pH-sensitive pullulan-based nanoparticle carrier of methotrexate and combretastatin A4 for the combination therapy
Yinsong Wang1, Hongli Chen, Yuanyuan Liu
1Research Center of Basic Medical Science, School of Pharmacy, Tianjin Key Laboratory on Technologies Enabling Development of Clinical Therapeutics and Diagnostics (Theranostics) & Cancer Institute and Hospital, Tianjin Medical University, No. 22 Qixiangtai Road, Heping District, Tianjin 300070, China. wangyinsong@tijmu.edu.cn
Abstract:
This study designs a pH-sensitive nanoparticle carrier of methotrexate (MTX) and combretastatin A4 (CA4) based on pullulan for the combination therapy against hepatocellular carcinoma (HCC). Briefly, N-urocanyl pullulan (URPA) with the degree of substitution (DS) of 5.2% was synthesized and then conjugated with MTX to form MTX-URPA, in which MTX content was 17.8%. MTX-URPA nanoparticles prepared by the dialysis method had spherical shape and the mean size of 187.1 nm, and showed high affinity for HepG2 cells. CA4 was successfully loaded into MTX-URPA nanoparticles and exhibited pH-sensitive in vitro release property. After intravenous injection to PLC/PRF/5-bearing nude mice, CA4 loaded MTX-URPA (CA4/MTX-URPA) nanoparticles achieved the enhanced antitumor and anti-angiogenic effects, the prolonged circulation time in blood, and the increased distributions both in the liver and the tumor. In conclusion, this drug carrier system has significant liver-targeting property and exhibits advantages for the combination therapy against hepatocellular carcinoma.
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