Cancer Science | |
Enhanced antitumor effect of anti‐tissue factor antibody‐conjugated epirubicin‐incorporating micelles in xenograft models | |
Yoshiyuki Yamamoto1  Ichinosuke Hyodo2  Yoshikatsu Koga1  Ryo Tsumura1  Ryuta Sato1  Toshihumi Obonai1  Hirobumi Fuchigami1  Fumiaki Furuya1  Masahiro Yasunaga1  Mitsunori Harada3  Yasuki Kato3  Atsushi Ohtsu4  | |
[1] Division of Developmental Therapeutics, Research Center for Innovative Oncology, National Cancer Center Hospital East, Kashiwa, Japan;Department of Gastroenterology and Hepatology, Institute of Clinical Medicine, Graduate School of Comprehensive Human Sciences, University of Tsukuba, Tsukuba, Japan;Research Division, NanoCarrier Co. Ltd., Kashiwa, Japan;Exploratory Oncology Research and Clinical Trial Center, National Cancer Center, Tokyo, Japan | |
关键词: Antibody drug conjugate; drug delivery system; epirubicin; polymeric micelles; tissue factor; | |
DOI : 10.1111/cas.12645 | |
来源: Wiley | |
【 摘 要 】
For the creation of a successful antibody–drug conjugate (ADC), both scientific and clinical evidence has indicated that highly toxic anticancer agents (ACA) should be conjugated to a monoclonal antibody (mAb) to administer a reasonable amount of ADC to patients without compromising the affinity of the mAb. For ordinary ACA, the conjugation of a mAb to ACA-loaded micellar nanoparticles is clinically applicable. Tissue factor (TF) is often overexpressed in various cancer cells and tumor vascular endothelium. Accordingly, anti-TF-NC-6300, consisting of epirubicin-incorporating micelles (NC-6300) conjugated with the F(ab')2 of anti-TF mAb was developed. The in vitro and in vivo efficacy and pharmacokinetics of anti-TF-NC-6300 were compared to NC-6300 using two human pancreatic cancer cell lines, BxPC3 (high TF expression) and SUIT2 (low TF expression), and a gastric cancer cell line, 44As3 (high TF expression). The intracellular uptake of epirubicin was faster and greater in BxPC3 cells treated with anti-TF-NC-6300, compared with NC-6300. Anti-TF-NC-6300 showed a superior antitumor activity in BxPC3 and 44As3 xenografts, compared with NC-6300, while the activities of both micelles were similar in the SUIT2 xenograft. A higher tumor accumulation of anti-TF-NC-6300 compared to NC-6300 was seen, regardless of the TF expression levels. However, anti-TF-NC-6300 appeared to be localized to the tumor cells with high TF expression. These results indicated that the enhanced antitumor effect of anti-TF-NC6300 may be independent of the tumor accumulation but may depend on the selective intratumor localization and the preferential internalization of anti-TF-NC-6300 into high TF tumor cells.Abstract
【 授权许可】
CC BY-NC-ND
© 2015 The Authors. Cancer Science published by Wiley Publishing Asia Pty Ltd on behalf of Japanese Cancer Association.
Creative Commons Attribution-NonCommercial-NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made.
【 预 览 】
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