A conjugate of an anti-midkine single-chain variable fragment to doxorubicin inhibits tumor growth

Brazilian Journal of Medical and Biological Research

Shuli Zhao¹  Guangfeng Zhao¹  Hao Xie¹  Yahong Huang¹  Yayi Hou¹ 

[1] ,Medical School & State Key Laboratory of Pharmaceutical Biotechnology Immunology and Reproductive Biology Laboratory Nanjing,China

关键词: Single-chain variable fragments;    Midkine;    Tumor targeting;    Doxorubicin;   

DOI  :  10.1590/S0100-879X2012007500009

来源: SciELO

【 摘 要 】

Doxorubicin (DOX) was conjugated to a single-chain variable fragment (scFv) against human midkine (MK), and the conjugate (scFv-DOX) was used to target the chemotherapeutic agent to a mouse solid tumor model in which the tumor cells expressed high levels of human MK. The His-tagged recombinant scFv was expressed in bacteria, purified by metal affinity chromatography, and then conjugated to DOX using oxidative dextran (Dex) as a linker. The molecular formula of this immunoconjugate was scFv(Dex)1.3(DOX)20. In vitro apoptosis assays showed that the scFv-DOX conjugate was more cytotoxic against MK-transfected human adenocarcinoma cells (BGC823-MK) than untransfected cells (55.3 ± 2.4 vs 22.4 ± 3.8%) for three independent experiments. Nude mice bearing BGC823-MK solid tumors received scFv-DOX or equivalent doses of scFv + DOX for 2 weeks and tumor growth was more effectively inhibited by the scFv-DOX conjugate than by scFv + DOX (51.83% inhibition vs 40.81%). Histological analysis of the tumor tissues revealed that the highest levels of DOX accumulated in tumors from mice treated with scFv-DOX and this resulted in more extensive tumor cell death than in animals treated with the equivalent dose of scFv + DOX. These results show that the scFv-DOX conjugate effectively inhibited tumor growth in vivo and suggest that antigen-specific scFv may be competent drug-carriers.

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