Improved antibody-guided surgery with a near-infrared dye on a PEGylated linker for CEA-positive tumors

Yazaki, Paul J.; Lwin, Thinzar M.; Minnix, Megan; Li, Lin; Sherman, Anakim; Molnar, Justin; Miller, Aaron David; Frankel, Paul; Chea, Junie; Poku, Erasmus; Bowles, Nicole; Hoffman, Robert M.; Shively, John E.; Bouvet, Michael

doi:10.1117/1.jbo.24.6.066012

Cited by 23 publications

(21 citation statements)

References 35 publications

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“…The remarkably high photostability of s775z makes it very attractive for incorporation into modern photon‐intensive microscopy experiments such as single‐molecule tracking or super resolution imaging, as well as emerging clinical procedures, such as fluorescence guided surgery, which require long periods of sustained light exposure . The synthetic modularity that underlies the structure of s775z enables easy customization of bioimaging performance by modifying the two shielding arms to rationally fine‐tune pharmacokinetics, or the polyene structure to enhance photophysical properties…”

Section: Resultsmentioning

confidence: 99%

Sterically Shielded Heptamethine Cyanine Dyes for Bioconjugation and High Performance Near‐Infrared Fluorescence Imaging

Schreiber

Smith

2020

Angewandte Chemie

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The near‐infrared window of fluorescent heptamethine cyanine dyes greatly facilitates biological imaging because there is deep penetration of the light and negligible background fluorescence. However, dye instability, aggregation, and poor pharmacokinetics are current drawbacks that limit performance and the scope of possible applications. All these limitations are simultaneously overcome with a new molecular design strategy that produces a charge balanced and sterically shielded fluorochrome. The key design feature is a meso‐aryl group that simultaneously projects two shielding arms directly over each face of a linear heptamethine polyene. Cell and mouse imaging experiments compared a shielded heptamethine cyanine dye (and several peptide and antibody bioconjugates) to benchmark heptamethine dyes and found that the shielded systems possess an unsurpassed combination of photophysical, physiochemical, and biodistribution properties that greatly enhance bioimaging performance.

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Section: Resultsmentioning

confidence: 99%

Sterically Shielded Heptamethine Cyanine Dyes for Bioconjugation and High Performance Near‐Infrared Fluorescence Imaging

Schreiber

Smith

2020

Angewandte Chemie

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“…Ther emarkably high photostability of s775z makes it very attractive for incorporation into modern photon-intensive microscopy experiments such as single-molecule tracking or super resolution imaging,aswell as emerging clinical procedures,such as fluorescence guided surgery,w hich require long periods of sustained light exposure. [4a] Thes ynthetic modularity that underlies the structure of s775z enables easy customization of bioimaging performance by modifying the two shielding arms to rationally fine-tune pharmacokinetics, [30,35] or the polyene structure to enhance photophysical properties. [36]…”

Section: Methodsmentioning

confidence: 99%

Sterically Shielded Heptamethine Cyanine Dyes for Bioconjugation and High Performance Near‐Infrared Fluorescence Imaging

2020

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The near-infrared window of fluorescent heptamethine cyanine dyes greatly facilitates biological imaging because there is deep penetration of the light and negligible background fluorescence.H owever,d ye instability,a ggregation, and poor pharmacokinetics are current drawbacks that limit performance and the scope of possible applications.A ll these limitations are simultaneously overcome with an ew molecular design strategy that produces acharge balanced and sterically shielded fluorochrome.T he key design feature is am eso-aryl group that simultaneously projects two shielding arms directly over each face of alinear heptamethine polyene. Cell and mouse imaging experiments compared as hielded heptamethine cyanine dye (and several peptide and antibody bioconjugates) to benchmark heptamethine dyes and found that the shielded systems possess an unsurpassed combination of photophysical, physiochemical, and biodistribution properties that greatly enhance bioimaging performance. Scheme 1. Chemical structures of heptamethine cyanine dyes.

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“…There is a growing interest in the development of optical molecular contrast agents for fluorescence-guided surgery [ 1 , 2 ]. In most cases, successful targeting vectors from nuclear imaging agents are repurposed, either by replacing the radiolabeling part with a fluorescent tag for single modal imaging, or by adding both a radioactive and a fluorescent chemical moiety for bi-modal imaging.…”

Section: Introductionmentioning

confidence: 99%

Necrosis binding of Ac-Lys0(IRDye800CW)-Tyr3-octreotate: a consequence from cyanine-labeling of small molecules

et al. 2021

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Background There is a growing body of nuclear contrast agents that are repurposed for fluorescence-guided surgery. New contrast agents are obtained by substituting the radioactive tag with, or adding a fluorescent cyanine to the molecular structure of antibodies or peptides. This enables intra-operative fluorescent detection of cancerous tissue, leading to more complete tumor resection. However, these fluorescent cyanines can have a remarkable influence on pharmacokinetics and tumor uptake, especially when labeled to smaller targeting vectors such as peptides. Here we demonstrate the effect of cyanine-mediated dead cell-binding of Ac-Lys0(IRDye800CW)-Tyr3-octreotate (800CW-TATE) and how this can be used as an advantage for fluorescence-guided surgery. Results Binding of 800CW-TATE could be blocked with DOTA0-Tyr3-octreotate (DOTA-TATE) on cultured SSTR2-positive U2OS cells and was absent in SSTR2 negative U2OS cells. However, strong binding was observed to dead cells, which could not be blocked with DOTA-TATE and was also present in dead SSTR2 negative cells. No SSTR2-mediated binding was observed in frozen tumor sections, possibly due to disruption of the cells in the process of sectioning the tissue before exposure to the contrast agent. DOTA-TATE blocking resulted in an incomplete reduction of 61.5 ± 5.8% fluorescence uptake by NCI-H69-tumors in mice. Near-infrared imaging and dead cell staining on paraffin sections from resected tumors revealed that fluorescence uptake persisted in necrotic regions upon blocking with DOTA-TATE. Conclusion This study shows that labeling peptides with cyanines can result in dead cell binding. This does not hamper the ultimate purpose of fluorescence-guided surgery, as necrotic tissue appears in most solid tumors. Hence, the necrosis binding can increase the overall tumor uptake. Moreover, necrotic tissue should be removed as much as possible: it cannot be salvaged, causes inflammation, and is tumorigenic. However, when performing binding experiments to cells with disrupted membrane integrity, which is routinely done with nuclear probes, this dead cell-binding can resemble non-specific binding. This study will benefit the development of fluorescent contrast agents.

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Improved antibody-guided surgery with a near-infrared dye on a PEGylated linker for CEA-positive tumors

Cited by 23 publications

References 35 publications

Sterically Shielded Heptamethine Cyanine Dyes for Bioconjugation and High Performance Near‐Infrared Fluorescence Imaging

Sterically Shielded Heptamethine Cyanine Dyes for Bioconjugation and High Performance Near‐Infrared Fluorescence Imaging

Sterically Shielded Heptamethine Cyanine Dyes for Bioconjugation and High Performance Near‐Infrared Fluorescence Imaging

Necrosis binding of Ac-Lys0(IRDye800CW)-Tyr3-octreotate: a consequence from cyanine-labeling of small molecules

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