含有电荷可逆的普鲁兰多糖基壳层和聚（β-氨基酯）/聚（乳酸-乙醇酸共聚物）核的逐步pH响应性纳米颗粒作为抗癌药物载体用于肝细胞癌联合治疗。

Stepwise pH-responsive nanoparticles containing charge-reversible pullulan-based shells and poly(β-amino ester)/poly(lactic-co-glycolic acid) cores as carriers of anticancer drugs for combination therapy on hepatocellular carcinoma.

作者信息

Zhang Cong, An Tong, Wang Dan, Wan Guoyun, Zhang Mingming, Wang Hemei, Zhang Sipei, Li Rongshan, Yang Xiaoying, Wang Yinsong

机构信息

School of Pharmacy, Tianjin Key Laboratory on Technologies Enabling Development of Clinical Therapeutics and Diagnostics (Theranostics), Tianjin Medical University, Tianjin 300070, PR China.

Tianjin Key Laboratory of Biomedical Materials, Institute of Biomedical Engineering, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin 300192, PR China.

出版信息

J Control Release. 2016 Mar 28;226:193-204. doi: 10.1016/j.jconrel.2016.02.030. Epub 2016 Feb 16.

DOI:10.1016/j.jconrel.2016.02.030

PMID:26896737

Abstract

Stepwise pH-responsive nanoparticle system containing charge reversible pullulan-based (CAPL) shell and poly(β-amino ester) (PBAE)/poly(lactic-co-glycolic acid) (PLAG) core is designed to be used as carriers of paclitaxel (PTX) and combretastatin A4 (CA4) for combining antiangiogenesis and chemotherapy to treat hepatocellular carcinoma (HCC). CAPL-coated PBAE/PLGA (CAPL/PBAE/PLGA) nanoparticles displayed step-by-step responses to weakly acidic tumor microenvironment (pH ≈6.5) and endo/lysosome (pH ≈5.5) respectively through the cleavage of β-carboxylic amide bond in CAPL and the "proton-sponge" effect of PBAE, thus realized the efficient and orderly releases of CA4 and PTX. In human HCC HepG2 cells and human umbilical vein endothelial cells, CAPL/PBAE/PLGA nanoparticles significantly enhanced synergistic effects of PTX and CA4 on cell proliferation and cell migration. In HepG2 tumor-bearing mice, CAPL/PBAE/PLGA nanoparticles showed excellent tumor-targeting capability and remarkably increased inhibitory effects of PTX and CA4 on tumor growth and angiogenesis. In conclusion, this novel nanoparticle system is a promising candidate as carrier for drugs against HCC.

摘要

含有电荷可逆普鲁兰多糖基（CAPL）壳层和聚（β-氨基酯）（PBAE）/聚乳酸-羟基乙酸共聚物（PLAG）核的逐步pH响应纳米颗粒系统被设计用作紫杉醇（PTX）和康普瑞汀A4（CA4）的载体，用于联合抗血管生成和化疗来治疗肝细胞癌（HCC）。CAPL包被的PBAE/PLGA（CAPL/PBAE/PLGA）纳米颗粒分别通过CAPL中β-羧酰胺键的断裂以及PBAE的“质子海绵”效应，对弱酸性肿瘤微环境（pH≈6.5）和内体/溶酶体（pH≈5.5）呈现逐步响应，从而实现了CA4和PTX的高效有序释放。在人肝癌HepG2细胞和人脐静脉内皮细胞中，CAPL/PBAE/PLGA纳米颗粒显著增强了PTX和CA4对细胞增殖和细胞迁移的协同作用。在荷HepG2肿瘤小鼠中，CAPL/PBAE/PLGA纳米颗粒表现出优异的肿瘤靶向能力，并显著增强了PTX和CA4对肿瘤生长和血管生成的抑制作用。总之，这种新型纳米颗粒系统作为抗HCC药物的载体是一种有前景的候选物。