title: Polymeric nanoparticulate system augmented the anticancer therapeutic efficacy of gemcitabine.
abstract: 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.
authors.affiliation: Departamento de Farmacia y Tecnología Farmacéutica, Facultad de Farmacia, Universidad de Granada, Granada, Spain.
authors.forename: José L
authors.initials: JL
authors.lastname: Arias
authors.forename: L Harivardhan
authors.initials: LH
authors.lastname: Reddy
authors.forename: Patrick
authors.initials: P
authors.lastname: Couvreur
mesh_terms: D000818:Animals; D000964:Antimetabolites, Antineoplastic / Q000008:administration & dosage* / Q000494:pharmacology; D003487:Cyanoacrylates / Q000737:chemistry; D003841:Deoxycytidine / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000494:pharmacology; D004337:Drug Carriers / Q000737:chemistry; D006863:Hydrogen-Ion Concentration; D007275:Injections, Intravenous; D007939:Leukemia L1210 / Q000188:drug therapy*; D051379:Mice; D008811:Mice, Inbred DBA; D053758:Nanoparticles; D011108:Polymers / Q000737:chemistry; D000093542:Gemcitabine
chemical_list: D000964:Antimetabolites, Antineoplastic; D003487:Cyanoacrylates; D004337:Drug Carriers; D011108:Polymers; C119247:octylcyanoacrylate; D003841:Deoxycytidine; D000093542:Gemcitabine