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Cancer Res. 2019 Mar 27. pii: canres.2839.2018. doi: 10.1158/0008-5472.CAN-18-2839. [Epub ahead of print]

Anti-CD24 antibody-nitric oxide conjugate (ANC) selectively and potently suppresses hepatic carcinoma.

Author information

1
School of Life Science & Technology, China Pharmaceutical University.
2
Center of Drug Discovery, China Pharmaceutical University.
3
School of Life Science & Technology, China Pharmaceutical University zhangjuan@cpu.edu.cn.

Abstract

Nitric oxide (NO) has a wide range of potential applications in tumor therapy. However, a targeted delivery system for NO donors has remained elusive, creating a bottleneck that limits its druggability. The antibody-drug conjugate (ADC) is a targeted drug delivery system composed of an antibody linked to an active cytotoxic drug. This design may compensate for the weak targeting ability and various biological functions of the NO donor. In this study, we designed the NO donor HL-2, which had a targeted, cleaved disulfide bond and an attachable maleimide terminal. We conjugated HL-2 with an antibody that targeted CD24 through a thioether bond to generate an ADC-like immunoconjugate, antibody-nitric oxide conjugate (ANC), which we named HN-01. HN-01 showed efficient internalization and significantly increased the release of NO in hepatic carcinoma cells in vitro. HN-01 induced apoptosis of tumor cells and suppressed tumor growth in hepatic carcinoma-bearing nude mice through antibody-dependent co-toxicity; HN-01 also increased NO levels in tumor cells. Collectively, this study expands the concept of ADC and provides an innovative NO donor and ANC to address current challenges in targeted delivery of NO. This new inspiration for an ANC design can also be used in future studies for other molecules with intracellular targets.

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