecithin ratio, type of lecithin and type/amount of surfactant) were studied on particle size (PS), polydispersity index (PDI), zeta potential (ZP), entrapment efficiency (EE), loading efficiency (% LE). Selected GEM-HNPs were further evaluated for physical morphology using TEM, solid state characterization, percent drug release, in vitro cytotoxicity on Hela cancer cells and in vivo cell uptake using confocal laser scanning microscopy. The efficacy and safety of intravaginal GEM-HNPs in the treatment of cervical cancer were assessed and compared with GEM intravenous administration (IV). Female wistar rats were divided into four groups: Group I: negative control; Group II: positive control (0.2 ml trichloroacetic acid) induced cervical cancer; Group III: rats receiving intravaginal GEM-HNPs and group IV: rats receiving IV GEM. the rat cervices were subjected to histological and biochemical analysis. Results: The selected GEM-HNPs exhibited acceptable PS of 235.9 ± 11.24 nm, PDI of 0.290 ± 0.004, ZP of 43.8 ± 0.495 mV, high EE of 76.8 ± 1.3%, complete drug release in 24 h, enhanced in vivo drug uptake and penetration in cervical cell. The IC50 of pure GEM was found to be insignificantly (p < 0.05) different than GEM-HNPs. In-Vivo Antitumor Efficacy and toxicity study on female wistar rat showed that intravaginal administration of GEM-HNPs succeeded to attenuate trichloroacetic acid-induced cervical cancer. This was demonstrated by significant reductions in anti-apoptotic proteins BCl2, P35, angiogenic biomarkers (VEGF, COX2) and inflammatory mediators (IL1b). Additionally, it restored depleted superoxide dismutase (SOD), which in turn reduced MDA levels in cervical tissue. The nephrotoxicity of gemcitabine was reduced compared to the intravenous treatment group.In conclusion, the current study is the first to demonstrate a successful intravaginal hybrid nanoparticle for the administration of GEM in the treatment of cervical cancer.

Keywords

• Gemcitabine
• Chitosan
• Lecithin
• Hybrid nanoparticles
• Intravaginal
• Cervical cancer