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

• Published in: Bioactive materials 2023-10, Vol.28, p.376-385
• Main Authors: 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
• Format: Article
• Language: English
• Subjects: Gene therapy; Nanoparticle; Nucleic acid delivery; Osteosarcoma; Patient-Derived Xenograft (PDX); Responsive
• ISSN: 2452-199X; 2452-199X
• DOI: 10.1016/j.bioactmat.2023.05.012

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. [Display omitted] •A kind of disulfide bond-based hydroxyl-rich polymeric nanoparticles (TC) was successfully prepared via one-pot ring-opening method.•TC-mediated delivery of miR-22 therapeutic system could effectively treat osteosarcoma both in vitro and in PDX models.•The mechanism of TC/miR-22/Volasertib in treating osteosarcoma may be inhibition of PI3K/AKT pathway.