Yan Chengyun, Gu Jiwei, Jing Hongying, Taishi Jinghua, Lee Robert J
College of Pharmacy, Guilin Medical University , Guilin, Guangxi People's Republic of China.
First Affiliated Hospital of Jiamusi University, Jiamusi of University , Jiamusi, Heilongjiang People's Republic of China.
Mol Pharm. 2017 Jun 5;14(6):1898-1905. doi: 10.1021/acs.molpharmaceut.6b01167. Epub 2017 May 9.
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.
本研究的目的是开发一种新型的反义寡核苷酸（OGX-011）负载的、带有Tat标签和叶酸修饰的N-琥珀酰壳聚糖（Tat-Suc-FA）纳米颗粒（NPs），以提高肿瘤靶向性。在本研究中，制备了Tat-Suc-FA/OGX-011纳米颗粒，并对其理化性质进行了评估。纳米颗粒的平均直径为73±16.6nm，zeta电位为+23.6±0.3mV，包封率高达89.6±6.6%。透射电子显微镜分析表明，纳米颗粒大多呈球形且分散良好。对该系统的递送效率进行了体外和体内研究。与非靶向的Lipofectamin2000/OGX-011和游离的OGX-011相比，Tat-Suc-FA/GOX-011在A549细胞中显示出最高的凋亡率，为14.2%±1.8%，且摄取显著。负载GOX-011的Tat-Suc-FA纳米颗粒可显著下调A549细胞中s-CLU的mRNA和蛋白水平。在A549荷瘤小鼠模型中，与Lipofectamin2000/OGX-011相比，Tat-Suc-FA/GOX-011对s-CLU的下调更有效。此外，Tat-Suc-FA/OGX-011与顺铂化疗联合使用对肿瘤生长的抑制作用最为显著，并大大提高了A549荷瘤小鼠的存活率。这些结果表明，Tat-Suc-FA纳米颗粒成功应用于将OGX-011高效、特异性地递送至A549细胞进行治疗。
