Wang Fen, Pang Jia-Dong, Huang Lei-Lei, Wang Ran, Li Dan, Sun Kang, Wang Lian-Tang, Zhang Li-Ming
Department of Pathology, The First Affiliated Hospital of Sun Yat-sen University.
PCFM Lab and GDHPPC Lab, School of Materials Science and Engineering, Sun Yat-sen University, Guangzhou.
Int J Nanomedicine. 2018 Feb 8;13:857-875. doi: 10.2147/IJN.S147747. eCollection 2018.
Nanomedicine, which is the application of nanotechnology in medicine to make medical diagnosis and treatment more accurate, has great potential for precision medicine. Despite some improvements in nanomedicine, the lack of efficient and low-toxic vectors remains a major obstacle.
The aim of this study was to prepare an efficient and low-toxic vector which could deliver astrocyte elevated gene-1 () small interfering RNA (siRNA; siAEG-1) into osteosarcoma cells effectively and silence the targeted gene both in vitro and in vivo.
We prepared a novel polysaccharide derivative by click conjugation of azidized chitosan with propargyl focal point poly (L-lysine) dendrons (PLLD) and subsequent coupling with folic acid (FA; Cs-g-PLLD-FA). We confirmed the complexation of siAEG-1and Cs-g-PLLD or Cs-g-PLLD-FA by gel retardation assay. We examined the cell cytotoxicity, cell uptake, cell proliferation and invasion abilities of Cs-g-PLLD-FA/siAEG-1 in osteosarcoma cells. In osteosarcoma 143B cells tumor-bearing mice models, we established the therapeutic efficacy and safety of Cs-g-PLLD-FA/siAEG-1.
Cs-g-PLLD-FA could completely encapsulate siAEG-1 and showed low cytotoxicity in osteosarcoma cells and tumour-bearing mice. The Cs-g-PLLD-FA/siAEG-1 nanocomplexes were capable of transferring siAEG-1 into osteosarcoma cells efficiently, and the knockdown of AEG-1 resulted in the inhibition of tumour cell proliferation and invasion. In addition, caudal vein injecting of Cs-g-PLLD-FA/siAEG-1 complexes inhibited tumor growth and lung metastasis in tumor-bearing mice by silencing AEG-1 and regulating MMP-2/9.
In summary, Cs-g-PLLD-FA nanoparticles are a promising system for the effective delivery of AEG-1 siRNA for treating osteosarcoma.
纳米医学是将纳米技术应用于医学领域，以使医学诊断和治疗更加精准，在精准医学方面具有巨大潜力。尽管纳米医学取得了一些进展，但缺乏高效低毒的载体仍是一个主要障碍。
本研究旨在制备一种高效低毒的载体，能够将星形胶质细胞上调基因1（AEG-1）小干扰RNA（siRNA；siAEG-1）有效递送至骨肉瘤细胞，并在体外和体内沉默靶向基因。
通过叠氮化壳聚糖与炔丙基焦点聚（L-赖氨酸）树枝状聚合物（PLLD）的点击共轭反应，随后与叶酸（FA；Cs-g-PLLD-FA）偶联，制备了一种新型多糖衍生物。通过凝胶阻滞试验证实了siAEG-1与Cs-g-PLLD或Cs-g-PLLD-FA的络合作用。检测了Cs-g-PLLD-FA/siAEG-1在骨肉瘤细胞中的细胞毒性、细胞摄取、细胞增殖和侵袭能力。在荷骨肉瘤143B细胞的小鼠模型中，确立了Cs-g-PLLD-FA/siAEG-1的治疗效果和安全性。
Cs-g-PLLD-FA能够完全包裹siAEG-1，在骨肉瘤细胞和荷瘤小鼠中显示出低细胞毒性。Cs-g-PLLD-FA/siAEG-1纳米复合物能够有效地将siAEG-1转运至骨肉瘤细胞中，AEG-1的敲低导致肿瘤细胞增殖和侵袭受到抑制。此外，尾静脉注射Cs-g-PLLD-FA/siAEG-1复合物通过沉默AEG-1和调节基质金属蛋白酶-2/9，抑制了荷瘤小鼠的肿瘤生长和肺转移。
总之，Cs-g-PLLD-FA纳米颗粒是一种有前景的系统，可有效递送AEG-1 siRNA用于治疗骨肉瘤。
