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Targeting potassium channels for increasing delivery of imaging agents and therapeutics to brain tumors
Divya Khaitan1, Nagendra S Ningaraj
1Department of Molecular Oncology Research, Scintilla Academy for Applied Sciences' Research and Education Bangalore, Karnataka, India.
Abstract:
Every year in the US, 20,000 new primary and nearly 200,000 metastatic brain tumor cases are reported. The cerebral microvessels/capillaries that form the blood-brain barrier not only protect the brain from toxic agents in the blood but also pose a significant hindrance to the delivery of small and large therapeutic molecules. Different strategies have been employed to circumvent the physiological barrier posed by blood-brain tumor barrier (BTB). Studies in our laboratory have identified significant differences in the expression levels of certain genes and proteins between normal and brain tumor capillary endothelial cells (ECs). In this study, we validated the non-invasive and clinically relevant dynamic contrast enhancing-magnetic resonance imaging (DCE-MRI) method with invasive, clinically irrelevant but highly accurate quantitative autoradiography method using rat glioma model. We also showed that DCE-MRI metric of tissue vessel perfusion-permeability is sensitive to changes in blood vessel permeability following administration of calcium-activated potassium (BKCa) channel activator NS-1619. Our results show that human gliomas and brain tumor ECs that overexpress BKCa channels can be targeted for increased BTB permeability for MRI enhancing agents to brain tumors. We conclude that monitoring the outcome of increased MRI enhancing agents' delivery to microsatellites and leading tumor edges in glioma patients would lead to beneficial clinical outcome.
Insights
Targeting brain tumors involves overcoming the blood-brain barrier (BBB). This study shows that dynamic contrast-enhancing MRI can track increased drug delivery to brain tumors by targeting specific channels, improving treatment outcomes.
Area of Science:
- Neuro-oncology
- Medical imaging
- Molecular biology
Background:
- Brain tumors pose significant therapeutic challenges due to the blood-brain barrier (BBB), hindering drug delivery.
- The blood-brain tumor barrier (BTB) presents a major obstacle for effective treatment of primary and metastatic brain tumors.
- Differences in gene and protein expression between normal and brain tumor endothelial cells offer potential therapeutic targets.
Purpose of the Study:
- To validate dynamic contrast-enhancing magnetic resonance imaging (DCE-MRI) as a non-invasive method to assess blood-brain tumor barrier (BTB) permeability.
- To investigate the effect of calcium-activated potassium (BKCa) channel activators on BTB permeability in a rat glioma model.
- To explore the potential of targeting BKCa channels for enhanced delivery of MRI contrast agents to brain tumors.
Main Methods:
- Validation of DCE-MRI against quantitative autoradiography in a rat glioma model.
- Assessment of DCE-MRI's sensitivity to changes in blood vessel permeability after NS-1619 administration.
- Analysis of BKCa channel expression in human gliomas and brain tumor endothelial cells.
Main Results:
- DCE-MRI accurately reflects tissue vessel perfusion-permeability, comparable to quantitative autoradiography.
- DCE-MRI metrics demonstrated sensitivity to altered blood vessel permeability induced by the BKCa channel activator NS-1619.
- Human gliomas and brain tumor endothelial cells show BKCa channel overexpression, suggesting a target for enhanced permeability.
Conclusions:
- Targeting BKCa channels can increase BTB permeability, facilitating the delivery of MRI contrast agents to brain tumors.
- DCE-MRI can monitor enhanced delivery of contrast agents to tumor sites, potentially improving therapeutic outcomes.
- This approach offers a promising strategy for improving drug delivery and treatment efficacy in glioma patients.
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