scholarly journals Evaluation of Ac-Lys0(IRDye800CW)Tyr3-octreotate as a novel tracer for SSTR2-targeted molecular fluorescence guided surgery in meningioma

2021 ◽  
Author(s):  
Bianca M. Dijkstra ◽  
Marion de Jong ◽  
Marcus C. M. Stroet ◽  
Fritz Andreae ◽  
Sebastiaan E. Dulfer ◽  
...  
Keyword(s):  
Binding Affinity ◽  
Ex Vivo ◽  
Specific Binding ◽  
Somatostatin Receptor ◽  
Receptor Subtype ◽  
Tumor Uptake ◽  
In Vivo Models ◽  
Guided Surgery ◽  
Fluorescence Guided Surgery ◽  
Molecular Fluorescence

Abstract Purpose Meningioma recurrence rates can be reduced by optimizing surgical resection with the use of intraoperative molecular fluorescence guided surgery (MFGS). We evaluated the potential of the fluorescent tracer 800CW-TATE for MFGS using in vitro and in vivo models. It targets somatostatin receptor subtype 2 (SSTR2), which is overexpressed in all meningiomas. Methods Binding affinity of 800CW-TATE was evaluated using [177Lu] Lu-DOTA-Tyr3-octreotate displacement assays. Tumor uptake was determined by injecting 800CW-TATE in (SSTR2-positive) NCI-H69 or (SSTR2-negative) CH-157MN xenograft bearing mice and FMT2500 imaging. SSTR2-specific binding was measured by comparing tumor uptake in NCI-H69 and CH-157MN xenografts, blocking experiments and non-targeted IRDye800CW-carboxylate binding. Tracer distribution was analyzed ex vivo, and the tumor-to-background ratio (TBR) was calculated. SSTR2 expression was determined by immunohistochemistry (IHC). Lastly, 800CW-TATE was incubated on frozen and fresh meningioma specimens and analyzed by microscopy. Results 800CW-TATE binding affinity assays showed an IC50 value of 72 nM. NCI-H69 xenografted mice showed a TBR of 21.1. 800CW-TATE detection was reduced after co-administration of non-fluorescent DOTA-Tyr3-octreotate or administration of IRDye800CW. CH-157MN had no tumor specific tracer staining due to absence of SSTR2 expression, thereby serving as a negative control. The tracer bound specifically to SSTR2-positive meningioma tissues representing all WHO grades. Conclusion 800CW-TATE demonstrated sufficient binding affinity, specific SSTR2-mediated tumor uptake, a favorable biodistribution, and high TBR. These features make this tracer very promising for use in MFGS and could potentially aid in safer and a more complete meningioma resection, especially in high-grade meningiomas or those at complex anatomical localizations.

scholarly journals Specific Targeting of Somatostatin Receptor Subtype-2 for Fluorescence-Guided Surgery

2019 ◽  
Vol 25 (14) ◽  
pp. 4332-4342 ◽  
Author(s):  
Servando Hernandez Vargas ◽  
Susanne Kossatz ◽  
Julie Voss ◽  
Sukhen C. Ghosh ◽  
Hop S. Tran Cao ◽  
...  
Keyword(s):  
Somatostatin Receptor ◽  
Receptor Subtype ◽  
Guided Surgery ◽  
Specific Targeting ◽  
Fluorescence Guided Surgery ◽  
Somatostatin Receptor Subtype 2

scholarly journals Translation of c-Met Targeted Image-Guided Surgery Solutions in Oral Cavity Cancer—Initial Proof of Concept Data

Cancers ◽  
2021 ◽  
Vol 13 (11) ◽  
pp. 2674
Author(s):  
Tessa Buckle ◽  
Maarten van Alphen ◽  
Matthias N. van Oosterom ◽  
Florian van Beurden ◽  
Nina Heimburger ◽  
...  
Keyword(s):  
Oral Cavity ◽  
Oral Cavity Cancer ◽  
Ex Vivo ◽  
Intermediate Step ◽  
Guided Surgery ◽  
Fluorescence Guided Surgery ◽  
Tumor Identification ◽  
Imaging Results ◽  
Pathological Evaluation ◽  
Fluorescence Camera

Intraoperative tumor identification (extension/margins/metastases) via receptor-specific targeting is one of the ultimate promises of fluorescence-guided surgery. The translation of fluorescent tracers that enable tumor visualization forms a critical component in the realization of this approach. Ex vivo assessment of surgical specimens after topical tracer application could help provide an intermediate step between preclinical evaluation and first-in-human trials. Here, the suitability of the c-Met receptor as a potential surgical target in oral cavity cancer was explored via topical ex vivo application of the fluorescent tracer EMI-137. Freshly excised tumor specimens obtained from ten patients with squamous cell carcinoma of the tongue were incubated with EMI-137 and imaged with a clinical-grade Cy5 prototype fluorescence camera. In-house developed image processing software allowed video-rate assessment of the tumor-to-background ratio (TBR). Fluorescence imaging results were related to standard pathological evaluation and c-MET immunohistochemistry. After incubation with EMI-137, 9/10 tumors were fluorescently illuminated. Immunohistochemistry revealed c-Met expression in all ten specimens. Non-visualization could be linked to a more deeply situated lesion. Tumor assessment was improved via video representation of the TBR (median TBR: 2.5 (range 1.8–3.1)). Ex vivo evaluation of tumor specimens suggests that c-Met is a possible candidate for fluorescence-guided surgery in oral cavity cancer.

