Chen Wenqi, Liu Yong, Liang Xiao, Huang Yu, Li Quanshun
Key Laboratory for Molecular Enzymology and Engineering of Ministry of Education, School of Life Sciences, Jilin University, Changchun 130012, China.
Key Laboratory for Molecular Enzymology and Engineering of Ministry of Education, School of Life Sciences, Jilin University, Changchun 130012, China.
Acta Biomater. 2017 Jul 15;57:238-250. doi: 10.1016/j.actbio.2017.05.030. Epub 2017 May 13.
Chondroitin sulfate (CS) was modified on a polyamidoamine dendrimer (PAMAM) through Michael addition to construct a tumor-targeted carrier CS-PAMAM for miR-34a delivery. The derivative CS-PAMAM was demonstrated to achieve an efficient cellular uptake of miR-34a in a CD44-dependent endocytosis way and further facilitate the endosomal escape of miR-34a after 4h. Through the miR-34a delivery, obvious inhibition of cell proliferation could be detected which was attributed to the enhancement of cell apoptosis and cell cycle arrest, and meanwhile the cell migration and invasion has been observed to be inhibited. Finally, the intravenous injection of CS-PAMAM/miR-34a formulation into mice bearing human lung adenocarcinoma cell A549 xenografts could efficiently inhibit the tumor growth and induce the tumor apoptosis owing to the enhanced accumulation of miR-34a in tumor tissue. Overall, CS-PAMAM is potential to be used as a tumor-targeted oligonucleotide carrier for achieving tumor gene therapy.
The cationic dendrimer PAMAM was modified by chondroitin sulfate (CS) through Michael addition to construct a tumor-targeted carrier CS-PAMAM for miR-34a delivery. The introduction of CS could achieve an efficient cellular uptake and intracellular transfection of miR-34a in a CD44-dependent endocytosis manner. The miR-34a delivery could execute the anti-proliferation activity by simultaneously inducing cell apoptosis and cell cycle arrest, and also the anti-migration activity. The CS-PAMAM-mediated systemic delivery of miR-34a showed significant inhibition of tumor growth and induction of tumor apoptosis using a mice model of subcutaneously implanted tumors.
通过迈克尔加成反应在聚酰胺胺树枝状大分子（PAMAM）上修饰硫酸软骨素（CS），构建用于递送miR-34a的肿瘤靶向载体CS-PAMAM。经证实，衍生物CS-PAMAM以CD44依赖的内吞作用方式实现了miR-34a的高效细胞摄取，并在4小时后进一步促进了miR-34a从内体中逃逸。通过递送miR-34a，可检测到明显的细胞增殖抑制，这归因于细胞凋亡的增强和细胞周期停滞，同时还观察到细胞迁移和侵袭受到抑制。最后，将CS-PAMAM/miR-34a制剂静脉注射到携带人肺腺癌细胞A549异种移植瘤的小鼠体内，由于miR-34a在肿瘤组织中的积累增加，可有效抑制肿瘤生长并诱导肿瘤凋亡。总体而言，CS-PAMAM有潜力用作肿瘤靶向寡核苷酸载体，以实现肿瘤基因治疗。
通过迈克尔加成反应，用硫酸软骨素（CS）修饰阳离子树枝状大分子PAMAM，构建用于递送miR-34a的肿瘤靶向载体CS-PAMAM。CS的引入能够以CD44依赖的内吞作用方式实现miR-34a的高效细胞摄取和细胞内转染。递送miR-34a可通过同时诱导细胞凋亡和细胞周期停滞来发挥抗增殖活性，还具有抗迁移活性。使用皮下植入肿瘤的小鼠模型，CS-PAMAM介导的miR-34a全身递送显示出对肿瘤生长的显著抑制和肿瘤凋亡的诱导作用。
