Chen Dafu, Lei Chengyue, Liu Weifeng, Shao Meiyu, Sun Meizhou, Guo Jianxun, Cao Jingjing, Nie Jing-Jun, Luo Peng, Luo Yuwen, Yu Bingran, Wang Renxian, Duan Shun, Xu Fu-Jian
Laboratory of Bone Tissue Engineering, Beijing Laboratory of Biomedical Materials, National Center for Orthopaedics, Beijing Research Institute of Traumatology and Orthopaedics, Beijing Jishuitan Hospital, Beijing, 100035, China.
State Key Laboratory of Chemical Resource Engineering, Key Lab of Biomedical Materials of Natural Macromolecules (Beijing University of Chemical Technology), Ministry of Education, Beijing Laboratory of Biomedical Materials, Beijing University of Chemical Technology, Beijing, 100029, China.
Bioact Mater. 2023 Jun 12;28:376-385. doi: 10.1016/j.bioactmat.2023.05.012. eCollection 2023 Oct.
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 . 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.
微小RNA（miRNAs）是基因表达的重要调节因子，在包括骨肉瘤在内的癌症发展过程中发挥关键作用。在骨肉瘤发展过程中，miR-22的表达显著下调，这使得miR-22成为一种有前景的抗骨肉瘤治疗靶点。为了设计并制备能将miR-22有效递送至骨肉瘤细胞的载体，本研究开发了一种富含羟基的还原响应型阳离子聚合物纳米颗粒TGIC-CA（TC），它还增强了沃拉替尼对骨肉瘤的治疗效果。TC通过一锅法由氨基和环氧基团之间的开环反应制备而成，其与核酸具有良好的络合能力、还原响应性降解能力及基因转染性能。TC/miR-22与沃拉替尼联合使用可抑制骨肉瘤细胞的增殖、迁移并促进其凋亡。其抗肿瘤机制表明，TC/miR-22和沃拉替尼可协同抑制PI3K/Akt信号通路。此外，该策略在原位骨肉瘤动物模型中表现出出色的肿瘤抑制性能，尤其是在患者来源的化疗耐药和化疗不耐受的患者来源异种移植（PDX）模型中，降低了肿瘤肺转移风险并克服了耐药性。因此，通过使用阳离子纳米载体结合非传统化疗药物局部、持续递送miR-22的策略，在有效治疗骨肉瘤转移和耐药方面具有巨大潜力。
