Tyloxapol and nanoliposomes induce selective delivery of 5-fluorouracil into hepatic tissues via VLDL/LDL-mediated pathway

This study aimed to enhance the hepatic targeting of 5-fluorouracil (5-FU) by tyloxapol (TYL) and nanoliposomes to promote drug efficacy and safety. The lipophilicity of 5-FU was increased by cholesterol conjugation (5-FUC). Nanoliposomes were prepared, characterized, and loaded with 5-FU and 5-FUC and injected into TYL-treated male Wistar albino rats. After 4 h, LDL and hepatic homogenate were isolated, and the concentrations of 5-FU and 5-FUC were investigated in both specimens. The pharmacokinetic parameters of 5-FU- and 5-FUC-loaded liposomes were also investigated. The present results revealed that the prepared liposomes have a nanoscale size, negative zeta potential, and prolonged drug release. TYL injection significantly elevated the plasma levels of nonhigh-density lipoproteins, triacylglycerol (TAG), and total cholesterol (TC). The isolated LDL nanoparticles had a nanosized homogenous vesicle structure and a negative zeta potential. 5-FUC-loaded liposomes and TYL augmented 5-FUC loading into LDL and hepatic tissues compared to that for 5-FU. Moreover, the present results indicated that 5-FUC-loaded liposomes significantly improved the Cmax, Tmax, AUC, MRT, and t1/2 compared to those for the 5-FUC solution and 5-FU-loaded liposomes. This study concluded that the triple approach of a lipophilic shift, nanoliposomes, and TYL is promising for enhancing drug bioavailability, LDL loading, and selective hepatic drug targeting. Practical applications: 5-Fluorouracil (5-FU) is a hydrophilic anticancer medicine that elicits multiple side effects due to high doses, short half-life, and nonspecific tissue distribution. In this study, 5-FU was shifted into a lipophilic form (5-FUC) by cholesterol conjugation. The 5-FUC was loaded into a nanoliposome. Rats were injected with tyloxapol (TYL) to induce a temporary hyperlipidemia that produces a lipophilic milieu. The hyperlipidemia was confirmed physically by plasma milky appearance and biochemically by marked elevation of non-HDL lipoproteins. Hyperlipidemia promotes 5-FUC loading into VLDL-LDL in vivo. The 5-FUC level was determined in isolated LDL and liver tissues using HPLC analysis. The lipophilic shift, liposomal loading, and TYL improve pharmacokinetic parameters and bioavailability of 5-FU with sustained action and hepatic targeting. This study opens a new avenue for endogenous drugs loading into lipoproteins as an approach for selective hepatic drug targeting.