Department of Gastrointestinal Colorectal and Anal Surgery, China-Japan Union Hospital, Jilin University, Changchun 130033, China.
Biomater Sci. 2019 Mar 26;7(4):1632-1642. doi: 10.1039/c8bm01385c.
In the present research, a tumor-targeted gene carrier, PPP, was constructed through the modification of phenylboronic acid onto the surface of a polyamidoamine dendrimer, and then miR-34a delivery was employed as a model to evaluate its anti-tumor efficacy. The carrier PPP was identified to possess favorable miR-34a binding and condensation ability and meanwhile protect miR-34a against nuclease degradation. Through confocal laser scanning microscopy and flow cytometry analysis, PPP-mediated cellular uptake of miR-34a was found to proceed through a sialic acid-dependent endocytosis pathway and the nanoparticles could achieve endosome/lysosome escape within 6 h. Further, an anti-proliferative effect could be obtained after PPP/miR-34a transfection through the induction of cell apoptosis. Meanwhile, the inhibition of migration and invasion could be realized through blocking the Notch-1 signaling pathway after PPP/miR-34a treatment. Finally, PPP possessed acceptable safety and inhibited in vivo tumor growth through the in situ apoptosis of tumor sites, which relied on the specific tumor-targeting ability and long circulation time in the blood. In summary, the derivative PPP could be potentially utilized as an efficient carrier for miR-34a delivery to achieve an anti-tumor response in clinical use.
在本研究中，通过将苯硼酸修饰到聚酰胺-胺树枝状大分子的表面，构建了一种肿瘤靶向基因载体 PPP，并将 miR-34a 递送来评估其抗肿瘤功效。载体 PPP 被鉴定具有良好的 miR-34a 结合和凝聚能力，同时能够保护 miR-34a 免受核酸酶的降解。通过共聚焦激光扫描显微镜和流式细胞术分析，发现 PPP 介导的 miR-34a 细胞摄取是通过唾液酸依赖性内吞作用途径进行的，并且纳米颗粒可以在 6 小时内实现内体/溶酶体逃逸。进一步，通过诱导细胞凋亡，PPP/miR-34a 转染后可获得抗增殖作用。同时，通过 PPP/miR-34a 处理阻断 Notch-1 信号通路，可实现迁移和侵袭的抑制。最后，通过原位凋亡肿瘤部位，PPP 具有可接受的安全性并抑制体内肿瘤生长，这依赖于其在血液中的特异性肿瘤靶向能力和长循环时间。总之，该衍生物 PPP 可作为一种有效的 miR-34a 递送载体，有望在临床应用中实现抗肿瘤反应。
