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Item does not contain fulltext, One of the main challenges of PET imaging with (89)Zr-labeled monoclonal antibodies (mAbs) remains the long blood circulation of the radiolabeled mAbs, leading to high background signals, decreasing image quality. To overcome this limitation, here we report the use of a bioorthogonal linker cleavage approach (click-to-release chemistry) to selectively liberate [(89)Zr]Zr-DFO from trans-cyclooctene-functionalized trastuzumab (TCO-Tmab) in blood, following the administration of a tetrazine compound (trigger) in BT-474 tumor-bearing mice. Methods: We created a series of TCO-DFO constructs and evaluated their performance in [(89)Zr]Zr-DFO release from Tmab in vitro using different trigger compounds. The in vivo behavior of the best performing [(89)Zr]Zr-TCO-Tmab was studied in healthy mice first to determine the optimal dose of the trigger. To find the optimal time for the trigger administration, the rate of [(89)Zr]Zr-TCO-Tmab internalization was studied in BT-474 cancer cells. Finally, the trigger was administered 6 h or 24 h after [(89)Zr]Zr-TCO-Tmab- administration in tumor-bearing mice to liberate the [(89)Zr]Zr-DFO fragment. PET scans were obtained of tumor-bearing mice that received the trigger 6 h post-[(89)Zr]Zr-TCO-Tmab administration. Results: The [(89)Zr]Zr-TCO-Tmab and trigger pair with the best in vivo properties exhibited 83% release in 50% mouse plasma. In tumor-bearing mice the tumor-blood ratios were markedly increased from 1.0 ± 0.4 to 2.3 ± 0.6 (p = 0.0057) and from 2.5 ± 0.7 to 6.6 ± 0.9 (p < 0.0001) when the trigger was administered at 6 h and 24 h post-mAb, respectively. Same day PET imaging clearly showed uptake in the tumor combined with a strongly reduced background due to the fast clearance of the released [(89)Zr]Zr-DFO-containing fragment from the circulation through the kidneys. Conclusions: This is the first demonstration of the use of trans-cyclooctene-tetrazine click-to-release chemistry to release a radioactive chelator from a mAb in mi

01 juli 2023, Contains fulltext : 294532.pdf (Publisher’s version ) (Open Access), PURPOSE: Incomplete resection of prostate cancer (PCa) results in increased risk of disease recurrence. Combined fluorescence-guided surgery with tumor-targeted photodynamic therapy (tPDT) may help to achieve complete tumor eradication. We developed a prostate-specific membrane antigen (PSMA) ligand consisting of a DOTA chelator for (111)In labeling and a fluorophore/photosensitizer IRDye700DX (PSMA-N064). We evaluated the efficacy of PSMA-tPDT using PSMA-N064 in cell viability assays, a mouse xenograft model and in an ex vivo incubation study on fresh human PCa tissue. METHODS: In vitro, therapeutic efficacy of PSMA-N064 was evaluated using PSMA-positive LS174T cells and LS174T wild-type cells. In vivo, PSMA-N064-mediated tPDT was tested in immunodeficient BALB/c mice-bearing PSMA-positive LS174T xenografts. Tumor growth and survival were compared to control mice that received either NIR light or ligand injection only. Ex vivo tPDT efficacy was evaluated in excised fresh human PCa tissue incubated with PSMA-N064. RESULTS: In vitro, tPDT led to a PSMA-specific light- and ligand dose-dependent loss in cell viability. In vivo, tPDT-induced tumor cell apoptosis, delayed tumor growth, and significantly improved survival (p = 0.004) of the treated PSMA-positive tumor-bearing mice compared with the controls. In fresh ex vivo human PCa tissue, apoptosis was significantly increased in PSMA-tPDT-treated samples compared to non-treated control samples (p = 0.037). CONCLUSION: This study showed the feasibility of PSMA-N064-mediated tPDT in cell assays, a xenograft model and excised fresh human PCa tissue. This paves the way to investigate the impact of in vivo PSMA-tPDT on surgical outcome in PCa patients.

