title: Preparation, optimization and in vitro characterization of stearoyl-gemcitabine polymeric micelles: a comparison with its self-assembled nanoparticles.
abstract: 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 (∼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.
authors.affiliation: Aerosol Research Laboratory, Department of Pharmaceutics, School of Pharmacy, Tehran University of Medical Sciences, Tehran, Iran.
authors.forename: Zahra
authors.initials: Z
authors.lastname: Daman
authors.affiliation: Department of Toxicology and Pharmacology, School of Pharmacy, Tehran University of Medical Sciences, Tehran, Iran.
authors.forename: SeyedNaser
authors.initials: S
authors.lastname: Ostad
authors.affiliation: Department of Medicinal Chemistry, School of Pharmacy, Tehran University of Medical Science, Tehran, Iran.
authors.forename: Mohsen
authors.initials: M
authors.lastname: Amini
authors.affiliation: Aerosol Research Laboratory, Department of Pharmaceutics, School of Pharmacy, Tehran University of Medical Sciences, Tehran, Iran; Medicinal Plants Research Center, Tehran University of Medical Sciences, Tehran, Iran. Electronic address: gilani@tums.ac.ir.
authors.forename: Kambiz
authors.initials: K
authors.lastname: Gilani
mesh_terms: D000964:Antimetabolites, Antineoplastic / Q000138:chemical synthesis* / Q000494:pharmacology; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D002626:Chemistry, Pharmaceutical; D003841:Deoxycytidine / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004337:Drug Carriers; D004355:Drug Stability; D006801:Humans; D007700:Kinetics; D008823:Micelles; D053758:Nanoparticles; D036103:Nanotechnology; D010190:Pancreatic Neoplasms / Q000473:pathology; D010316:Particle Size; D011091:Polyesters / Q000737:chemistry; D011092:Polyethylene Glycols / Q000737:chemistry; D011108:Polymers / Q000737:chemistry*; D011355:Prodrugs / Q000138:chemical synthesis* / Q000494:pharmacology; D012995:Solubility; D012997:Solvents / Q000737:chemistry; D013678:Technology, Pharmaceutical / Q000379:methods
chemical_list: C525761:4-(N)-stearoylgemcitabine; D000964:Antimetabolites, Antineoplastic; D004337:Drug Carriers; D008823:Micelles; D011091:Polyesters; D011108:Polymers; D011355:Prodrugs; D012997:Solvents; D003841:Deoxycytidine; D011092:Polyethylene Glycols; C033616:poly(lactide)
keywords: Pancreatic cancer; Poly(ethylene glycol)–poly(d,l-lactide); Polymeric micelles; Self-assembly; Stearoyl gemcitabine