Dataset Information

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

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.

SUBMITTER: Dijkstra BM

PROVIDER: S-EPMC8211583 | biostudies-literature | 2021 Jun

REPOSITORIES: biostudies-literature

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Publications

Evaluation of Ac-Lys<sup>0</sup>(IRDye800CW)Tyr<sup>3</sup>-octreotate as a novel tracer for SSTR<sub>2</sub>-targeted molecular fluorescence guided surgery in meningioma.

Dijkstra Bianca M BM de Jong Marion M Stroet Marcus C M MCM Andreae Fritz F Dulfer Sebastiaan E SE Everts Marieke M Kruijff Schelto S Nonnekens Julie J den Dunnen Wilfred F A WFA Kruyt Frank A E FAE Groen Rob J M RJM

Journal of neuro-oncology 20210326 2

<h4>Purpose</h4>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 (SSTR<sub>2</sub>), which is overexpressed in all meningiomas.<h4>Methods</h4>Binding affinity of 800CW-TATE was evaluated using [<sup>177</sup>Lu] Lu-DOTA-Tyr<sup>3</sup>-octreota ...[more]

PMID: 33768405

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Project description:BackgroundThere 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.ResultsBinding 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.ConclusionThis 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.

Project description:PurposeTherapy with [177Lu-DOTA,Tyr3]octreotate is effective in patients with grade I/II metastasized and/or inoperable bronchial neuroendocrine tumour (NET) or gastroenteropancreatic NET (GEP-NET). In this study, we investigated the efficacy and safety of salvage treatment with [177Lu-DOTA,Tyr3]octreotate.MethodsPatients with progressive bronchial NET or GEP-NET were selected for re-(re)treatment if they had benefited from initial peptide receptor radionuclide therapy (I-PRRT) with a minimal progression-free survival (PFS) of 18 months. Patients received an additional cumulative dose of 14.8 GBq of [177Lu-DOTA,Tyr3]octreotate over two cycles per retreatment with PRRT (R-PRRT) or re-retreatment with PRRT (RR-PRRT).ResultsThe safety and efficacy analyses included 181 patients and 168 patients, respectively, with bronchial NET or GEP-NET. Overall median follow-up was 88.6 months (95% CI 79.0-98.2). Median cumulative doses were 44.7 GBq (range 26.3-46.4 GBq) during R-PRRT (168 patients) and 59.7 GBq (range 55.2-≤60.5 GBq) during RR-PRRT (13 patients). Objective response and stable disease, as best response, were observed in 26 patients (15.5%) and 100 patients (59.5%) following R-PRRT, and in 5 patients (38.5%) and 7 patients (53.8%) following RR-PRRT, respectively. Median PFS was 14.6 months (95% CI 12.4-16.9) following R-PRRT and 14.2 months (95% CI 9.8-18.5) following RR-PRRT. Combined overall survival (OS) after I-PRRT plus R-PRRT and RR-PRRT was 80.8 months (95% CI 66.0-95.6). Grade III/IV bone marrow toxicity occurred in 6.6% and 7.7% of patients after R-PRRT and RR-PRRT, respectively. Salvage therapy resulted in a significantly longer OS in patients with bronchial NET, GEP-NET and midgut NET than in a nonrandomized control group. The total incidence of acute myeloid leukaemia (AML) and myelodysplastic syndrome (MDS) was 2.2%. No PRRT-related grade III/IV nephrotoxicity was observed.ConclusionA cumulative dose of up to 60.5 GBq salvage PRRT with [177Lu-DOTA,Tyr3]octreotate is safe and effective in patients with progressive disease (relapse-PD) following I-PRRT with [177Lu-DOTA,Tyr3]octreotate. Safety appears similar to that of I-PRRT as no higher incidence of AML or MDS was observed. No grade III/IV renal toxicity occurred after retreatment.

Project description:Background13C tracer analysis is increasingly used to monitor cellular metabolism in vivo and in intact cells, but data interpretation is still the key element to unveil the complexity of metabolic activities. The distinct 13C labeling patterns (e.g., M + 1 species in vivo but not in vitro) of metabolites from [U-13C]-glucose or [U-13C]-glutamine tracing in vivo and in vitro have been previously reported by multiple groups. However, the reason for the difference in the M + 1 species between in vivo and in vitro experiments remains poorly understood.MethodsWe have performed [U-13C]-glucose and [U-13C]-glutamine tracing in sarcoma-bearing mice (in vivo) and in cancer cell lines (in vitro). 13C enrichment of metabolites in cultured cells and tissues was determined by LC coupled with high-resolution mass spectrometry (LC-HRMS). All p-values are obtained from the Student's t-test two-tailed using GraphPad Prism 8 unless otherwise noted.ResultsWe observed distinct enrichment patterns of tricarboxylic acid cycle intermediates in vivo and in vitro. As expected, citrate M + 2 or M + 4 was the dominant mass isotopologue in vitro. However, citrate M + 1 was unexpectedly the dominant isotopologue in mice receiving [U-13C]-glucose or [U-13C]-glutamine infusion, but not in cultured cells. Our results are consistent with a model where the difference in M + 1 species is due to the different sources of CO2 in vivo and in vitro, which was largely overlooked in the past. In addition, a time course study shows the generation of high abundance citrate M + 1 in plasma of mice as early as few minutes after [U-13C]-glucose infusion.ConclusionsAltogether, our results show that recycling of endogenous CO2 is substantial in vivo. The production and recycling of 13CO2 from the decarboxylation of [U-13C]-glucose or [U-13C]-glutamine is negligible in vitro partially due to dilution by the exogenous HCO3-/CO2 source, but in vivo incorporation of endogenous 13CO2 into M + 1 metabolites is substantial and should be considered. These findings provide a new paradigm to understand carbon atom transformations in vivo and should be taken into account when developing mathematical models to better reflect carbon flux.

Dataset Information

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

Purpose

Methods

Results

Conclusion

Publications

Evaluation of Ac-Lys<sup>0</sup>(IRDye800CW)Tyr<sup>3</sup>-octreotate as a novel tracer for SSTR<sub>2</sub>-targeted molecular fluorescence guided surgery in meningioma.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets

Dataset Information

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

Purpose

Methods

Results

Conclusion

Publications

Evaluation of Ac-Lys<sup>0</sup>(IRDye800CW)Tyr<sup>3</sup>-octreotate as a novel tracer for SSTR<sub>2</sub>-targeted molecular fluorescence guided surgery in meningioma.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets

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