Localization of sunitinib, its metabolites and its target receptors in tumour-bearing mice: a MALDI-MS imaging study
1Department of tumor Biology, National Korányi Institute of Pulmonology, Budapest, Hungary; Division of Thoracic Surgery, Department of Surgery, Comprehensive Cancer Center, Medical University of Vienna, Vienna, Austria; Clinical Protein Science and Imaging, Biomedical Center, Department of Biomedical Engineering, Lund University, Lund, Sweden.
Background And Purpose:
The clinical effects of anti-angiogenic agents remain controversial. Therefore, elucidating the pharmacological properties of these compounds is a pivotal issue.
Experimental Approach:
The effects of treatment with sunitinib on tumour and normal tissues of mice bearing C-26 adenocarcinoma cells were analysed by matrix-assisted laser desorption ionization MS imaging (MALDI-MSI). Expression of the key targets of sunitinib--angiogenic receptors--was studied by immunofluorescent labelling.
Key Results:
MALDI-MS assays showed that sunitinib and its fragment ions were present throughout tumour and normal tissues. Major metabolites were identified in blood and solid tissues, while minor drug metabolites were detectable only in blood. Tumour growth and intratumour VEGF receptor-2 expressions were significantly reduced in sunitinib-treated mice, while the expression of the other targeted receptors, PDGF receptor -α or -β and fibroblast growth factor receptor-1, remained unaffected. Within tumour tissue, the close proximity of sunitinib metabolites to the precursor ion suggested in situ metabolism of the administered drug. There were intratumour areas where the signal intensity of sunitinib correlated with expression of VEGF receptor-2.
Conclusions And Implications:
This is the first study that demonstrates MALDI-MSI is a versatile platform to study the intratumour localization of an unlabelled anti-angiogenic drug. The combination of MALDI-MSI and immunofluorescence analysis can provide further insights into the molecular interaction of drug compounds and their targets within tumour tissue.
Insights
Matrix-assisted laser desorption ionization MS imaging (MALDI-MSI) effectively tracked sunitinib's distribution in tumors and normal tissues. This method revealed sunitinib's impact on VEGF receptor-2, aiding anti-angiogenic drug research.
Area of Science:
- Pharmacology
- Molecular Imaging
- Cancer Research
Background:
- The clinical efficacy of anti-angiogenic agents is debated.
- Understanding their pharmacological properties is crucial.
Purpose of the Study:
- To investigate the tissue distribution and metabolic fate of sunitinib.
- To correlate drug localization with its molecular targets in vivo.
Main Methods:
- Matrix-assisted laser desorption ionization MS imaging (MALDI-MSI) was used to analyze sunitinib distribution in C-26 adenocarcinoma mouse models.
- Immunofluorescence labeling assessed the expression of key sunitinib targets (angiogenic receptors).
Main Results:
- Sunitinib and its metabolites were detected in both tumor and normal tissues.
- Tumor growth and intratumoral VEGF receptor-2 expression were significantly reduced by sunitinib.
- Drug metabolites were found in blood and solid tissues, with minor metabolites only in blood.
Conclusions:
- MALDI-MSI is a versatile tool for studying the intratumoral localization of unlabelled anti-angiogenic drugs.
- Combining MALDI-MSI with immunofluorescence provides insights into drug-target interactions within tumors.
