NSTI Nanotech 2009

Epirubicin hydrochloride loaded poly (butyl cyanoacrylate) nanoparticles: formulation optimization, characterization and in vitro evaluation on human breast cancer cell lines

P.R. Dantuluri, N.M. Shah, R.S.R. Murthy, M.R.S. Kumar, B.S.S. Rao
The M.S. University of Baroda, IN

Keywords: poly(butylcyano acrylate) nanoparticles, breast cancer, epirubicin hydrochloride, drug delivery


INTRODUCTION: Breast cancer is the second leading cause of deaths in women today after lung cancer, the mortality rate of patients with breast cancer around the world is rising steadily over time. Metastatic spread is the major cause of breast cancer deaths. The tumor associated lymphatics have long been believed to be the main route for early spread of tumor cells. Polyalkyl cyanoacrylate nanoparticles have gained significant interest in targeting and drug delivery in recent times because of ease of synthesis, biodegradability, ability to alter biodistribution of drugs, lower the drug toxicity and above all it also overcomes multidrug resistance associated with tumors. In the present study poly (n-butyl cyanoacrylate) (PBCA) nanoparticles containing Epirubicin Hydrochloride (EPI) were synthesized by emulsion polymerization and dispersion polymerization methods. METHODS: Epirubicin loaded poly (butyl cyanoacrylate (PBCA) nanoparticles were synthesized by anionic polymerization in acidic medium in the presence of dextran 40, Poloxamer 407 and Poloxamine 904. The various formulation parameters like stabilizer concentration, Epirubicin loading and aqueous phase pH which are likely to affect the final product were studied on particle size and entrapment efficiency. Aqueous phase volume, stirring speed, polymerization temperature and polymerization time were fixed to constant. The in-vitro drug release study was carried out in phosphate buffer saline pH 7.4 at 37C in screw capped centrifuge tubes. RESULTS: The optimum particle size and entrapment efficiency was observed at 0.05% w/v EPI loading, at pH 2.5 and at 1% monomer and surfactant concentration. The zeta potential of drug-loaded nanoparticles produced in the presence of surfactants carries a negative surface charge. The obtained particle size, zeta potential and entrapment efficiency for Dextran 40 stabilized nanoparticles were (178nm, -11.6 mv and 68.3%), for poloxamer 407 stabilized nanoparticle formulations (103nm, -7mv and 56.21%) and for poloxamine 904 stabilized nanoparticle formulations (98nm, -16 mv and 65.31%). Transmission Electron Microscopy studies indicated that nanoparticles had spherical shape and confirmed the nanosize. The in-vitro release of EPI from all the EPI-PBCA nanoparticles in phosphate-buffered saline pH 7.4 at 37C showed an initial burst of around 25% and followed by sustained release of 75% of EPI from nanoparticles up to 60hrs. CONCLUSION: Particulate systems, administered interstitially, for lymphatic targeting purposes should drain well from the site of injection and be well retained in the regional lymph nodes. The currently investigated polymeric nanoparticles with their small size and negative surface charge satisfy the physicochemical aspects required for preferential uptake of the nanoparticles from the interstitium to the lymph nodes. Further in vivo studies to prove the targeting ability of the nanoparticles to lymph nodes are required. Note: The in vitro cytotoxicity studies of EPI and EPI-PBCA nanoparticles against human breast cancer cell lines MCF-7 (estrogen receptor-positive) and MDA-MB-231 (estrogen receptor-negative) are under progress. The in vitro cell line studies would be expected to show better and long term toxicity when compared with free drug on the breast cancer cells evaluated.
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