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

Abstract

AbstractThis 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.