Towards (99m)Tc-based imaging agents with effective doxorubicin mimetics: a molecular and cellular study
S Imstepf1, V Pierroz2, P Raposinho3
1Department of Chemistry, University of Zurich, Winterthurerstrasse 190, CH-8057 Zurich, Switzerland.
Abstract:
Doxorubicin is a clinical benchmark drug, which is applied in the treatment of numerous cancers. Known for its accumulation in the nucleus and ability to intercalate into DNA, it targets quickly dividing i.e. hypermitotic cells. Through this mechanism, it could be an ideal structural motif for a new class of imaging agents, given that the new entity approximates the in vitro profile of the parent drug. Here we describe design, synthesis and biological activity of a small array of Doxorubicin-metalloconjugates (M = (99m)Tc, Re). We demonstrate that the conjugates preferably accumulate in the nuclear compartment, tightly bind to DNA and retain an appreciable cytotoxicity. Moreover, the Re conjugates effectively act as inhibitors of the human Topoisomerase II enzyme, which is the widely accepted mechanism of action of the parent drug. Since the conjugates effectively mimic the in vitro behavior of native Doxorubicin, the (99m)Tc compounds are prospective imaging agents.
Insights
Researchers developed Doxorubicin-metalloconjugates for cancer imaging and therapy. These new compounds target cancer cell DNA, showing potent anti-cancer activity and potential as diagnostic imaging agents.
Area of Science:
- Oncology
- Radiochemistry
- Molecular Biology
Background:
- Doxorubicin is a widely used chemotherapy drug targeting DNA in hypermitotic cancer cells.
- Its nuclear accumulation and DNA intercalation suggest potential for novel imaging agents.
Purpose of the Study:
- To design, synthesize, and evaluate Doxorubicin-metalloconjugates for cancer applications.
- To assess their DNA binding, cytotoxicity, and potential as imaging agents.
Main Methods:
- Synthesis of Doxorubicin-metalloconjugates with technetium-99m (99mTc) and rhenium (Re).
- In vitro evaluation of nuclear accumulation, DNA binding, cytotoxicity, and Topoisomerase II inhibition.
Main Results:
- Conjugates showed preferential nuclear accumulation and tight DNA binding.
- Doxorubicin-metalloconjugates retained significant cytotoxicity.
- Rhenium conjugates inhibited human Topoisomerase II, mimicking Doxorubicin's action.
Conclusions:
- Doxorubicin-metalloconjugates effectively mimic Doxorubicin's in vitro profile.
- 99mTc conjugates are promising candidates for nuclear imaging agents.
- Re conjugates show therapeutic potential through Topoisomerase II inhibition.
