Preparation, optimization and in vitro characterization of stearoyl-gemcitabine polymeric micelles: A comparison with its self-assembled nanoparticles

Although gemcitabine (Gem) constitutes first-line therapy for pancreatic cancer, its clinical outcome suffers from rapid metabolism and acquired drug resistance. To overcome its limitations, several lipophilic prodrugs including 4-(N)-stearoyl Gem (GemC18) have been studied for their efficacy over Gem. Herein, we aimed to prepare and characterize the GemC18-loaded poly(ethylene glycol)-poly(D,L-lactide) (PEG-PLA) polymeric micelles (PMs) as well as its self-assembled nanoparticles (NPs). A D-optimal design was also utilized to investigate the effects of formulation variables, namely initial drug/polymer ratio, total solid content, and the type of organic solvent on properties of GemC18-loaded PMs. The optimized formulation showed a particle size of about 120 nm, encapsulation efficiency >90%, and a sustained release behavior of the drug. Alternatively, the prodrug NPs were harvested in larger size (similar to 300 nm) and more negative zeta potential, but less chemical stability compared to the optimized PMs. In Panc-1 and AsPC-1 cell lines, both GemC18-loaded PMs and NPs were significantly more cytotoxic than GemC18 solution. Chiefly, they could effectively reduce the viability of Gem high-resistant AsPC-1 cells in culture, whereas the molar equivalent doses of Gem did not show any acceptable cytotoxicity. Thus, these results suggest a promising direction for alternative Gem delivery systems for future therapeutic applications. (C) 2014 Elsevier B.V. All rights reserved.