Efficient miRNA Inhibitor with GO-PEI Nanosheets for Osteosarcoma Suppression by Targeting PTEN

Abstract

Lingling Ou,1 Haiyingjie Lin,2 Yuwei Song,1 Guoqiang Tan,1 Xiujuan Gui,1 Jinyuan Li,1 Xiaoting Chen,3 Zhendong Deng,3 Shaoqiang Lin1,3 1Department of Stomatology, The First Affiliated Hospital of Jinan University, Guangzhou 510632, People’s Republic of China; 2Department of Orthopedics, The Third Affiliated Hospital, Southern Medical University, Guangzhou 510630, People’s Republic of China; 3Integrated Traditional and Western Medicine Research Center of the First Affiliated Hospital of Guangdong Pharmaceutical University, Guangzhou 510000, People’s Republic of ChinaCorrespondence: Lingling OuThe First Affiliated Hospital of Jinan University, No. 613 West Huangpu Avenue, Guangzhou 510632, People’s Republic of ChinaEmail [email protected] LinIntegrated Traditional and Western Medicine Research Center of the First Affiliated Hospital of Guangdong Pharmaceutical University, No. 19 Nonglinxia Road, Guangzhou 510000, People’s Republic of ChinaEmail [email protected]: Gene therapy is considered a novel way to treat osteosarcoma, and microRNAs are potential therapeutic targets for osteosarcoma. miR-214 has been found to promote osteosarcoma aggression and metastasis. Graphene oxide (GO) is widely used for gene delivery for the distinct physiochemical properties and minimal cytotoxicity.Methods: Polyethyleneimine (PEI)-functionalized GO complex was well-prepared and loaded with miR-214 inhibitor at different concentrations. The load efficacy was tested by gel retardation assay and the cy3-labeled fluorescence of cellular uptake. The experiments of wound healing, immunofluorescence staining, Western blot, qRT-PCR and immunohistochemical staining were performed to measure the inhibitory effect of the miR-214 inhibitor systematically released from the complexes against MG63, U2OS cells and xenograft tumors.Results: The systematic mechanistic elucidation of the efficient delivery of the miR-214 inhibitor by GO-PEI indicated that the inhibition of cellular miR-214 caused a decrease in osteosarcoma cell invasion and migration and an increase in apoptosis by targeting phosphatase and tensin homolog (PTEN). The synergistic combination of the GO-PEI-miR-214 inhibitor and CDDP chemotherapy showed significant cell death. In a xenograft mouse model, the GO-PEI-miR-214 inhibitor significantly inhibited tumor volume growth.Conclusion: This study indicates the potential of functionalized GO-PEI as a vehicle for miRNA inhibitor delivery to treat osteosarcoma with low toxicity and miR-214 can be a good target for osteosarcoma therapy.Keywords: osteosarcoma, GO-PEI-miR-214 inhibitor, tumor suppression

Keywords

• osteosarcoma
• go-pei-mir-214 inhibitor
• tumor suppression