Preclinical studies of N3-O-toluyl-fluorouracil-loaded lipid-based nanosuspensions in H22-bearing mice

Abstract

Purpose N 3 -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 H 22 -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. Conclusion 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.

In vivo biodistribution, biocompatibility, and efficacy of sorafenib-loaded lipid-based nanosuspensions evaluated experimentally in cancer

“…43 Similar results have been reported in other studies. 30,44,45 After administration of sorafenib-LNS formulation, sorafenib was accumulated in liver to a considerable extent compared with other organs. The passive targeting of sorafenib-LNS to liver indicates the potential for an increased therapeutic effect on HCC and requires further investigation.…”

“…29 In our previous work, we prepared docetaxelloaded LNS and N3-O-toluyl-fluorouracil-loaded LNS by high-pressure homogenization, and both exhibited good antitumor activity and better tumor accumulation than the free drug, which suggested that LNS may be a promising drug delivery system for cancer therapy. 29,30 In this study, sorafenib-loaded LNS (sorafenib-LNS) were prepared by nanoprecipitation as an intravenous (IV) injectable formulation that we expected would increase the therapeutic efficiency and reduce gastrointestinal irritation. The particle size, zeta potential, and in vitro release properties of sorafenib-LNS were characterized.…”

Multiple nanoemulsion system for an oral combinational delivery of oxaliplatin and 5-fluorouracil: preparation and in vivo evaluation

“…Moreover, the nanoemulsion system incorporating OXA/DCK and 5-FU demonstrated a prolonged half-life for OXA and 5-FU, which was extended 5.68-and 1.82-fold, respectively, than the half-life after intravenously administration of OXA and 5-FU, suggesting prolonged therapeutic activity of the drug. 53,54 Like other platinum-based compounds, OXA exerts its cytotoxic effect mostly through DNA damage. Apoptosis of cancer cells can be caused by formation of DNA lesions, arrest of DNA synthesis, inhibition of RNA synthesis, and triggering of immunologic reactions.…”