Fluorine-labeled Dasatinib Nanoformulations as Targeted Molecular Imaging Probes in a PDGFB-driven Murine Glioblastoma Model

• DOI: 10.1593/neo.121750
• Publication Date: 2015-04-23T13:05:14Z
• Authors: Miriam Benezra; Dolores Hambardzu...; Oula Penate-Medina; Darren R. Veach; Nagavarakishore P...; Peter Smith-Jones; Evan Phillips; Tatsuya Ozawa; Pat B. Zanzonico; Valerie Longo; Eric C. Holland; Steven M. Larson; Michelle S. Bradbury
• Keywords: Fluorine Radioisotopes; Cell Survival; Dasatinib; Neoplasms. Tumors. Oncology. Including cancer and carcinogens; Apoptosis; Cell Cycle Checkpoints; Kaplan-Meier Estimate; Nanoconjugates; Proto-Oncogene Proteins c-sis; 3. Good health; Disease Models, Animal; Mice; Pyrimidines; Cell Line, Tumor; Positron-Emission Tomography; Liposomes; NIH 3T3 Cells; Animals; Molecular Targeted Therapy; Glioblastoma; Protein Kinase Inhibitors; RC254-282; Micelles

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.