scholarly journals Near-Infrared Molecular Imaging of Glioblastoma by Miltuximab®-IRDye800CW as a Potential Tool for Fluorescence-Guided Surgery

Cancers ◽  
2020 ◽  
Vol 12 (4) ◽  
pp. 984 ◽  
Author(s):  
Dmitry M. Polikarpov ◽  
Douglas H. Campbell ◽  
Lucinda S. McRobb ◽  
Jiehua Wu ◽  
Maria E. Lund ◽  
...  
Keyword(s):  
Molecular Imaging ◽  
Near Infrared ◽  
Ex Vivo ◽  
Extent Of Resection ◽  
Fluorescent Imaging ◽  
Control Group ◽  
Guided Surgery ◽  
Fluorescence Guided Surgery ◽  
Specific Accumulation

Glioblastoma (GBM) is one of the most aggressive tumors and its 5-year survival is approximately 5%. Fluorescence-guided surgery (FGS) improves the extent of resection and leads to better prognosis. Molecular near-infrared (NIR) imaging appears to outperform conventional FGS, however, novel molecular targets need to be identified in GBM. Proteoglycan glypican-1 (GPC-1) is believed to be such a target as it is highly expressed in GBM and is associated with poor prognosis. We hypothesize that an anti-GPC-1 antibody, Miltuximab®, conjugated with the NIR dye, IRDye800CW (IR800), can specifically accumulate in a GBM xenograft and provide high-contrast in vivo fluorescent imaging in rodents following systemic administration. Miltuximab® was conjugated with IR800 and intravenously administered to BALB/c nude mice bearing a subcutaneous U-87 GBM hind leg xenograft. Specific accumulation of Miltuximab®-IR800 in subcutaneous xenograft tumor was detected 24 h later using an in vivo fluorescence imager. The conjugate did not cause any adverse events in mice and caused strong fluorescence of the tumor with tumor-to-background ratio (TBR) reaching 10.1 ± 2.8. The average TBR over the 10-day period was 5.8 ± 0.6 in mice injected with Miltuximab®-IR800 versus 2.4 ± 0.1 for the control group injected with IgG-IR800 (p = 0.001). Ex vivo assessment of Miltuximab®-IR800 biodistribution confirmed its highly specific accumulation in the tumor. The results of this study confirm that Miltuximab®-IR800 holds promise for intraoperative fluorescence molecular imaging of GBM and warrants further studies.

Influence of dexamethasone on visible 5-ALA fluorescence and quantitative protoporphyrin IX accumulation measured by fluorescence lifetime imaging in glioblastomas: is pretreatment obligatory before fluorescence-guided surgery?

2021 ◽  
pp. 1-9
Author(s):  
Lisa I. Wadiura ◽  
David Reichert ◽  
Veronika Sperl ◽  
Alexandra Lang ◽  
Barbara Kiesel ◽  
...  
Keyword(s):  
Fluorescence Lifetime ◽  
Aminolevulinic Acid ◽  
Ex Vivo ◽  
Protoporphyrin Ix ◽  
Fluorescence Lifetime Imaging ◽  
Lifetime Imaging ◽  
Guided Surgery ◽  
Fluorescence Guided Surgery ◽  
Significant Difference ◽  
The Mean

OBJECTIVE Fluorescence-guided surgery using 5-aminolevulinic acid (5-ALA) is nowadays widely applied for improved resection of glioblastomas (GBMs). Initially, pretreatment with dexamethasone was considered to be essential for optimal fluorescence effect. However, recent studies reported comparably high rates of visible fluorescence in GBMs despite absence of dexamethasone pretreatment. Recently, the authors proposed fluorescence lifetime imaging (FLIM) for the quantitative analysis of 5-ALA–induced protoporphyrin IX (PpIX) accumulation. The aim of this study was thus to investigate the influence of dexamethasone on visible fluorescence and quantitative PpIX accumulation. METHODS The authors prospectively analyzed the presence of visible fluorescence during surgery in a cohort of patients with GBMs. In this study, patients received dexamethasone preoperatively only if clinically indicated. One representative tumor sample was collected from each GBM, and PpIX accumulation was analyzed ex vivo by FLIM. The visible fluorescence status and mean FLIM values were correlated with preoperative intake of dexamethasone. RESULTS In total, two subgroups with (n = 27) and without (n = 20) pretreatment with dexamethasone were analyzed. All patients showed visible fluorescence independent from preoperative dexamethasone intake. Furthermore, the authors did not find a statistically significant difference in the mean FLIM values between patients with and without dexamethasone pretreatment (p = 0.097). CONCLUSIONS In this first study to date, the authors found no significant influence of dexamethasone pretreatment on either visible 5-ALA fluorescence during GBM surgery or PpIX accumulation based on FLIM. According to these preliminary data, the authors recommend administering dexamethasone prior to fluorescence-guided surgery of GBMs only when clinically indicated.

