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


Authors: Benezra, M.; Hambardzumyan, D.; Penate-Medina, O.; Veach, D. R.; Pillarsetty, N.; Smith-Jones, P.; Phillips, E.; Ozawa, T.; Zanzonico, P. B.; Longo, V.; Holland, E. C.; Larson, S. M.; Bradbury, M. S.
Article 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 18F-SKI249380 and 18F-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 18F-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 18F-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. 18F-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. © 2012 Neoplasia Press, Inc. All rights reserved.
Keywords: signal transduction; mitogen activated protein kinase; protein kinase b; controlled study; protein expression; protein phosphorylation; unclassified drug; dose response; nonhuman; flow cytometry; positron emission tomography; cell proliferation; animal cell; mouse; animal tissue; cell viability; cell survival; cell cycle; apoptosis; tumor volume; animal experiment; animal model; molecular imaging; dasatinib; platelet derived growth factor receptor; drug synthesis; necrosis; glioblastoma; myc protein; western blotting; immunoprecipitation; immunoblotting; ras protein; fluorine 18; mitogen activated protein kinase kinase; liposome; drug delivery system; nanocarrier; platelet derived growth factor b; ski 249380
Journal Title: NeoPlasia
Volume: 14
Issue: 12
ISSN: 1522-8002
Publisher: Elsevier Science Inc.  
Date Published: 2012-12-01
Start Page: 1132
End Page: 1143
Language: English
DOI: 10.1593/neo.121750
PROVIDER: scopus
PMCID: PMC3540940
PUBMED: 23308046
DOI/URL:
Notes: --- - "Cited By (since 1996): 1" - "Export Date: 1 February 2013" - "CODEN: NEOPF" - "Source: Scopus"
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MSK Authors
  1. Darren Veach
    87 Veach
  2. Eric Holland
    224 Holland
  3. Pat B Zanzonico
    342 Zanzonico
  4. Tatsuya Ozawa
    16 Ozawa
  5. Steven M Larson
    941 Larson
  6. Valerie Ann Longo
    36 Longo
  7. Miriam Benezra
    12 Benezra