(99) Combination Nanotherapeutics for the Treatment of Advanced Prostate Cancer

Objective : To develop stealth, PLGA-PEG nanoparticles for the site-specific delivery of brusatol and docetaxel in the treatment of prostate cancer. Combination therapy in a nanoparticle platform will greatly inhibit tumor progression, enhance therapeutic efficacy, reverse chemoresistance and confer sensitivity to docetaxel therapy because of brusatol modulation of Nrf2.

Methods: Using the oil-in-water emulsification-solvent evaporation technique, various formulation factors were found to have a profound effect on the particle size of the fabricated nanoparticles. Using Minitab® software, we generated a 24 full factorial statistical experimental design leading to a model for predicting and optimization of particle size. Additionally, particle size and size distribution, morphology and the release profile of nanoparticles were determined. Cell cycle analysis of the dual-loaded nanoparticle was done using flow cytometry to evaluate the impact of loaded drugs on the cell cycle.

Results: Optimization of blank nanoparticles gave a formulation with a mean size of 169.1nm ±4.8nm in agreement with the predicted size of 168.333nm. Structural morphology using transmission electron microscopy showed smooth spherical nanoparticles coated with polyethylene glycol. Drug loading of brusatol and docetaxel are 0.9% and 2.04% respectively. Drug release profile shows that the encapsulated drugs were released over 24 hours. Cell cycle arrest at the G1 and G2/M phases corresponding to brusatol, and docetaxel arrest respectively was observed in PC-3 and LNCaP prostate cancer cell lines, followed by cell death.

Conclusions: The developed nanoparticles are suitable for the treatment of prostate cancer and may potentially be used in cases of docetaxel resistance.