发明名称 |
SITE-SPECIFIC DNA-DOXORUBICIN CONJUGATES DISPLAY ENHANCED CYTOTOXICITY TO BREAST CANCER CELLS |
摘要 |
Doxorubicin (Dox) is widely used for breast cancer treatment but causes serious side- effects including cardiotoxicity that may adversely impact patient lifespan even if treatment is successful. The present invention relates to selective conjugation of Dox to a single site in a DNA hairpin resulting in a highly stable complex that enables Dos to be used more effectively. Selective conjugation of Dox to G15 in the hairpin loop was verified using site-specific labeling with [2- 15N3-2'-deoxyguanosme in conjunction with [1 H-15NJ 2D NM R while 1:1 stoichiometry for the conjugate was validated by ESI-QTOF mass spectrometry and UV spectroscopy. Molecular modeling indicated covalently bound Dox also intercalated into the stem of the hairpin and stability studies demonstrated the resulting Dox-conjugated hairpin (DCH) complex had a half-life > 30 h, considerably longer than alternative covalent and non- covalent complexes. Secondary conjugation of DCH with folic acid (FA) resulted in increased internalization into breast cancer cells. The dual conjugate, DCH-FA, can be used tor safer and more effective chemotherapy with Dox and this conjugation strategy can be expanded to include additional anti-cancer drugs. |
申请公布号 |
WO2015120112(A1) |
申请公布日期 |
2015.08.13 |
申请号 |
WO2015US14549 |
申请日期 |
2015.02.05 |
申请人 |
WAKE FOREST UNIVERSITY |
发明人 |
LIVELY, MARK, O.;GMEINER, WILLIAM, H.;SALSBURY, FREDDIE, R.;STUART, CHRIS, H. |
分类号 |
A61K48/00;A61K38/00;A61P35/00 |
主分类号 |
A61K48/00 |
代理机构 |
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