title: Polymeric nanoparticles for oral delivery of 5-fluorouracil: Formulation optimization, cytotoxicity assay and pre-clinical pharmacokinetics study.
abstract: Poly(lactic acid) (PLA) or poly(lactic acid)-poly(ethylene glycol) (PLA-PEG) blend nanoparticles were developed loading 5-fluorouracil (5-FU), an antitumor agent broadly used in therapy. A 2(3) factorial experimental design was conducted to indicate an optimal formulation and demonstrate the influence of the interactions of components on the mean particle size and drug encapsulation efficiency. Optimized PLA nanoparticles presented 294nm and 51% of 5-FU encapsulation efficiency and PLA-PEG blend nanoparticles presented 283nm and 55% of 5-FU encapsulation efficiency. In vitro release assay demonstrated after 320h about 50% of 5-FU was released from PLA and PLA-PEG blend nanoparticles. Release kinetics of 5-FU from nanoparticles followed second order and the release mechanism calculated by Korsmeyer-Peppas model was diffusion and erosion. In the assessment of cytotoxicity over Hep-2 tumor cells, PLA or PLA-PEG blend nanoparticles presented similar IC50 value than free 5-FU. Pharmacokinetic parameters after oral administration of 5-FU were improved by nanoencapsulation. Bioavailability, Cmax, Tmax, t1/2 and distribution volume were significantly improved, while clearance were decreased. PEG presence in nanoparticles didn't influence physicochemical and biological parameters evaluated. PLA and PLA-PEG nanoparticles can be potential carriers for oral delivery of 5-FU.
authors.affiliation: Post-graduation Program in Pharmaceutical Sciences, Universidade Estadual do Centro-Oeste/UNICENTRO, Brazil.
authors.forename: Ana Cristina de
authors.initials: AC
authors.lastname: Mattos
authors.affiliation: Post-graduation Program in Pharmaceutical Sciences, Universidade Estadual do Centro-Oeste/UNICENTRO, Brazil.
authors.forename: Clescila
authors.initials: C
authors.lastname: Altmeyer
authors.affiliation: Department of Physics, Universidade Estadual do Centro-Oeste/UNICENTRO, Brazil.
authors.forename: Tania Toyomi
authors.initials: TT
authors.lastname: Tominaga
authors.affiliation: Department of Pharmacy, Universidade Estadual do Centro-Oeste/UNICENTRO, Rua Simeão Camargo Varela de Sá, 03, 85040-080 Guarapuava, PR, Brazil.
authors.forename: Najeh Maissar
authors.initials: NM
authors.lastname: Khalil
authors.affiliation: Department of Pharmacy, Universidade Estadual do Centro-Oeste/UNICENTRO, Rua Simeão Camargo Varela de Sá, 03, 85040-080 Guarapuava, PR, Brazil. Electronic address: rubianamainardes@hotmail.com.
authors.forename: Rubiana Mara
authors.initials: RM
authors.lastname: Mainardes
mesh_terms: D000818:Animals; D000964:Antimetabolites, Antineoplastic / Q000008:administration & dosage* / Q000097:blood / Q000493:pharmacokinetics; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D002626:Chemistry, Pharmaceutical; D004337:Drug Carriers / Q000008:administration & dosage* / Q000493:pharmacokinetics; D005472:Fluorouracil / Q000008:administration & dosage* / Q000097:blood / Q000493:pharmacokinetics; D006801:Humans; D008297:Male; D053758:Nanoparticles / Q000008:administration & dosage*; D011091:Polyesters / Q000008:administration & dosage* / Q000493:pharmacokinetics; D011092:Polyethylene Glycols / Q000008:administration & dosage* / Q000493:pharmacokinetics; D017208:Rats, Wistar
chemical_list: D000964:Antimetabolites, Antineoplastic; D004337:Drug Carriers; D011091:Polyesters; C542623:monomethoxypolyethyleneglycol-polylactide block copolymer; D011092:Polyethylene Glycols; C033616:poly(lactide); D005472:Fluorouracil
keywords: 5-fluorouracil; Bioavailability; Cytotoxicity; Nanoparticles; Poly(lactic acid)