pH-Gradient Incorporation of 9-Nitrocamptothecin in PEGylated Liposomes: Formulation Properties and Efficacy In Vitro and In Vivo

Shuang      Chang; Li      Xie; Hong      Ding; Yu      Nie; Yao      Wu; Bin      He; Zhongwei      Gu

Abstract

9-Nitrocamptothecin (9-NC) is an efficient antitumor reagent with poor drug-to-lipid entrapment (1:72) in the conventional liposomes formulation. In order to improve the encapsulation and therapeutic efficacy, PEGylated cholesterol (Chol-PEG) was introduced into the 9-NC loaded liposomes formulation by pH gradient encapsulation method. Comparing with conventional composition, 9-NC/lipid molar ratio was increased from 1:72 up to 1:6 in the Chol-PEG based liposomes with uniform size distribution (~120 nm). PEGylated formulation showed obvious lower IC50 value than 9-NC solution (from > 50μmol/L to 5.5 μmol/L on breast cancer 4T1 cells, while from > 50μmol/L to 25.4 μmol/L on hepatoma HepG2 cells) in cytotoxicity measurement. The safety of PEGylated 9-NC liposomes formulation was also illustrated in ex vivo hemolysis test. The enhanced tumor inhibition efficiency of PEGylated 9-NC liposomes was confirmed from tumor-bearing BALB/c mice model using same dosage of 9-NC solution as control (from 28.6% to 70.1% in tumor inhibition). These results suggest that this Chol-PEG based liposome formulation may serve as a promising nanoscale platform for 9-NC controlled delivery.

Keywords: pH-gradient, 9-nitrocamptothecin, PEGylated in vitro, in vivo, cholesterol, liposomes.

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