Site-Specific DNA–Doxorubicin Conjugates Display
Enhanced Cytotoxicity to Breast Cancer Cells
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Abstract
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. Herein, we
describe selective conjugation of Dox to a single site in a DNA hairpin
resulting in a highly stable complex that enables Dox to be used more
effectively. Selective conjugation of Dox to G15 in the hairpin loop
was verified using site-specific labeling with [2-<sup>15</sup>N]-2′-deoxyguanosine
in conjunction with [<sup>1</sup>H–<sup>15</sup>N] 2D NMR,
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 noncovalent 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 for safer and
more effective chemotherapy with Dox and this conjugation strategy
can be expanded to include additional anticancer drugs