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Updated: May 15, 2026
Fluorescence Molecular Tomography for In Vivo Imaging of Glioblastoma Xenografts
Published on: April 26, 2018
Fluorine-labeled dasatinib nanoformulations as targeted molecular imaging probes in a PDGFB-driven murine
Miriam Benezra1, Dolores Hambardzumyan, Oula Penate-Medina
1Department of Radiology, Sloan Kettering Institute for Cancer Research, New York, NY 10065, USA.
Abstract:
Dasatinib, a new-generation Src and platelet-derived growth factor receptor (PDGFR) inhibitor, is currently under evaluation in high-grade glioma clinical trials. To achieve optimum physicochemical and/or biologic properties, alternative drug delivery vehicles may be needed. We used a novel fluorinated dasatinib derivative (F-SKI249380), in combination with nanocarrier vehicles and metabolic imaging tools (microPET) to evaluate drug delivery and uptake in a platelet-derived growth factor B (PDGFB)-driven genetically engineered mouse model (GEMM) of high-grade glioma. We assessed dasatinib survival benefit on the basis of measured tumor volumes. Using brain tumor cells derived from PDGFB-driven gliomas, dose-dependent uptake and time-dependent inhibitory effects of F-SKI249380 on biologic activity were investigated and compared with the parent drug. PDGFR receptor status and tumor-specific targeting were non-invasively evaluated in vivo using (18)F-SKI249380 and (18)F-SKI249380-containing micellar and liposomal nanoformulations. A statistically significant survival benefit was found using dasatinib (95 mg/kg) versus saline vehicle (P < .001) in tumor volume-matched GEMM pairs. Competitive binding and treatment assays revealed comparable biologic properties for F-SKI249380 and the parent drug. In vivo, Significantly higher tumor uptake was observed for (18)F-SKI249380-containing micelle formulations [4.9 percentage of the injected dose per gram tissue (%ID/g); P = .002] compared to control values (1.6%ID/g). Saturation studies using excess cold dasatinib showed marked reduction of tumor uptake values to levels in normal brain (1.5%ID/g), consistent with in vivo binding specificity. Using (18)F-SKI249380-containing micelles as radiotracers to estimate therapeutic dosing requirements, we calculated intratumoral drug concentrations (24-60 nM) that were comparable to in vitro 50% inhibitory concentration values. (18)F-SKI249380 is a PDGFR-selective tracer, which demonstrates improved delivery to PDGFB-driven high-grade gliomas and facilitates treatment planning when coupled with nanoformulations and quantitative PET imaging approaches.
Insights
This study shows a new fluorinated dasatinib derivative (F-SKI249380) improves drug delivery to high-grade gliomas using nanocarriers. This approach aids in planning effective cancer treatments.
Area of Science:
- Oncology
- Pharmacology
- Biomedical Engineering
Background:
- High-grade gliomas are aggressive brain tumors often requiring novel therapeutic strategies.
- Dasatinib, a Src and platelet-derived growth factor receptor (PDGFR) inhibitor, is being investigated for glioma treatment.
- Optimizing drug delivery and targeting is crucial for enhancing therapeutic efficacy in gliomas.
Purpose of the Study:
- To evaluate a novel fluorinated dasatinib derivative (F-SKI249380) for improved drug delivery and uptake in a platelet-derived growth factor B (PDGFB)-driven high-grade glioma model.
- To assess the therapeutic potential of F-SKI249380 using nanocarrier formulations and quantitative PET imaging.
- To compare the biologic activity and tumor targeting of F-SKI249380 with the parent drug, dasatinib.
Main Methods:
- Utilized a platelet-derived growth factor B (PDGFB)-driven genetically engineered mouse model (GEMM) of high-grade glioma.
- Administered a novel fluorinated dasatinib derivative (F-SKI249380) via micellar and liposomal nanoformulations.
- Employed quantitative microPET imaging with (18)F-SKI249380 to assess in vivo drug delivery, tumor uptake, and receptor binding specificity.
Main Results:
- Dasatinib demonstrated a statistically significant survival benefit in tumor volume-matched GEMM pairs.
- F-SKI249380 exhibited comparable biologic activity to dasatinib in dose-dependent and time-dependent assays.
- Micellar nanoformulations of (18)F-SKI249380 showed significantly higher tumor uptake (4.9% ID/g) compared to controls (1.6% ID/g), with specificity confirmed by saturation studies.
Conclusions:
- (18)F-SKI249380 is a potent and selective PDGFR tracer that demonstrates enhanced delivery to PDGFB-driven high-grade gliomas when formulated in micelles.
- Quantitative PET imaging with (18)F-SKI249380-loaded micelles facilitates non-invasive evaluation of tumor targeting and can aid in treatment planning.
- This novel nanoformulation and imaging approach holds promise for optimizing dasatinib-based therapies for high-grade gliomas.
