Encapsulation of vinorelbine into cholesterol-polyethylene glycol coated vesicles: drug loading and pharmacokinetic studies

Objectives Pegylated liposome formulations of vinorelbine with prolonged circulation half‐life (t½) are desirable. However, DSPE‐PEG could affect vinorelbine loading into vesicles due to electrostatic interactions. To resolve this problem, chol‐PEG was used to prepare pegylated liposomal vinorelbine and the factors affecting drug loading and plasma pharmacokinetics were investigated. Methods Vinorelbine was loaded into liposomes using a novel triethylamine 5‐sulfosalicylate gradient. The effects of cholesterol and chol‐PEG on drug loading were investigated. Pharmacokinetic studies were performed in normal KunMing mice treated with different liposomal vinorelbine formulations. To clarify the effects of chol‐PEG on membrane permeability, drug release experiments were performed based on the fluorescence dequenching phenomenon of a fluorescence marker. Key findings In contrast to DSPE‐PEG, even at high PEG grafting density (～8.3 mol%), chol‐PEG had no effect on vinorelbine loading into HSPC/cholesterol (3 : 1, mass ratio) vesicles. However, for the formulations with low cholesterol content (HSPC/cholesterol 4 : 1), loading efficiency decreased with increasing chol‐PEG content. In vivo, the vinorelbine t½ of low cholesterol formulations decreased with increasing chol‐PEG content, but for high cholesterol liposomes, the maximum vinorelbine t½ was achieved at ～3 mol% chol‐PEG grafting density. The resulting vinorelbine circulation t½ was ～9.47 h, which was greater than that of non‐pegylated liposomes (～5.55 h). Drug release experiments revealed that chol‐PEG might induce membrane defects and concomitant release of entrapped marker, especially at high chol‐PEG density. Conclusions Through the investigation of the effects of chol‐PEG and cholesterol, an optimum pegylated liposomal vinorelbine formulation with prolonged t½ was achieved. In plasma, the membrane defect induced by chol‐PEG may counteract the long circulation characteristics that chol‐PEG afforded. When these two opposite effects reached equilibrium, the maximum vinorelbine t½ was achieved.