Enhanced liver targeting by synthesis of N1-stearyl-5-Fu and incorporation into solid lipid nanoparticles.
To enhance the liver targeting and reduce the side effects of 5-fluorouracil (5-Fu), it was acylated by stearyl chloride to obtain N1-stearyl-5-Fu (5-FuS). The chemical structure of the prodrug was confirmed by Nuclear Magnetic Resonance and Infrared Spectrometry. 5-FuS was incorporated into solid lipid nanoparticles (SLN), which were prepared by the physical agglomeration method. The mean diameter of 5-FuS-SLN was 240.19 nm and the drug loading was 20.53%. The release characteristics in vitro of 5-FuS-SLN were fitted to the first-order pharmacokinetic model. Compared with 5-Fu injection, a study on the distribution of 5-FuS-SLN in mice showed that 5-FuS-SLN could double 5-Fu concentration in mice livers. The main pharmacokinetic parameters of 5-FuS-SLN in rabbits is shown as follows: Vd=0.04336 L/kg, T(1/2) beta=1.2834 h, CL=0.1632 L/h. In conclusion, 5-FuS-SLN has significant liver targeting properties. The employment of a prodrug to enhance drug liposoluble properties and the preparation method presented in this paper, seem to be an alternative strategy to the traditional colloidal delivery system.
Yu
Bo-Tao
BT
West China School of Pharmacy, Sichuan University, Chengdu 610041, People's Republic of China.
Sun
Xun
X
Zhang
Zhi-Rong
ZR
D000818:Animals; D016503:Drug Delivery Systems / Q000379:methods*; D004355:Drug Stability; D005260:Female; D005472:Fluorouracil / Q000008:administration & dosage* / Q000138:chemical synthesis / Q000493:pharmacokinetics; D008081:Liposomes; D008099:Liver / Q000187:drug effects* / Q000378:metabolism; D008297:Male; D051379:Mice; D008854:Microscopy, Electron; D036103:Nanotechnology / Q000379:methods*; D010316:Particle Size; D011817:Rabbits; D013229:Stearic Acids / Q000008:administration & dosage* / Q000138:chemical synthesis / Q000493:pharmacokinetics
D008081:Liposomes; D013229:Stearic Acids; C031183:stearic acid; D005472:Fluorouracil