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Contains fulltext : 299300.pdf (Publisher’s version ) (Open Access), Curative treatment of colon cancer and soft tissue sarcomas remains largely based on complete removal of the tumor during surgery. It can be difficult for surgeons to see or feel exactly which tissue needs to be removed during surgery. In this thesis, Jan Marie de Gooyer and colleagues show that a combination of radioactivity and fluorescent light can be applied to help surgeons detect and delineate tumors during surgical procedures. It turns out that it is possible to detect and delineate even the most hidden tumors deposits with radioactively and fluorescently labelled molecules that stick to tumor cells. The efficacy of this technique tested was demonstrated in several experimental studies; for example on biopsies taken from tumors that had been removed during regular surgery. The thesis concludes with one of the first clinical studies which shows that this technique can be safely and successfully applied in patients undergoing surgical treatment for colon cancer., Radboud University, 08 december 2023, Promotores : Wilt, J.H.W. de, Rijpkema, M.J.P., 169 p.

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Contains fulltext : 252039.pdf (Publisher’s version ) (Open Access), INTRODUCTION: The first generation ligands for prostate-specific membrane antigen (PSMA)-targeted radio- and fluorescence-guided surgery followed by adjuvant photodynamic therapy (PDT) have already shown the potential of this approach. Here, we developed three new photosensitizer-based dual-labeled PSMA ligands by crucial modification of existing PSMA ligand backbone structures (PSMA-1007/PSMA-617) for multimodal imaging and targeted PDT of PCa. METHODS: Various new PSMA ligands were synthesized using solid-phase chemistry and provided with a DOTA chelator for (111)In labeling and the fluorophore/photosensitizer IRDye700DX. The performance of three new dual-labeled ligands was compared with a previously published first-generation ligand (PSMA-N064) and a control ligand with an incomplete PSMA-binding motif. PSMA specificity, affinity, and PDT efficacy of these ligands were determined in LS174T-PSMA cells and control LS174T wildtype cells. Tumor targeting properties were evaluated in BALB/c nude mice with subcutaneous LS174T-PSMA and LS174T wildtype tumors using microSPECT/CT imaging, fluorescence imaging, and biodistribution studies after dissection. RESULTS: In order to synthesize the new dual-labeled ligands, we modified the PSMA peptide linker by substitution of a glutamic acid into a lysine residue, providing a handle for conjugation of multiple functional moieties. Ligand optimization showed that the new backbone structure leads to high-affinity PSMA ligands (all IC50 < 50 nM). Moreover, ligand-mediated PDT led to a PSMA-specific decrease in cell viability in vitro (P < 0.001). Linker modification significantly improved tumor targeting compared to the previously developed PSMA-N064 ligand (>/= 20 +/- 3%ID/g vs 14 +/- 2%ID/g, P < 0.01) and enabled specific visualization of PMSA-positive tumors using both radionuclide and fluorescence imaging in mice. CONCLUSION: The new high-affinity dual-labeled PSMA-targeting ligands with optimized backbone compositions showed

Contains fulltext : 282880.pdf (Publisher’s version ) (Open Access), OBJECTIVE: Activated synovial fibroblasts are key effector cells in RA. Selectively depleting these based upon their expression of fibroblast activation protein (FAP) is an attractive therapeutic approach. Here we introduce FAP imaging of inflamed joints using 68Ga-FAPI-04 in a RA patient, and aim to assess feasibility of anti-FAP targeted photodynamic therapy (FAP-tPDT) ex vivo using 28H1-IRDye700DX on RA synovial explants. METHODS: Remnant synovial tissue from RA patients was processed into 6 mm biopsies and, from several patients, into primary fibroblast cell cultures. Both were treated using FAP-tPDT. Cell viability was measured in fibroblast cultures and biopsies were evaluated for histological markers of cell damage. Selectivity of the effect of FAP-tPDT was assessed using flow cytometry on primary fibroblasts and co-cultured macrophages. Additionally, one RA patient intravenously received 68Ga-FAPI-04 and was scanned using PET/CT imaging. RESULTS: In the RA patient, FAPI-04 PET imaging showed high accumulation of the tracer in arthritic joints with very low background signal. In vitro, FAP-tPDT induced cell death in primary RA synovial fibroblasts in a light dose-dependent manner. An upregulation of cell damage markers was observed in the synovial biopsies after FAP-tPDT. No significant effects of FAP-tPDT were noted on macrophages after FAP-tPDT of neighbouring fibroblasts. CONCLUSION: In this study the feasibility of selective FAP-tPDT in synovium of rheumatoid arthritis patients ex vivo is demonstrated. Furthermore, this study provides the first indication that FAP-targeted PET/CT can be used to image arthritic joints, an important step towards application of FAP-tPDT as a targeted locoregional therapy for RA.

