title: 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: Department of Radiology, Sloan Kettering Institute for Cancer Research, New York, NY 10065, USA.
authors: Miriam
authors: M
authors: Benezra
authors: Dolores
authors: D
authors: Hambardzumyan
authors: Oula
authors: O
authors: Penate-Medina
authors: Darren R
authors: DR
authors: Veach
authors: Nagavarakishore
authors: N
authors: Pillarsetty
authors: Peter
authors: P
authors: Smith-Jones
authors: Evan
authors: E
authors: Phillips
authors: Tatsuya
authors: T
authors: Ozawa
authors: Pat B
authors: PB
authors: Zanzonico
authors: Valerie
authors: V
authors: Longo
authors: Eric C
authors: EC
authors: Holland
authors: Steven M
authors: SM
authors: Larson
authors: Michelle S
authors: MS
authors: Bradbury
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D059447:Cell Cycle Checkpoints / Q000187:drug effects; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D000069439:Dasatinib; D004195:Disease Models, Animal; D005462:Fluorine Radioisotopes / Q000493:pharmacokinetics; D005909:Glioblastoma / Q000000981:diagnostic imaging / Q000188:drug therapy* / Q000473:pathology; D053208:Kaplan-Meier Estimate; D008081:Liposomes; D051379:Mice; D008823:Micelles; D058990:Molecular Targeted Therapy; D041681:NIH 3T3 Cells; D058726:Nanoconjugates / Q000008:administration & dosage* / Q000627:therapeutic use; D049268:Positron-Emission Tomography; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage* / Q000493:pharmacokinetics / Q000627:therapeutic use; D020574:Proto-Oncogene Proteins c-sis / Q000378:metabolism; D011743:Pyrimidines / Q000008:administration & dosage* / Q000493:pharmacokinetics / Q000627:therapeutic use; D011849:Radioactive Tracers; D020796:Receptor, Platelet-Derived Growth Factor alpha / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D013844:Thiazoles / Q000008:administration & dosage* / Q000493:pharmacokinetics / Q000627:therapeutic use
chemical_list: D005462:Fluorine Radioisotopes; D008081:Liposomes; D008823:Micelles; D058726:Nanoconjugates; D047428:Protein Kinase Inhibitors; D020574:Proto-Oncogene Proteins c-sis; D011743:Pyrimidines; D011849:Radioactive Tracers; D013844:Thiazoles; D020796:Receptor, Platelet-Derived Growth Factor alpha; D000069439:Dasatinib