QUALITY BY DESIGN-ASSISTED OPTIMIZATION, FORMULATION DEVELOPMENT, PHYSICOCHEMICAL CHARACTERIZATION, DRUG RELEASE KINETICS, CELLULAR UPTAKE, AND IN VITRO ANTICANCER EVALUATION OF TAMOXIFEN CITRATE-LOADED PLGA NANOPARTICLES AGAINST MCF-7 BREAST CANCER

Abstract

In this paper, a Quality by Design (QbD) approach has been used to formulate Tamoxifen citrate loaded poly (lactic-co-glycolic acid), PLGA, nanoparticles to be targeted towards MCF-7 breast cancer cells. The critical quality attributes were determined through the risk assessment process, and polymer to drug ratio, surfactant level, and homogenization speed were optimized by using a Box- Behnken design. The multiple emulsion solvent evaporation method was used to prepare nanoparticles which were characterized for particle size, polydispersity index, zeta potential, % of entrapment efficiency, surface morphology and drug polymer compatibility by fourier transform infrared spectrometry and differential scanning calorimetry. Results showed that the mean particle size of the optimized formulation (F4) was 158 nm, zeta potential was minus 24.6 mV and the entrapment efficiency was 81.3 percent. The IVR of the drug in PBS at pH 7.4 was biphasic; there was a burst release of 8 per cent followed by sustained release where 87.4 per cent was released at 48 hours and the release was well explained by the Korsmeyer-Peppas model with a release exponent of 0.46 indicating Fickian diffusion-controlled mechanism. Time-dependent internalization of nanoparticles, labeled with coumarin-6, was observed in MCF-7 cells by confocal microscopy. The optimized nanoparticle formulation with IC50 value of 6.7 micrograms per milliliter (µg/mL) at 48 hours was 2.7 fold more potent than free tamoxifen citrate with IC50 value of 18.4 µg/mL at 48 hours and measured by MTT assay. These results suggest that PLGA nanoparticles can be used as a good platform to increase the anticancer effect and uptake of tamoxifen citrate in estrogen receptor positive breast cancer treatments.