title: Preclinical studies of N₃-O-toluyl-fluorouracil-loaded lipid-based nanosuspensions in H₂₂-bearing mice.
abstract: OBJECTIVE
  N3-O-toluyl-fluorouracil (TFU) is a potential antitumor prodrug of 5-fluorouracil (5-FU), but its poor solubility has limited its use in clinic. This study aimed to improve the bioavailability of TFU by preparing TFU-loaded lipid-based nanosuspensions (TFU-LNS) and perform a preclinical evaluation.
  
  
  METHODS
  TFU-LNS were prepared through high-pressure homogenization and were lyophilized afterwards. For in vitro test, the physicochemical properties and cytotoxicity against HegG2 cells were conducted. For in vivo evaluation, the pharmacokinetics, tissue distribution, and antitumor efficacy were investigated in H22-bearing Kunming mice.
  
  
  RESULTS
  TFU showed different degradability in four media; in particular, nearly all of it converted to an equimolar amount of 5-FU in blank plasma of Wistar rats. The lyophilized TFU-LNS had a mean particle size of 180.03±3.11 nm and zeta potential of -8.02±1.43 mV and showed no discernible changes after storage at 4°C for 3 months. In the in vivo antitumor study, the antitumor efficacy of TFU-LNS was consistent with that of 5-FU injection. Furthermore, TFU-LNS released a lower concentration of 5-FU in heart and kidney throughout the tissue distribution studies.
  
  
  CONCLUSIONS
  TFU-LNS exhibited convincing antitumor activity and easy scale-up opportunity, which suggests that TFU-LNS might be a promising drug delivery system for cancer therapy.
authors.affiliation: School of Pharmaceutical Science, Shandong University, Ji'nan, People's Republic of China.
authors.forename: Juan
authors.initials: J
authors.lastname: Zhang
authors.affiliation: School of Pharmaceutical Science, Shandong University, Ji'nan, People's Republic of China.
authors.forename: Min
authors.initials: M
authors.lastname: Li
authors.affiliation: School of Pharmaceutical Science, Shandong University, Ji'nan, People's Republic of China.
authors.forename: Zhihong
authors.initials: Z
authors.lastname: Liu
authors.affiliation: School of Pharmaceutical Science, Shandong University, Ji'nan, People's Republic of China.
authors.forename: Lili
authors.initials: L
authors.lastname: Wang
authors.affiliation: School of Pharmaceutical Science, Shandong University, Ji'nan, People's Republic of China.
authors.forename: Yongjun
authors.initials: Y
authors.lastname: Liu
authors.affiliation: School of Pharmaceutical Science, Shandong University, Ji'nan, People's Republic of China.
authors.forename: Na
authors.initials: N
authors.lastname: Zhang
mesh_terms: D000818:Animals; D006528:Carcinoma, Hepatocellular / Q000188:drug therapy* / Q000473:pathology*; D004058:Diffusion; D004353:Drug Evaluation, Preclinical; D005260:Female; D005472:Fluorouracil / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000737:chemistry; D056945:Hep G2 Cells; D006801:Humans; D008081:Liposomes / Q000737:chemistry*; D051379:Mice; D053769:Nanocapsules / Q000737:chemistry* / Q000648:ultrastructure; D010316:Particle Size; D051381:Rats; D017208:Rats, Wistar; D013535:Suspensions; D016896:Treatment Outcome
chemical_list: D008081:Liposomes; C517181:N3-o-toluyl-fluorouracil; D053769:Nanocapsules; D013535:Suspensions; D005472:Fluorouracil
keywords: 5-fluorouracil; cancer therapy; cytotoxicity; high-pressure homogenization