Tat-Tagged and Folate-Modified N-Succinyl-chitosan (Tat-Suc-FA) Self-assembly Nanoparticle for Therapeutic Delivery OGX-011 to A549 Cells,Molecular Pharmaceutics

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Tat-Tagged and Folate-Modified N-Succinyl-chitosan (Tat-Suc-FA) Self-assembly Nanoparticle for Therapeutic Delivery OGX-011 to A549 Cells
Molecular Pharmaceutics ( IF 4.5 ) Pub Date : 2017-05-02 00:00:00 , DOI: 10.1021/acs.molpharmaceut.6b01167
Chengyun Yan _{1,

2} , Jiwei Gu ₁ , Hongying Jing ₁ , Jinghua Taishi ₁ , Robert J. Lee ₃

Affiliation

The objective of this study was to develop a novel type of an antisense oligonucleotide (OGX-011) loaded Tat-tagged and folate-modified N-succinyl-chitosan (Tat-Suc-FA) nanoparticles (NPs) for improving tumor targetability. In this study, Tat-Suc-FA/OGX-011NPs were prepared and its physicochemical characterizations were also evaluated. The nanoparticles showed an average diameter of 73 ± 16.6 nm, the zeta potential of +23.6 ± 0.3 mV, and a high entrapment efficiency of 89.6 ± 6.6%. Transmission electron microscopy analysis showed the nanoparticles were mostly spherical and well dispersed. The delivery efficiency of this system was investigated both in vitro and in vivo. In comparison with nontargeted Lipofectamin2000/OGX-011 and free OGX-011, Tat-Suc-FA/GOX-011 showed the highest apoptosis rate of 14.2% ± 1.8% and significant uptake in A549 cells. Tat-Suc-FA NPs loaded with GOX-011 induced significant down-regulation of s-CLU mRNA and protein levels in A549 cells. In A549 tumor-bearing mice model, Tat-Suc-FA/GOX-011 produced a more efficient down-regulation of s-CLU compared to Lipofectamin2000/OGX-011. Furthermore, the combined use of Tat-Suc-FA/OGX-011 with DDP chemotherapy showed a most significant inhibition of tumor growth and greatly enhanced the survival rate of A549 tumor-bearing mice. These findings suggested successful application of Tat-Suc-FA NPs for the high efficiency and specificity in therapeutic delivery of OGX-011 to A549 cells.

中文翻译：

Tat标记和叶酸修饰的N-琥珀酰-壳聚糖（Tat-Suc-FA）自组装纳米颗粒，用于将OGX-011治疗性递送至A549细胞

这项研究的目的是开发一种新型的反义寡核苷酸（OGX-011），该寡核苷酸负载了Tat标签和叶酸修饰的N-琥珀酰-壳聚糖（Tat-Suc-FA）纳米颗粒（NPs），以改善肿瘤的靶向性。在这项研究中，制备了Tat-Suc-FA / OGX-011NP，并评估了其理化特性。纳米粒子的平均直径为73±16.6 nm，ζ电位为+23.6±0.3 mV，高捕获效率为89.6±6.6％。透射电子显微镜分析表明，纳米颗粒大部分为球形并且分散良好。在体外和体内研究了该系统的递送效率。与非靶向Lipofectamin2000 / OGX-011和游离OGX-011相比，Tat-Suc-FA / GOX-011在A549细胞中显示出最高的细胞凋亡率，为14.2％±1.8％，并具有明显的摄取能力。载有GOX-011的Tat-Suc-FA NP诱导A549细胞中s-CLU mRNA和蛋白水平显着下调。在A549荷瘤小鼠模型中，与Lipofectamin2000 / OGX-011相比，Tat-Suc-FA / GOX-011产生了更有效的s-CLU下调。此外，Tat-Suc-FA / OGX-011与DDP化疗联合使用显示出对肿瘤生长的最显着抑制作用，并大大提高了A549荷瘤小鼠的存活率。这些发现表明，Tat-Suc-FA NPs在OGX-011到A549细胞的治疗性递送中具有高效和高特异性的成功应用。

更新日期：2017-05-10

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