Development of a Biocompatible Copolymer Nanocomplex to Deliver VEGF siRNA for Triple Negative Breast Cancer
Development of a Biocompatible Copolymer Nanocomplex to Deliver VEGF siRNA for Triple Negative Breast Cancer
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DOI：
10.7150/thno.34314
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发表时间：
2019-06
期刊：
影响因子：
12.4
通讯作者：
Zhen Zhao;Yuanke Li;R. Shukla;Hao Liu;Akshay Jain;Ashutosh J Barve;K. Cheng
中科院分区：
文献类型：
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作者：
Zhen Zhao;Yuanke Li;R. Shukla;Hao Liu;Akshay Jain;Ashutosh J Barve;K. Cheng
乳腺癌（TNBC）是最困难的乳腺癌亚型，与非TNBC患者相比，肿瘤的血管内皮生长因子（VEGF）的表达明显更高。是因此，TNBC的潜在治疗：一种新型的生物相容性的共聚物聚合物（ε-Lys-pei）Glut-Peg）（PLEGP），以提供TNBC治疗的VEGF sirna。 ED到共聚物中，没有诱导的进行了各种体外研究，以评估VEGF siRNA纳米胶质体的稳定性，肿瘤穿透和生物学活性。与siRNA的拟南芥，并保护它们免受血清降解。 sirna/plegp1800纳米复合物暴露于可忽略的细胞毒性，但在体外活性研究中显示出高的细胞摄取，高转化效率和高肿瘤的渗透。调节的VEGF表达结论：PLEGP1800是一种安全有效的共聚物，可以通过更改货物并掺入肿瘤特异性配体来实现TNBC治疗的siRNA。
Triple negative breast cancer (TNBC) is the most difficult breast cancer subtype to treat. TNBC patients have significantly higher expression of vascular endothelial growth factor (VEGF) in tumors compared to non-TNBC patients. VEGF not only exerts its pro-angiogenic effects on endothelial cells but also acts as a survival and autocrine growth factor for VEGF receptor (VEGFR) expressing cancer cells. Silencing the expression of VEGF is therefore a potential therapy for TNBC. Methods: A novel biocompatible linear copolymer poly[bis(ε-Lys-PEI)Glut-PEG] (PLEGP) was developed to deliver VEGF siRNA for TNBC therapy. The copolymer is composed of lysine and glutaric acid, a natural metabolite of amino acids in the body. Low-molecular weight polyethyleneimine (PEI) was grafted to the copolymer to efficiently condense siRNA into nanocomplex without inducing cytotoxicity. Various in vitro studies were performed to evaluate the stability, cellular uptake, tumor penetration, and biological activities of the VEGF siRNA nanocomplex. The anti-tumor activities of the nanocomplex was also evaluated in an orthotopic TNBC mouse model. Results: PEIs with different molecular weights were evaluated, and the copolymer PLEGP1800 was able to easily form a stable nanocomplex with siRNAs and protect them from serum degradation. The siRNA/PLEGP1800 nanocomplex exhibited negligible cytotoxicity but showed high cellular uptake, high transfection efficiency, and high tumor penetration. In vitro activity studies showed that the siRNA nanocomplex significantly inhibited migration and invasion of TNBC cells. Moreover, the VEGF siRNA nanocomplex efficiently inhibited tumor growth in an orthotopic TNBC mouse model and down-regulated VEGF expression in the tumor. Conclusion: PLEGP1800 is a safe and efficient copolymer to deliver siRNAs for TNBC therapy. It could potentially be applied to other cancers by changing the cargo and incorporating tumor-specific ligands.