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An optical probe for noninvasive molecular imaging of orthotopic brain tumors overexpressing epidermal growth factor receptor.

ABSTRACT: We have developed a near-infrared (NIR) probe that targets cells overexpressing the EGF receptor (EGFR) for imaging glioblastoma brain tumors in live subjects. A peptide specific for the EGFR was modified with various lengths of monodiscrete polyethylene glycol (PEG) units and a NIR Cy5.5 fluorescence dye. The lead compound, compound 2, with one unit of PEG displayed good binding (8.9 ?mol/L) and cellular uptake in glioblastoma cells overexpressing EGFR in vitro. The in vivo studies have shown that the probe was able to selectively label glioblastoma-derived orthotopic brain tumors. In vivo image analyses of peptide binding to the tumors using fluorescence-mediated molecular tomography revealed that the compound could distinguish between tumors expressing different levels of EGFR. The data presented here represent the first demonstration of differential quantitation of tumors expressing EGFR in live animals by a targeted NIR fluorescence probe using a molecular imaging device.

SUBMITTER: Agnes RS

PROVIDER: S-EPMC3829608 | biostudies-literature | 2012 Oct

REPOSITORIES: biostudies-literature

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An optical probe for noninvasive molecular imaging of orthotopic brain tumors overexpressing epidermal growth factor receptor.

Agnes Richard S RS Broome Ann-Marie AM Wang Jing J Verma Anjali A Lavik Kari K Basilion James P JP

Molecular cancer therapeutics 20120717 10

We have developed a near-infrared (NIR) probe that targets cells overexpressing the EGF receptor (EGFR) for imaging glioblastoma brain tumors in live subjects. A peptide specific for the EGFR was modified with various lengths of monodiscrete polyethylene glycol (PEG) units and a NIR Cy5.5 fluorescence dye. The lead compound, compound 2, with one unit of PEG displayed good binding (8.9 μmol/L) and cellular uptake in glioblastoma cells overexpressing EGFR in vitro. The in vivo studies have shown t ...[more]

PMID: 22807580

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Project description:INTRODUCTION:The ?v?3 integrin, which is expressed by angiogenic epithelium and some tumor cells, is an attractive target for the development of both imaging agents and therapeutics. While optimal implementation of ?v?3-targeted therapeutics will require a priori identification of the presence of the target, the clinical evaluation of these compounds has typically not included parallel studies with ?v?3-targeted diagnostics. This is at least partly due to the relatively limited availability of PET radiopharmaceuticals in comparison to those labeled with (99m)Tc. In an effort to begin to address this limitation, we evaluated the tumor uptake of (99m)Tc-NC100692, a cyclic RGD peptide that binds to ?v?3 with ~1-nM affinity, in an ?v?3-positive tumor model as well as its in vivo specificity. METHODS:MicroSPECT imaging was used to assess the ability of cilengitide, a therapeutic with high affinity for ?v?3, to block and displace (99m)Tc-NC100692 in an orthotopic U87 glioma tumor. The specificity of (99m)Tc-NC100692 was quantitatively evaluated in mice bearing subcutaneous U87MG tumors, by comparison of the biodistribution of (99m)Tc-NC100692 with that of the non-specific structural analogue (99m)Tc-AH-111744 and by blocking uptake of (99m)Tc-NC100692 with excess unlabeled NC100692. RESULTS:MicroSPECT imaging studies demonstrated that uptake of (99m)Tc-NC100692 in the intracranial tumor model was both blocked and displaced by the ?v?3-targeted therapeutic cilengitide. Biodistribution studies provided quantitative confirmation of these imaging results. Tumor uptake of (99m)Tc-NC100692 at 1h post-injection was 2.8 ± 0.7% ID/g compared to 0.38 ± 0.1% ID/g for (99m)Tc-AH-111744 (p < 0.001). Blocking (99m)Tc-NC100692 uptake by pre-injecting the mice with excess unlabeled NC100692 reduced tumor uptake by approximately five-fold, to 0.68 ± 0.3% ID/g (p = 0.01). CONCLUSION:These results confirm that (99m)Tc-NC100692 does, in fact, target the ?v?3 integrin and may, therefore, be useful in identifying patients prior to anti-?v?3 therapy as well as monitoring the response of these patients to therapy.

Dataset Information

An optical probe for noninvasive molecular imaging of orthotopic brain tumors overexpressing epidermal growth factor receptor.

Publications

An optical probe for noninvasive molecular imaging of orthotopic brain tumors overexpressing epidermal growth factor receptor.

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