scholarly journals Anti-GD2-IRDye800CW as a targeted probe for fluorescence-guided surgery in neuroblastoma

2020 ◽  
Vol 10 (1) ◽  
Author(s):  
Lianne M. Wellens ◽  
Marion M. Deken ◽  
Cornelis F. M. Sier ◽  
Hannah R. Johnson ◽  
Fàtima de la Jara Ortiz ◽  
...  
Keyword(s):  
Near Infrared ◽  
Time Window ◽  
Specific Binding ◽  
Neoadjuvant Treatment ◽  
Xenograft Model ◽  
Fluorescence Signal ◽  
Human Neuroblastoma ◽  
Guided Surgery ◽  
Fluorescence Guided Surgery ◽  
Wide Range

Abstract Neuroblastoma resection represents a major challenge in pediatric surgery, because of the high risk of complications. Fluorescence-guided surgery (FGS) could lower this risk by facilitating discrimination of tumor from normal tissue and is gaining momentum in adult oncology. Here, we provide the first molecular-targeted fluorescent agent for FGS in pediatric oncology, by developing and preclinically evaluating a GD2-specific tracer consisting of the immunotherapeutic antibody dinutuximab-beta, recently approved for neuroblastoma treatment, conjugated to near-infrared (NIR) fluorescent dye IRDye800CW. We demonstrated specific binding of anti-GD2-IRDye800CW to human neuroblastoma cells in vitro and in vivo using xenograft mouse models. Furthermore, we defined an optimal dose of 1 nmol, an imaging time window of 4 days after administration and show that neoadjuvant treatment with anti-GD2 immunotherapy does not interfere with fluorescence imaging. Importantly, as we observed universal, yet heterogeneous expression of GD2 on neuroblastoma tissue of a wide range of patients, we implemented a xenograft model of patient-derived neuroblastoma organoids with differential GD2 expression and show that even low GD2 expressing tumors still provide an adequate real-time fluorescence signal. Hence, the imaging advancement presented in this study offers an opportunity for improving surgery and potentially survival of a broad group of children with neuroblastoma.

scholarly journals Necrosis Binding of Ac-Lys0(IRDye800CW)-Tyr3-octreotate: Pros and Cons of Using Cyanine-labeled Small Molecules

2021 ◽  
Author(s):  
Marcus Cornelis Maria Stroet ◽  
Bianca M. Dijkstra ◽  
Sebastiaan E. Dulfer ◽  
Schelto Kruijff ◽  
Wilfred F.A. den Dunnen ◽  
...  
Keyword(s):  
Contrast Agents ◽  
Membrane Integrity ◽  
Fluorescent Detection ◽  
Dead Cell ◽  
Tumor Uptake ◽  
Necrotic Tissue ◽  
Cell Binding ◽  
Paraffin Sections ◽  
Guided Surgery ◽  
Fluorescence Guided Surgery

Abstract 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. 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. 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 the purpose of fluorescence guided surgery. We exposed cultured U2OS cells (alive or dead, with or without SSTR2-expression) and frozen human tumor tissue sections of NCI-H69 (SSTR2 positive) and CH-157MN (SSTR2 negative) to 800CW-TATE. We then injected 800CW-TATE into NCI-H69-tumor-bearing mice. Blocking experiment were included with DOTA0-Tyr3-octreotate (DOTA-TATE). Paraffin sections of the resected tumors were imaged for near infrared fluorescence and cell death staining was performed. Results Binding of 800CW-TATE could be blocked with DOTA-TATE and was absent in SSTR2 negative 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 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 incomplete reduction of 61.5 ± 5.8% fluorescence uptake by the tumors in the mice. Paraffin sections revealed that fluorescence uptake persisted in necrotic regions upon blocking. 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 development fluorescent contrast agents.

scholarly journals Correction to: Evaluation of Ac-Lys0(IRDye800CW)Tyr3-octreotate as a novel tracer for SSTR2-targeted molecular fluorescence guided surgery in meningioma

2021 ◽  
Author(s):  
Bianca M. Dijkstra ◽  
Marion de Jong ◽  
Marcus C. M. Stroet ◽  
Fritz Andreae ◽  
Sebastiaan E. Dulfer ◽  
...  
Keyword(s):  
Guided Surgery ◽  
Fluorescence Guided Surgery ◽  
Molecular Fluorescence

A correction to this paper has been published: https://doi.org/10.1007/s11060-021-03769-9

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

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Marcus C. M. Stroet ◽  
Bianca M. Dijkstra ◽  
Sebastiaan E. Dulfer ◽  
Schelto Kruijff ◽  
Wilfred F. A. den Dunnen ◽  
...  
Keyword(s):  
Contrast Agents ◽  
Membrane Integrity ◽  
Fluorescent Detection ◽  
Dead Cell ◽  
Tumor Uptake ◽  
Necrotic Tissue ◽  
Cell Binding ◽  
Guided Surgery ◽  
Fluorescence Guided Surgery ◽  
U2os Cells

Abstract 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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