School of Chinese Medicine
Tumor cell-targeted delivery of CRISPR/Cas9 by aptamer-functionalized lipopolymer for therapeutic genome editing of VEGFA in osteosarcoma
Osteosarcoma (OS) is a highly aggressive pediatric cancer, characterized by frequent lung metastasis and pathologic bone destruction. Vascular endothelial growth factor A (VEGFA), highly expressed in OS, not only contributes to angiogenesis within the tumor microenvironment via paracrine stimulation of vascular endothelial cells, but also acts as an autocrine survival factor for tumor cell themselves, thus making it a promising therapeutic target for OS. CRISPR/Cas9 is a versatile genome editing technology and holds tremendous promise for cancer treatment. However, a major bottleneck to achieve the therapeutic potential of the CRISPR/Cas9 is the lack of in vivo tumor-targeted delivery systems. Here, we screened an OS cell-specific aptamer (LC09) and developed a LC09-functionalized PEG-PEI-Cholesterol (PPC) lipopolymer encapsulating CRISPR/Cas9 plasmids encoding VEGFA gRNA and Cas9. Our results demonstrated that LC09 facilitated selective distribution of CRISPR/Cas9 in both orthotopic OS and lung metastasis, leading to effective VEGFA genome editing in tumor, decreased VEGFA expression and secretion, inhibited orthotopic OS malignancy and lung metastasis, as well as reduced angiogenesis and bone lesion with no detectable toxicity. The delivery system simultaneously restrained autocrine and paracrine VEGFA signaling in tumor cells and could facilitate translating CRISPR-Cas9 into clinical cancer treatment.
Osteosarcoma, CRISPR/Cas9, VEGFA, Aptamer, In vivo delivery
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© 2017 Published by Elsevier Ltd.
This study was supported by the Ministry of Science and Technology of China (2013ZX09301307 to A.L.), the Hong Kong General Research Fund (HKBU479111 to G.Z., HKBU478312 to G.Z., HKBU262913 to G.Z., HKBU12102914 to G.Z., HKBU261113 to A.L. HKBU212111 to H.Z., HKBU212613 to H.Z., CUHK14112915 to B.Z. and CUHK489213 to B.Z.), the Natural Science Foundation Council of China (81272045 to G.Z., 81703049 to F.L., 81272045 to B.G., 81401833 to B.G. and 81470072 to X.H.), the Research Grants Council and Natural Science Foundation Council of China (N_HKBU435/12 to G.Z.), the Croucher Foundation (Gnt#CAS14BU/CAS14201 to G.Z.), the Interdisciplinary Research Matching Scheme (IRMS) of Hong Kong Baptist University (RC-IRMS/12-13/02 to A.L., RC-IRMS/13-14/02 to G.Z. and RC-IRMS/15-16/01 to A.L.), the Hong Kong Baptist University Strategic Development Fund (SDF13-1209-P01 to A.L.), the Hong Kong Research Grants Council Early Career Scheme (489213 to G.Z.), the Inter-institutional Collaborative Research Scheme of Hong Kong Baptist University (RC-ICRS/14-15/01 to G.Z.), the Faculty Research Grant of Hong Kong Baptist University (FRG1/13-14/024 to G.Z., FRG2/13-14/006 to G.Z., FRG2/14-15/010 to G.Z. and FRG2/14-15/063 to H.Z.), the China Academy of Chinese Medical Sciences (Z0252 and Z0293 to A.L.), Science and Technology Innovation Commission of Shenzhen Municipality Funds (JCYJ20170307161659648 to F. L.).
Link to Publisher's Edition
Liang, Chao, Fangfei Li, Luyao Wang, Zong-Kang Zhang, Chao Wang, Bing He, Jie Li, Zhihao Chen, Atik Badshah Shaikh, Jin Liu, Xiaohao Wu, Songlin Peng, Lei Dang, Baosheng Guo, Xiaojuan He, D. W. T. Au, Cheng Lu, Hai Long Zhu, Bao-Ting Zhang, Aiping Lu, and Ge Zhang. "Tumor cell-targeted delivery of CRISPR/Cas9 by aptamer-functionalized lipopolymer for therapeutic genome editing of VEGFA in osteosarcoma." Biomaterials (2017).