Fluorine-labeled dasatinib nanoformulations as targeted molecular imaging probes in a PDGFB-driven murine glioblastoma model.

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.

• Authors: Miriam Benezra, Dolores Hambardzumyan, Oula Penate-Medina, Darren R Veach, Nagavarakishore Pillarsetty, Peter Smith-Jones, Evan Phillips, Tatsuya Ozawa, Pat B Zanzonico, Valerie Longo, Eric C Holland, Steven M Larson, Michelle S Bradbury
• Journal: Neoplasia (New York, N.Y.) (Neoplasia) Vol. 14 Issue 12 Pg. 1132-43 (Dec 2012) ISSN: 1476-5586 [Electronic] United States
• PMID: 23308046 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Fluorine Radioisotopes
• Liposomes
• Micelles
• Nanoconjugates
• Protein Kinase Inhibitors
• Proto-Oncogene Proteins c-sis
• Pyrimidines
• Radioactive Tracers
• Thiazoles
• Receptor, Platelet-Derived Growth Factor alpha
• Dasatinib

Topics

• Animals
• Apoptosis (drug effects)
• Cell Cycle Checkpoints (drug effects)
• Cell Line, Tumor
• Cell Survival (drug effects)
• Dasatinib
• Disease Models, Animal
• Fluorine Radioisotopes (pharmacokinetics)
• Glioblastoma (diagnostic imaging, drug therapy, pathology)
• Kaplan-Meier Estimate
• Liposomes
• Mice
• Micelles
• Molecular Targeted Therapy
• NIH 3T3 Cells
• Nanoconjugates (administration & dosage, therapeutic use)
• Positron-Emission Tomography
• Protein Kinase Inhibitors (administration & dosage, pharmacokinetics, therapeutic use)
• Proto-Oncogene Proteins c-sis (metabolism)
• Pyrimidines (administration & dosage, pharmacokinetics, therapeutic use)
• Radioactive Tracers
• Receptor, Platelet-Derived Growth Factor alpha (metabolism)
• Signal Transduction (drug effects)
• Thiazoles (administration & dosage, pharmacokinetics, therapeutic use)