pH- and redox-responsive nanoparticles composed of charge-reversible pullulanbased shells and disulfide-containing poly(ß-amino ester) cores for co-delivery of a gene and chemotherapeutic agent
pH- and redox-responsive nanoparticles composed of charge-reversible pullulanbased shells and disulfide-containing poly(ß-amino ester) cores for co-delivery of a gene and chemotherapeutic agent
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pH 和氧化还原响应纳米颗粒由电荷可逆普鲁兰基壳和含二硫化物的聚（氨基酯）核组成，用于共同递送基因和化疗剂
DOI：
10.1088/1361-6528/aac4b5
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发表时间：
2018
期刊：
影响因子：
3.5
通讯作者：
Wang Yinsong
中科院分区：
文献类型：
--
作者：
Zhang Sipei;Wang Dan;Li Yating;Li Ling;Chen Hongli;Xiong Qingqing;Liu Yuanyuan;Wang Yinsong
基于电荷可逆普鲁兰多糖衍生物（CAPL）和含二硫键的聚β-氨基酯（ssPBAE），设计了一种新型pH和氧化还原响应纳米粒系统，用于肝癌靶向基因和化疗药物的共递送。将ssPBAE的末端烯基与二乙烯三胺反应，形成氨基改性的ssPBAE（NH-ssPBAE）。然后将化疗剂甲氨蝶呤（MTX）通过酰胺键与NH-ssPBAE缀合以获得聚合物前药ssPBAE-MTX。ssPBAE-MTX表现出良好的浓缩基因的能力，包括质粒DNA（pDNA）和四甲基罗丹明标记的DNA（TAMRA-DNA），并且在5/1的重量比下几乎完全浓缩pDNA以形成具有均匀尺寸的球形纳米复合物。在D，L-二硫苏糖醇溶液中，ssPBAE-MTX/pDNA纳米复合物显示出pDNA和MTX的快速释放，表明它们的氧化还原响应能力。将含有β-羧酰胺键的普鲁兰多糖衍生物CAPL高效包覆于ssPBAE-MTX/pDNA纳米复合物表面，形成多糖壳层，实现基因与化疗药物的共载。CAPL/ssPBAE-MTX/pDNA纳米粒在弱酸性条件下由于β-羧酰胺键的断裂而表现出明显的pH响应性电荷反转能力。在人肝癌HepG 2细胞中，CAPL/ssPBAE-MTX/TAMRA-DNA纳米粒通过内吞作用被有效地内化，并成功地从内/溶酶体逃逸到细胞质中，CAPL/ssPBAE-MTX/pDNA纳米粒显著抑制细胞生长。综上所述，这种基于CAPL和ssPBAE的纳米颗粒系统在肝癌的联合基因/化疗中显示出巨大的潜力。
A novel pH-and redox-responsive nanoparticle system was designed based on a charge-reversible pullulan derivative (CAPL) and disulfide-containing poly (β-amino ester)(ssPBAE) for the co-delivery of a gene and chemotherapeutic agent targeting hepatoma. The end-alkene groups of ssPBAE were reacted with diethylenetriamine to form amino-modified ssPBAE (NH-ssPBAE). Methotrexate (MTX), a chemotherapy agent, was then conjugated to NH-ssPBAE via an amide bond to obtain the polymeric prodrug ssPBAE-MTX. ssPBAE-MTX exhibited a good capability for condensing genes, including plasmid DNA (pDNA) and tetramethyl rhodamine-labeled DNA (TAMRA-DNA), and almost completely condensed pDNA at the weight ratio of 5/1 to form spherical nanocomplexes with a uniform size. In a D, L-dithiothreitol solution, the ssPBAE-MTX/pDNA nanocomplexes showed rapid release of pDNA and MTX, indicating their redox-responsive capability. CAPL, a pullulan derivative containing β-carboxylic amide bond, was efficiently coated on the surfaces of ssPBAE-MTX/pDNA nanocomplexes to form polysaccharide shells, thus realizing co-loading of the gene and chemotherapeutic agent. CAPL/ssPBAE-MTX/pDNA nanoparticles displayed an obvious pH-responsive charge reversal ability due to the rupture of the β-carboxylic amide bond under the weakly acidic condition. In human hepatoma HepG2 cells, CAPL/ssPBAE-MTX/TAMRA-DNA nanoparticles were efficiently internalized via endocytosis and successfully escaped from the endo/lysosomes into the cytoplasm, and CAPL/ssPBAE-MTX/pDNA nanoparticles remarkably inhibited the cell growth. In summary, this nanoparticle system based on CAPL and ssPBAE showed great potential for combined gene/chemotherapy on hepatomas.