Site-Specific DNA–Doxorubicin Conjugates Display Enhanced Cytotoxicity to Breast Cancer Cells
| Autor: | Christopher H. Stuart, David A. Horita, Michael J. Thomas, Freddie R. Salsbury, Mark O. Lively, William H. Gmeiner |
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| Rok vydání: | 2014 |
| Předmět: |
Magnetic Resonance Spectroscopy
Molecular model media_common.quotation_subject Biomedical Engineering Pharmaceutical Science Breast Neoplasms Bioengineering Article chemistry.chemical_compound Cell Line Tumor polycyclic compounds medicine Humans Doxorubicin Internalization Cytotoxicity media_common Pharmacology Cardiotoxicity Antibiotics Antineoplastic Organic Chemistry DNA 3. Good health Biochemistry chemistry Covalent bond Female Biotechnology Conjugate medicine.drug |
| Zdroj: | Bioconjugate Chemistry |
| ISSN: | 1520-4812 1043-1802 |
| DOI: | 10.1021/bc4005427 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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