Lee, Sungjin Ahn, Hyung Jun 2024-01-19T20:01:43Z 2024-01-19T20:01:43Z 2021-09-02 2019-06 1742-7061 https://pubs.kist.re.kr/handle/201004/119940 Adeno-associated virus (AAV) is a promising vector for systemic delivery of siRNA because of its long-term expression ability without immunogenicity and pathogenicity. However, its broad host tropism and lack of tissue specificity have limited clinical applications such as cancer therapy. Therefore, redirecting the natural tropism of AAV vectors to unique cell surface antigens is an important requirement for in vivo RNAi-based cancer therapy. To use the overexpression property of epithelial cell adhesion molecule (EpCAM) in specific cancer types, we herein created anti-EpCAM antibody-conjugated AAV serotype 2 (AAV2) vectors through a streptavidin-biotin bridge. Upon intravenous injection, anti-EpCAM-conjugated AAV2 vectors showed prominent tumor-specific accumulation in EpCAM-positive tumor bearing mice without undesirable sequestration in liver. In addition, when loaded with transgenes to express shRNA against epidermal growth factor receptor (EGFR), systemically injected anti-EpCAM-conjugated AAV2/shEGFR vectors induced significant downregulation of EGFR expression in tumors and eventually suppressed tumor growth even at the long dosing interval of two weeks. This in vivo antitumor effect represents the increased infection efficacy of tropism-modified AAV2 vectors and prolonged expression of EGFR shRNA in tumor tissues. Thus, this study suggests the great potential of anti-EpCAM-conjugated AAV2/shEGFR vectors as RNAi-based cancer therapeutics. Statement of Significance Adeno-associated virus (AAV) is a promising vector for systemic delivery of siRNA, but its broad host tropism has limited clinical applications. By using the overexpression property of epithelial cell adhesion molecule (EpCAM) on tumors, we demonstrate that anti-EpCAM-conjugated AAV2 vectors through a streptavidin-biotin bridge are redirected to EpCAM-positive tumors in vivo. In addition, when loaded with transgenes to express shRNA against epidermal growth factor receptor (EGFR), systemically injected anti-EpCAM-conjugated AAV2/shEGFR vectors significantly downregulate EGFR expression in tumors, eventually suppressing tumor growth for long periods. We herein suggest the potential of anti-EpCAM-AAV2/shEGFR vectors as an antitumor agent. Furthermore, redirection of AAV2 infection through EpCAM would provide a powerful means for systemic delivery of short hairpin RNA to tumor sites. (C) 2019 Acta Materialia Inc. Published by Elsevier Ltd. All rights reserved. English ELSEVIER SCI LTD GROWTH-FACTOR RECEPTOR IMMUNE-RESPONSES VIRAL VECTORS THERAPEUTIC TARGET GENE-EXPRESSION BREAST-CANCER AAV VECTORS HEMOPHILIA ADENOVIRUS BIOLOGY Anti-EpCAM-conjugated adeno-associated virus serotype 2 for systemic delivery of EGFR shRNA: Its retargeting and antitumor effects on OVCAR3 ovarian cancer in vivo Article 10.1016/j.actbio.2019.04.044 1 ACTA BIOMATERIALIA, v.91, pp.258 - 269 ACTA BIOMATERIALIA 91 258 269 scie scopus 000470053700021 2-s2.0-85064709072 Engineering, Biomedical Materials Science, Biomaterials Engineering Materials Science Article GROWTH-FACTOR RECEPTOR IMMUNE-RESPONSES VIRAL VECTORS THERAPEUTIC TARGET GENE-EXPRESSION BREAST-CANCER AAV VECTORS HEMOPHILIA ADENOVIRUS BIOLOGY AAV2 vector Systemic delivery of siRNA Tumor-specific targeting Redirected tropism Antitumor effect Long-term silencing