Gemcitabine hydrochloride is an anticancer
nucleoside analogue indicated in clinic for the treatment of various solid
tumors. Although this
drug has been demonstrated to display anticancer activity against a wide variety of
tumors, it is needed to be administered at high doses to elicit the required therapeutic response, simultaneously leading to severe adverse effects. We hypothesized that the efficient delivery of
gemcitabine to
tumors using a biodegradable carrier system could reduce the dose required to elicit sufficient therapeutic response. Thus, we have developed a nanoparticle formulation of
gemcitabine suitable for parenteral administration based on the biodegradable
polymer poly(
octylcyanoacrylate) (
POCA). The nanoparticles were synthesized by anionic polymerization of the corresponding monomer. Two
drug loading methods were analyzed: the first one based on
gemcitabine surface adsorption onto the preformed nanoparticles, and the second method being
gemcitabine addition before the polymerization process leading to
drug entrapment in the polymeric network. A detailed investigation of the capabilities of the
polymer particles to load this
drug is described.
Gemcitabine entrapment into the
polymer matrix yielded a higher
drug loading and a slower drug release profile as compared with
drug adsorption procedure. The main factors determining the
gemcitabine incorporation to the
polymer network were the nanoparticles preparation procedure, the monomer concentration, the
surfactant concentration, the pH, and the
drug concentration. The release kinetic of
gemcitabine was found to be controlled by the pH and the type of
drug incorporation. The cytotoxicity studies performed on L1210
tumor cells revealed a similar anticancer activity of the
gemcitabine-loaded
POCA (
GPOCA) nanoparticle as free
gemcitabine. Following
intravenous administration into the mice bearing L1210 wt subcutaneous
tumor, the
GPOCA nanoparticles displayed significantly greater anticancer activity compared to free
gemcitabine; this has been additionally confirmed by histology and immunohistochemistry studies, suggesting the potential of
GPOCA for the efficient treatment of
cancer.