骨肉瘤
癌症研究
纳米载体
PI3K/AKT/mTOR通路
小RNA
转移
蛋白激酶B
PTEN公司
化学
细胞凋亡
医学
癌症
药理学
药品
内科学
生物化学
基因
作者
Dafu Chen,Chengyue Lei,Weifeng Liu,Meiyu Shao,Meizhou Sun,Jianxun Guo,Jingjing Cao,Jing‐Jun Nie,Peng Luo,Yuqi Luo,Bingran Yu,Renxian Wang,Shun Duan,Fu‐Jian Xu
标识
DOI:10.1016/j.bioactmat.2023.05.012
摘要
miRNAs are important regulators of gene expression and play key roles in the development of cancer, including osteosarcoma. During the development of osteosarcoma, the expression of miR-22 is significantly downregulated, making miR-22 as a promising therapeutic target against osteosarcoma. To design and fabricate efficient delivery carriers of miR-22 into osteosarcoma cells, a hydroxyl-rich reduction-responsive cationic polymeric nanoparticle, TGIC-CA (TC), was developed in this work, which also enhanced the therapeutic effects of Volasertib on osteosarcoma. TC was prepared by the ring-opening reaction between amino and epoxy groups by one-pot method, which had the good complexing ability with nucleic acids, reduction-responsive degradability and gene transfection performance. TC/miR-22 combined with volasertib could inhibit proliferation, migration and promote apoptosis of osteosarcoma cells in vitro. The anti-tumor mechanisms were revealed as TC/miR-22 and volasertib could inhibit the PI3K/Akt signaling pathway synergistically. Furthermore, this strategy showed outstanding tumor suppression performance in animal models of orthotopic osteosarcoma, especially in patient-derived chemo-resistant and chemo-intolerant patient-derived xenograft (PDX) models, which reduced the risk of tumor lung metastasis and overcame drug resistance. Therefore, it has great potential for efficient treatment of metastasis and drug resistance of osteosarcoma by the strategy of localized, sustained delivery of miR-22 using the cationic nanocarriers combined with non-traditional chemotherapy drugs.
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