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Live-fibroblast IR imaging of a cytoprotective PhotoCORM Activated with Visible Light
Fabio Zobi1, Luca Quaroni, Giuseppe Santoro
1Institute of Inorganic Chemistry, University of Zürich , Winterthurerstrasse 190, CH-8057 Zürich, Switzerland.
Abstract:
Carbon monoxide releasing molecules (CORMs) are an emerging class of pharmaceutical compounds currently evaluated in several preclinical disease models. There is general consensus that the therapeutic effects elicited by the molecules may be directly ascribed to the biological function of the released CO. It remains unclear, however, if cellular internalization of CORMs is a critical event in their therapeutic action. To address the problem of cellular delivery, we have devised a general strategy which entails conjugation of a CO-releasing molecule (here a photoactivated CORM) to the 5'-OH ribose group of vitamin B12. Cyanocobalamin (B12) functions as the biocompatible water-soluble scaffold which actively transports the CORM against a concentration gradient into the cells. The uptake and cellular distribution of this B12-photoCORM conjugate is demonstrated via synchrotron FTIR spectromicroscopy measurements on living cells. Intracellular photoinduced CO release prevents fibroblasts from dying under conditions of hypoxia and metabolic depletion, conditions that may occur in vivo during insufficient blood supply to oxygen-sensitive tissues such as the heart or brain.
Insights
Researchers developed a novel vitamin B12-conjugated carbon monoxide releasing molecule (CORM) for enhanced cellular delivery. This strategy improves therapeutic potential by ensuring intracellular delivery of CO for treating conditions like hypoxia.
Area of Science:
- Biomedical Sciences
- Pharmacology
- Cell Biology
Background:
- Carbon monoxide releasing molecules (CORMs) show therapeutic promise, with effects attributed to released carbon monoxide (CO).
- The necessity of CORM cellular internalization for therapeutic efficacy remains uncertain.
- Efficient cellular delivery is crucial for maximizing CORM therapeutic potential.
Purpose of the Study:
- To investigate the role of cellular uptake in CORM-mediated therapeutic effects.
- To develop a novel strategy for targeted cellular delivery of CORMs.
- To assess the therapeutic efficacy of a vitamin B12-conjugated CORM under hypoxic conditions.
Main Methods:
- Conjugation of a photoactivated CORM to the 5'-OH ribose group of vitamin B12 (cyanocobalamin).
- Utilizing vitamin B12 as a biocompatible scaffold for active cellular transport.
- Employing synchrotron FTIR spectromicroscopy to track cellular uptake and distribution of the B12-photoCORM conjugate in living cells.
Main Results:
- Demonstrated successful cellular internalization and distribution of the B12-photoCORM conjugate.
- Confirmed intracellular photoinduced CO release from the conjugate.
- Showed that intracellular CO release protected fibroblasts from cell death under hypoxia and metabolic depletion.
Conclusions:
- Vitamin B12 serves as an effective scaffold for delivering CORMs into cells.
- Targeted intracellular delivery of CO via B12-CORMs can protect cells from hypoxic injury.
- This approach holds potential for treating conditions involving insufficient blood supply to tissues like the heart and brain.
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