Dual-responsive nanoparticles based on oxidized pullulan and a disulfide-containing poly(beta-amino) ester for efficient delivery of genes and chemotherapeutic agents targeting hepatoma
Dual-responsive nanoparticles based on oxidized pullulan and a disulfide-containing poly(beta-amino) ester for efficient delivery of genes and chemotherapeutic agents targeting hepatoma
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基于氧化普鲁兰多糖和含二硫化物的聚（β-氨基）酯的双响应纳米颗粒，用于有效递送针对肝癌的基因和化疗药物
DOI：
10.1039/c6py01664b
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发表时间：
2016
影响因子：
4.6
通讯作者：
Wang Yinsong
中科院分区：
文献类型：
--
作者：
Wang Hemei;Wan Guoyun;Liu Yuanyuan;Chen Bowei;Chen Hongli;Zhang Sipei;Wang Dan;Xiong Qingqing;Zhang Ning;Wang Yinsong
基于氧化普鲁兰多糖（oxPL）和含二硫键的聚（β-氨基）酯（ssPBAE）设计了一种双响应纳米颗粒系统，用于通过响应肿瘤细胞内pH和氧化还原状态的聚合物降解来有效地递送基因和化疗药物。通过高碘酸盐氧化普鲁兰多糖得到含大量醛基的oxPL。用二乙烯三胺对ssPBAE进行改性，然后通过Schiff碱反应接枝到oxPL上。阿霉素通过酸可裂解的腙键与ssPBAE-oxPL缀合，从而获得其中DOX含量为约3.6%的ssPBAE-oxPL-DOX。ssPBAE-oxPL-DOX具有一定的体外肝癌靶向性，对质粒DNA（pDNA）和荧光素标记寡聚DNA（FAM-DNA）等基因具有良好的凝聚能力。ssPBAE-oxPL-DOX/pDNA纳米颗粒具有非球形形状和相对均匀的尺寸。DOX和pDNA从ssPBAE-oxPL-DOX/pDNA纳米粒的体外释放显示出显著的pH和氧化还原响应特性。在肝癌HepG 2细胞中，ssPBAE-oxPL-DOX/pDNA纳米粒能有效抑制细胞增殖，诱导细胞凋亡，并使细胞周期阻滞在S期。此外，ssPBAE-oxPL-DOX/FAM-DNA纳米粒在HepG 2细胞中可有效地将DOX和FAM-DNA分别递送到细胞核和细胞质中，并且在静脉注射后在HepG 2荷瘤小鼠中也表现出明显的肝癌靶向性。总之，这种新型的双应答纳米粒系统在肝癌的基因治疗和化疗联合治疗中显示了巨大的潜力。
A dual-responsive nanoparticle system was designed based on oxidized pullulan (oxPL) and a disulfide-containing poly(β-amino) ester (ssPBAE) for the efficient delivery of genes and chemotherapeutic agents through polymer degradation responding to the tumor intracellular pH and redox state. oxPL containing abundant aldehyde groups was obtained through the periodate oxidation of pullulan. ssPBAE was modified with diethylenetriamine and then grafted onto oxPL by the Schiff's base reaction. Doxorubicin was conjugated to ssPBAE-oxPL via the acid-cleavable hydrazone bond, thus obtaining ssPBAE-oxPL-DOX in which the DOX content was about 3.6%. ssPBAE-oxPL-DOX exhibited in vitro hepatoma-targeting properties to some extent and good ability for condensing genes including plasmid DNA (pDNA) and fluorescein-labeled oligoDNA (FAM-DNA). ssPBAE-oxPL-DOX/pDNA nanoparticles had non-spherical shapes and relatively uniform sizes. The in vitro releases of DOX and pDNA from ssPBAE-oxPL-DOX/pDNA nanoparticles displayed significant pH- and redox-responsive properties. In hepatoma HepG2 cells, ssPBAE-oxPL-DOX/pDNA nanoparticles effectively inhibited cell proliferation, and induced cell apoptosis and cell cycle arrest at the S-phase. Moreover, ssPBAE-oxPL-DOX/FAM-DNA nanoparticles efficiently delivered DOX and FAM-DNA respectively into the nucleus and the cytoplasm in HepG2 cells, and also exhibited distinct hepatoma targeting properties in HepG2 tumor-bearing mice after intravenous injection. In summary, this novel dual-responsive nanoparticle system showed great potential for the combined gene therapy and chemotherapy on hepatoma.