Tracers for Fluorescence-Guided Surgery: How Elongation of the Polymethine Chain in Cyanine Dyes Alters the Pharmacokinetics of a Dual-Modality c[RGDyK] Tracer

• DOI: 10.2967/jnumed.117.205575
• Publication Date: 2018-02-16T01:35:23Z
• Authors: Tessa Buckle; Danny M. van Will...; Silvia J. Spa; Albertus W. Hensb...; Steffen van der Wal; Clarize M. de Korne; Mick M. Welling; Henk G. van der Poel; James C.H. Hardwick; Fijs W.B. van Lee...
• Keywords: Cyanine; Biodistribution; TRACER

The potential of receptor-mediated fluorescence-based image-guided surgery tracers is generally linked to the near-infrared emission profile and good-manufacturing-production availability fluorescent dyes. Surprisingly, little known about critical interaction between structural composition dyes pharmacokinetics tracers. In this study, a dual-modality tracer design was used systematically quantitatively evaluate influence elongation polymethine chain in cyanine dye on imaging targeted tracer. <b>Methods:</b> As model system, integrin marker α_vβ₃ using arginylglycylaspartisc acid [RGD]–based vectors functionalized with ¹¹¹In-diethylenetriaminepentaacetic (DTPA) chelate dye: (Cy3-(SO₃)methyl-COOH [emission wavelength (λ_em), 580 nm], Cy5-(SO₃)methyl-COOH [λ_em, 680 or Cy7-(SO₃)methyl-COOH 780 nm]). Tracers were analyzed for differences photophysical properties, serum protein binding, chemical optical stability, signal penetration through tissue. Receptor affinities evaluated saturation competition experiments. vivo biodistribution (SPECT percentage injected dose per gram tissue) assessed tumor-bearing mice complemented ex fluorescence images obtained clinical-grade multispectral laparoscope. <b>Results:</b> Two carbon-atom-step variations shown significantly characteristics (e.g., brightness, tissue penetration) hybrid RGD DTPA-Cy5-(SO₃)methyl-COOH-c[RGDyK] structurally outperformed its Cy3 Cy7 derivatives. Radioactivity-based evaluation yielded lowest nonspecific uptake highest tumor-to-background ratio (13.2 ± 1.7), analogs trailing at respective ratios 5.7 0.7 4.7 0.7. Fluorescence-based assessment tumor visibility revealed similar trend. <b>Conclusion:</b> These findings underline that lengths have profound targeting capabilities direct comparison, intermediate-length (Cy5) superior c[RGDyK] tracer, compared shorter (Cy3) longer (Cy7) analogs.