Reduction-responsive nucleic acid nanocarrier-mediated miR-22 inhibition of PI3K/AKT pathway for the treatment of patient-derived tumor xenograft osteosarcoma

作     者：Dafu Chen Chengyue Lei Weifeng Liu Meiyu Shao Meizhou Sun Jianxun Guo Jingjing Cao Jing-Jun Nie Peng Luo Yuwen Luo Bingran Yu Renxian Wang Shun Duan Fu-Jian Xu 

作者机构：Laboratory of Bone Tissue EngineeringBeijing Laboratory of Biomedical MaterialsNational Center for OrthopaedicsBeijing Research Institute of Traumatology and OrthopaedicsBeijing Jishuitan HospitalBeijing100035China State Key Laboratory of Chemical Resource EngineeringKey Lab of Biomedical Materials of Natural Macromolecules(Beijing University of Chemical Technology)Ministry of EducationBeijing Laboratory of Biomedical MaterialsBeijing University of Chemical TechnologyBeijing100029China Department of Orthopaedic Oncology SurgeryBeijing Jishuitan HospitalPeking UniversityBeijing100035China JST Sarcopenia Research CentreBeijing Research Institute of Traumatology and OrthopaedicsBeijing Jishuitan HospitalBeijing100035China 

出 版 物：《Bioactive Materials》 (生物活性材料（英文）)

年 卷 期：2023年第28卷第10期

页      面：376-385页

核心收录：

学科分类：1002[医学-临床医学] 100214[医学-肿瘤学] 10[医学] 

基　　金：supported by National Natural Science Foundation of China(Grant Nos.51973021,52221006,52173275,51932002 and 51903013) Beijing Municipal Health Commission(BJRITO-RDP-2023,PXM 2020_026275_000002 and BMHC-2021-6) National Key Research and Development Program(Grant No.2021YFC2400500) Beijing Jishuitan Hospital Nova Program(Grant Nos.XKXX202115 and XKXX202114) Beijing Outstanding Young Scientist Program(Grant No.BJJWZYJH01201910010024) 

主　　题：Nucleic acid delivery Nanoparticle Gene therapy Osteosarcoma Responsive Patient-Derived Xenograft(PDX) 

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.