具有 pH 响应性和可聚乙二醇化特性的智能聚合物纳米粒子（二）：紫杉醇和 VEGF siRNA 的共递送用于协同治疗小鼠乳腺癌。
Smart Polymeric Nanoparticles with pH-Responsive and PEG-Detachable Properties (II): Co-Delivery of Paclitaxel and VEGF siRNA for Synergistic Breast Cancer Therapy in Mice.
机构信息
State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100050, People's Republic of China.
Beijing Key Laboratory of Drug Delivery Technology and Novel Formulations, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100050, People's Republic of China.
出版信息
Int J Nanomedicine. 2021 Aug 13;16:5479-5494. doi: 10.2147/IJN.S313339. eCollection 2021.
BACKGROUND
The dual-loaded nano-delivery system can realize chemotherapeutic drug and small interfering RNA (siRNA) co-loading as well as enhance the therapeutic effect of drugs on tumors through a synergistic effect, while reducing their toxic and side effects on normal tissues.
METHODS
Previously, we developed layered smart nanoparticles (NPs) to co-deliver survivin siRNA as well as small molecule drugs for lung cancer. In this study, we used such smart NPs to co-deliver paclitaxel (PTX) and siRNA against vascular endothelial growth factor (VEGF) gene for breast cancer therapy in mice models. For the prepared NPs, characterizations such as particle size, zeta potential, gel electrophoresis imaging and in vitro stability were investigated. Then, 4T1 cells were used to evaluate the in vitro VEGF silencing capacity, tumor cell inhibitory and anti-apoptotic abilities. Finally, an orthotopic model of mouse breast cancer was established to evaluate the in vivo antitumor effects and safety properties of PTX-siRNA-NPs.
RESULTS
We prepared PTX-siRNA-NPs with particle size of 85.25 nm, PDI of 0.261, and zeta potential of 5.25 mV. The NPs with VEGF siRNA effectively knocked down the expression of VEGF mRNA. Cell counting kit-8 (CCK-8) and apoptosis assays revealed that the PTX-siRNA-NPs exhibited antiproliferation effect of PTX on 4T1 cells. The in vivo anti-tumor study indicated that PTX-siRNA-NPs could exert an antitumor effect by inhibiting the formation and development of new blood vessels in tumor tissues, thereby cutting off nutrient and blood supplies required for tumor tissue growth. Both the anti-tumor efficacy and in vivo safety of the PTX-siRNA-NPs group were better than that of the PTX-NPs and siRNA-NPs groups.
CONCLUSION
The combination of PTX and VEGF siRNA exerts good antitumor effect on 4T1 tumor cells. This study provides a theoretical and practical basis for breast cancer therapy.
背景
双载纳米递药系统能够实现化疗药物和小干扰 RNA（siRNA）的共载，通过协同作用增强药物对肿瘤的治疗效果，同时降低其对正常组织的毒性和副作用。
方法
之前，我们开发了层状智能纳米颗粒（NPs）来共递送生存素 siRNA 以及小分子药物用于肺癌治疗。在这项研究中，我们使用这种智能 NPs 共递紫杉醇（PTX）和针对血管内皮生长因子（VEGF）基因的 siRNA 用于乳腺癌的小鼠模型治疗。对所制备的 NPs 进行了粒径、Zeta 电位、凝胶电泳成像和体外稳定性等方面的表征。然后，使用 4T1 细胞评估了体外 VEGF 沉默能力、肿瘤细胞抑制和抗凋亡能力。最后，建立了小鼠乳腺癌原位模型以评估 PTX-siRNA-NPs 的体内抗肿瘤作用和安全性。
结果
我们制备了粒径为 85.25nm、PDI 为 0.261、Zeta 电位为 5.25mV 的 PTX-siRNA-NPs。具有 VEGF siRNA 的 NPs 有效地敲低了 VEGF mRNA 的表达。细胞计数试剂盒-8（CCK-8）和凋亡实验表明，PTX-siRNA-NPs 对 4T1 细胞表现出了 PTX 的增殖抑制作用。体内抗肿瘤研究表明，PTX-siRNA-NPs 通过抑制肿瘤组织中新血管的形成和发展，从而切断肿瘤组织生长所需的营养和血液供应，发挥抗肿瘤作用。PTX-siRNA-NPs 组的抗肿瘤疗效和体内安全性均优于 PTX-NPs 和 siRNA-NPs 组。
结论
PTX 和 VEGF siRNA 的联合对 4T1 肿瘤细胞发挥了良好的抗肿瘤作用。本研究为乳腺癌治疗提供了理论和实践基础。
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