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Development of a Biocompatible Copolymer Nanocomplex to Deliver VEGF siRNA for Triple Negative Breast Cancer.
Theranostics ( IF 12.4 ) Pub Date : 2019-06-09 , DOI: 10.7150/thno.34314 Zhen Zhao 1 , Yuanke Li 1 , Ravi Shukla 1 , Hao Liu 1 , Akshay Jain 1 , Ashutosh Barve 1 , Kun Cheng 1
Theranostics ( IF 12.4 ) Pub Date : 2019-06-09 , DOI: 10.7150/thno.34314 Zhen Zhao 1 , Yuanke Li 1 , Ravi Shukla 1 , Hao Liu 1 , Akshay Jain 1 , Ashutosh Barve 1 , Kun Cheng 1
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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.
中文翻译：
生物相容性共聚物纳米复合物的开发，可为三阴性乳腺癌提供VEGF siRNA。
三阴性乳腺癌（TNBC）是最难治疗的乳腺癌亚型。与非TNBC患者相比，TNBC患者在肿瘤中的血管内皮生长因子（VEGF）表达明显更高。VEGF不仅对内皮细胞发挥促血管生成作用，而且还充当表达VEGF受体（VEGFR）的癌细胞的存活和自分泌生长因子。因此，沉默VEGF的表达是TNBC的潜在疗法。方法：开发了一种新型的生物相容性线性共聚物聚[bis（ε-Lys-PEI）Glut-PEG]（PLEGP），可将VEGF siRNA用于TNBC治疗。该共聚物由赖氨酸和戊二酸组成，后者是人体中氨基酸的天然代谢产物。将低分子量聚乙烯亚胺（PEI）接枝到共聚物上，以有效地将siRNA浓缩为纳米复合物，而不会引起细胞毒性。进行了各种体外研究，以评估VEGF siRNA纳米复合物的稳定性，细胞摄取，肿瘤渗透和生物学活性。纳米复合物的抗肿瘤活性也在原位TNBC小鼠模型中进行了评估。结果：评估了不同分子量的PEI，共聚物PLEGP1800能够轻松地与siRNA形成稳定的纳米复合物，并保护其免受血清降解。siRNA / PLEGP1800纳米复合物显示出可忽略的细胞毒性，但显示出高细胞摄取，高转染效率和高肿瘤渗透性。体外活性研究表明，siRNA纳米复合物可显着抑制TNBC细胞的迁移和侵袭。此外，VEGF siRNA纳米复合物可有效抑制原位TNBC小鼠模型中的肿瘤生长，并下调肿瘤中VEGF的表达。结论：PLEGP1800是一种安全有效的可为TNBC治疗提供siRNA的共聚物。通过改变货物并掺入肿瘤特异性配体，有可能将其应用于其他癌症。
更新日期：2019-01-01
中文翻译：
生物相容性共聚物纳米复合物的开发，可为三阴性乳腺癌提供VEGF siRNA。
三阴性乳腺癌（TNBC）是最难治疗的乳腺癌亚型。与非TNBC患者相比，TNBC患者在肿瘤中的血管内皮生长因子（VEGF）表达明显更高。VEGF不仅对内皮细胞发挥促血管生成作用，而且还充当表达VEGF受体（VEGFR）的癌细胞的存活和自分泌生长因子。因此，沉默VEGF的表达是TNBC的潜在疗法。方法：开发了一种新型的生物相容性线性共聚物聚[bis（ε-Lys-PEI）Glut-PEG]（PLEGP），可将VEGF siRNA用于TNBC治疗。该共聚物由赖氨酸和戊二酸组成，后者是人体中氨基酸的天然代谢产物。将低分子量聚乙烯亚胺（PEI）接枝到共聚物上，以有效地将siRNA浓缩为纳米复合物，而不会引起细胞毒性。进行了各种体外研究，以评估VEGF siRNA纳米复合物的稳定性，细胞摄取，肿瘤渗透和生物学活性。纳米复合物的抗肿瘤活性也在原位TNBC小鼠模型中进行了评估。结果：评估了不同分子量的PEI，共聚物PLEGP1800能够轻松地与siRNA形成稳定的纳米复合物，并保护其免受血清降解。siRNA / PLEGP1800纳米复合物显示出可忽略的细胞毒性，但显示出高细胞摄取，高转染效率和高肿瘤渗透性。体外活性研究表明，siRNA纳米复合物可显着抑制TNBC细胞的迁移和侵袭。此外，VEGF siRNA纳米复合物可有效抑制原位TNBC小鼠模型中的肿瘤生长，并下调肿瘤中VEGF的表达。结论：PLEGP1800是一种安全有效的可为TNBC治疗提供siRNA的共聚物。通过改变货物并掺入肿瘤特异性配体，有可能将其应用于其他癌症。
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