State Key Laboratory of Natural Medicines, Department of Pharmaceutics, China Pharmaceutical University , Nanjing, 210009, China.
Center for Drug Delivery and Nanomedicine, Department of Pharmaceutical Sciences, University of Nebraska Medical Center , Omaha Nebraska 68198, United States.
Biomacromolecules. 2018 Feb 12;19(2):392-401. doi: 10.1021/acs.biomac.7b01487. Epub 2018 Jan 19.
Chemokine receptor CXCR4 plays an important role in cancer cell invasion and metastasis. Recent findings suggest that anti-VEGF therapies upregulate CXCR4 expression, which contributes to resistance to antiangiogenic therapies. Here, we report the development of novel derivatives of polyethylenimine (PEI) that effectively inhibit CXCR4 while delivering anti-VEGF siRNA. PEI was alkylated with different amounts of a CXCR4-binding cyclam derivative to prepare PEI-C. Modification with the cyclam derivatives resulted in a considerable decrease in cytotoxicity when compared with unmodified PEI. All the PEI-C showed significant CXCR4 antagonism and the ability to inhibit cancer cell invasion. Polyplexes of PEI-C prepared with siVEGF showed effective silencing of the VEGF expression in vitro. In vivo testing in a syngeneic breast cancer model showed promising antitumor and antimetastatic activity of the PEI-C/siVEGF polyplexes. Our data demonstrate the feasibility of using PEI-C as a carrier for simultaneous VEGF silencing and CXCR4 inhibition for enhanced antiangiogenic cancer therapies.
趋化因子受体 CXCR4 在癌细胞侵袭和转移中发挥重要作用。最近的研究结果表明，抗血管内皮生长因子 (VEGF) 治疗会上调 CXCR4 的表达，从而导致对抗血管生成治疗产生耐药性。在这里，我们报告了聚乙二烯亚胺 (PEI) 的新型衍生物的开发，该衍生物可有效抑制 CXCR4 同时传递抗 VEGF siRNA。用不同数量的 CXCR4 结合环脒衍生物对 PEI 进行烷基化以制备 PEI-C。与未修饰的 PEI 相比，环脒衍生物的修饰导致细胞毒性显著降低。所有的 PEI-C 均表现出显著的 CXCR4 拮抗作用和抑制癌细胞侵袭的能力。用 siVEGF 制备的 PEI-C 形成的多聚物在体外有效地抑制了 VEGF 的表达。在同种异体乳腺癌模型中的体内试验表明，PEI-C/siVEGF 多聚物具有有前途的抗肿瘤和抗转移活性。我们的数据证明了使用 PEI-C 作为载体同时进行 VEGF 沉默和 CXCR4 抑制以增强抗血管生成癌症治疗的可行性。
