Engineered knottin peptide enables noninvasive optical imaging of intracranial medulloblastoma
| Autor: | Jennifer R. Cochran, Jamie M. Bergen, You Rong S. Su, Melanie Hayden Gephart, Helen Rayburn, Sarah J. Moore, Matthew P. Scott |
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| Rok vydání: | 2013 |
| Předmět: |
Diagnostic Imaging
Male Patched Receptors Pathology medicine.medical_specialty Peptidomimetic Green Fluorescent Proteins Brain tumor Mice Nude Mice Transgenic Receptors Cell Surface Biology Protein Engineering Sensitivity and Specificity Mice In vivo Genetic model medicine Animals Cerebellar Neoplasms Fluorescent Dyes Mice Knockout Medulloblastoma Multidisciplinary Cystine knot Biological Sciences Cystine-Knot Miniproteins medicine.disease Molecular Imaging Microscopy Fluorescence Cancer research Female Molecular imaging Ex vivo Integrin alpha5beta1 Protein Binding |
| Zdroj: | Proceedings of the National Academy of Sciences. 110:14598-14603 |
| ISSN: | 1091-6490 0027-8424 |
| DOI: | 10.1073/pnas.1311333110 |
| Popis: | Central nervous system tumors carry grave clinical prognoses due to limited effectiveness of surgical resection, radiation, and chemotherapy. Thus, improved strategies for brain tumor visualization and targeted treatment are critically needed. We demonstrate that mouse cerebellar medulloblastoma (MB) can be targeted and illuminated with a fluorescent, engineered cystine knot (knottin) peptide that binds with high affinity to α v β 3 , α v β 5 , and α 5 β 1 integrin receptors. This integrin-binding knottin peptide, denoted EETI 2.5F, was evaluated as a molecular imaging probe in both orthotopic and genetic models of MB. Following tail vein injection, fluorescence arising from dye-conjugated EETI 2.5F was localized to the tumor compared with the normal surrounding brain tissue, as measured by optical imaging. The imaging signal intensity correlated with tumor volume. Due to its unique ability to bind to α 5 β 1 integrin, EETI 2.5F showed superior in vivo and ex vivo brain tumor imaging contrast compared with other engineered integrin-binding knottin peptides and with c(RGDfK), a well-studied integrin-binding peptidomimetic. Next, EETI 2.5F was fused to an antibody fragment crystallizable (Fc) domain (EETI 2.5F–Fc) to determine if a larger integrin-binding protein could also target intracranial brain tumors. EETI 2.5F–Fc, conjugated to a fluorescent dye, illuminated MB following i.v. injection and was able to distribute throughout the tumor parenchyma. In contrast, brain tumor imaging signals were not detected in mice injected with EETI 2.5F proteins containing a scrambled integrin-binding sequence, demonstrating the importance of target specificity. These results highlight the potential of using EETI 2.5F and EETI 2.5–Fc as targeted molecular probes for brain tumor imaging. |
| Databáze: | OpenAIRE |
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