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1.
Mol Imaging ; 10(6): 469-80, 2011 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-22201538

RESUMO

Labeling of RGD peptides with near-infrared fluorophores yields optical probes for noninvasive imaging of tumors overexpressing ανß3 integrins. An important prerequisite for optimum detection sensitivity in vivo is strongly absorbing and highly emissive probes with a known fluorescence lifetime. The RGD-Cy5.5 optical probe was derived by coupling Cy5.5 to a cyclic arginine-glycine-aspartic acid-d-phenylalanine-lysine (RGDfK) peptide via an aminohexanoic acid spacer. Spectroscopic properties of the probe were studied in different matrices in comparison to Cy5.5. For in vivo imaging, human glioblastoma cells were subcutaneously implanted into nude mice, and in vivo fluorescence intensity and lifetime were measured. The fluorescence quantum yield and lifetime of Cy5.5 were found to be barely affected on RGD conjugation but dramatically changed in the presence of proteins. By time domain fluorescence imaging, we demonstrated specific binding of RGD-Cy5.5 to glioblastoma xenografts in nude mice. Discrimination of unspecific fluorescence by lifetime-gated analysis further enhanced the detection sensitivity of RGD-Cy5.5-derived signals. We characterized RGD-Cy5.5 as a strongly emissive and stable probe adequate for selective targeting of ανß3 integrins. The specificity and thus the overall detection sensitivity in vivo were optimized with lifetime gating, based on the previous determination of the probes fluorescence lifetime under application-relevant conditions.


Assuntos
Glioblastoma/metabolismo , Imagem Molecular/métodos , Sondas Moleculares/química , Oligopeptídeos/química , Espectroscopia de Luz Próxima ao Infravermelho/métodos , Animais , Carbocianinas/química , Linhagem Celular Tumoral , Corantes Fluorescentes/química , Glioblastoma/química , Humanos , Integrina alfaVbeta3/metabolismo , Masculino , Camundongos , Camundongos Nus , Sondas Moleculares/metabolismo , Transplante de Neoplasias , Oligopeptídeos/metabolismo , Ligação Proteica , Transplante Heterólogo
2.
J Biomed Opt ; 17(7): 076028, 2012 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-22894511

RESUMO

We investigated the potential of the pH-sensitive dye, CypHer5E, conjugated to Herceptin (pH-Her) for the sensitive detection of breast tumors in mice using noninvasive time-domain near-infrared fluorescence imaging and different methods of data analysis. First, the fluorescence properties of pH-Her were analyzed as function of pH and/or dye-to-protein ratio, and binding specificity was confirmed in cell-based assays. Subsequently, the performance of pH-Her in nude mice bearing orthotopic HER2-positive (KPL-4) and HER2-negative (MDA-MB-231) breast carcinoma xenografts was compared to that of an always-on fluorescent conjugate Alexa Fluor 647-Herceptin (Alexa-Her). Subtraction of autofluorescence and lifetime (LT)-gated image analyses were performed for background fluorescence suppression. In mice bearing HER2-positive tumors, autofluorescence subtraction together with the selective fluorescence enhancement of pH-Her solely in the tumor's acidic environment provided high contrast-to-noise ratios (CNRs). This led to an improved sensitivity of tumor detection compared to Alexa-Her. In contrast, LT-gated imaging using LTs determined in model systems did not improve tumor-detection sensitivity in vivo for either probe. In conclusion, pH-Her is suitable for sensitive in vivo monitoring of HER2-expressing breast tumors with imaging in the intensity domain and represents a promising tool for detection of weak fluorescent signals deriving from small tumors or metastases.


Assuntos
Anticorpos Monoclonais Humanizados/análise , Biomarcadores Tumorais/análise , Neoplasias da Mama/química , Neoplasias da Mama/diagnóstico , Carbocianinas , Microscopia de Fluorescência/métodos , Espectroscopia de Luz Próxima ao Infravermelho/métodos , Animais , Linhagem Celular Tumoral , Feminino , Corantes Fluorescentes , Concentração de Íons de Hidrogênio , Camundongos , Camundongos Nus , Sensibilidade e Especificidade , Trastuzumab
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