Radboud University, 08 september 2022, Promotores : Heskamp, S., Rijpkema, M.J.P. Co-promotores : Lütje, S., Lowik, D.W.P.M., Contains fulltext : 252882.pdf (Publisher’s version ) (Open Access)

Item does not contain fulltext, In recent years, clinical use of novel advanced imaging modalities in prostate cancer detection, staging, and therapy has intensified and is currently reforming clinical guidelines. In the future, advanced imaging technologies will continue to develop and become even more accurate, which will offer new opportunities for improving patient selection, surgical treatment, and radiotherapy, with the potential to guide prostate cancer therapy.

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Contains fulltext : 234271.pdf (Publisher’s version ) (Open Access), Introduction: Postoperative cognitive dysfunction occurs frequently after coronary artery bypass grafting (CABG). The underlying mechanisms remain poorly understood, but neuroinflammation might play a pivotal role. We hypothesise that systemic inflammation induced by the surgical trauma could activate the innate immune (glial) cells of the brain. This could lead to an exaggerated neuroinflammatory cascade, resulting in neuronal dysfunction and loss of neuronal cells. Therefore, the aims of this study are to assess neuroinflammation in vivo presurgery and postsurgery in patients undergoing major cardiac surgery and investigate whether there is a relationship of neuroinflammation to cognitive outcomes, changes to brain structure and function, and systemic inflammation. Methods and analysis: The FOCUS study is a prospective, single-centre observational study, including 30 patients undergoing elective on-pump CABG. Translocator protein (TSPO) positron emission tomography neuroimaging will be performed preoperatively and postoperatively using the second generation tracer 18F-DPA-714 to assess the neuroinflammatory response. In addition, a comprehensive cerebral MRI will be performed presurgery and postsurgery, in order to discover newly developed brain and vascular wall lesions. Up to 6 months postoperatively, serial extensive neurocognitive assessments will be performed and blood will be obtained to quantify systemic inflammatory responses and peripheral immune cell activation. Ethics and dissemination: Patients do not benefit directly from engaging in the study, but imaging neuroinflammation is considered safe and no side effects are expected. The study protocol obtained ethical approval by the Medical Research Ethics Committee region Arnhem-Nijmegen. This work will be published in peer-reviewed international medical journals and presented at medical conferences. Trial registration number NCT04520802.

Item does not contain fulltext, Accurate assessment of lymph node (LN) metastases in prostate cancer (PCa) patients is critical for prognosis and patient management. Both prostate-specific membrane antigen (PSMA) PET/CT and ferumoxtran-10 nanoparticle-enhanced MRI (nano-MRI) are imaging modalities with high potential to identify LN metastases in PCa patients. The aim of this study was to compare the results of these imaging technologies in terms of characteristics and anatomic localization of suspicious LNs in order to assess the feasibility of their complementary use for imaging in PCa patients. Methods: In total, 45 patients with either primary PCa (n = 8) or recurrence (n = 36) were included in this retrospective study. All patients underwent both (68)Ga-PSMA PET/CT and nano-MRI between October 2015 and July 2017 within 3 wk. Both scans were performed at the same institution according to local clinical protocols. All scans were analyzed independently by experienced nuclear medicine physicians and radiologists. The size, anatomic location, and level of suspicion were determined for all visible LNs. Subsequently, the findings from (68)Ga-PSMA PET/CT and nano-MRI were compared without respect to a reference standard. Results: In total, 179 suspicious LNs were identified. Significantly more suspicious LNs per patient were detected by nano-MRI (P < 0.001): 160 were identified in 33 patients by nano-MRI, versus 71 in 25 patients by (68)Ga-PSMA PET/CT. Of all suspicious LNs, 108 were identified only by nano-MRI (60%), 19 (11%) only by (68)Ga-PSMA PET/CT, and 52 (29%) by both methods. The mean size of the suspicious LNs as identified by nano-MRI was significantly smaller (5.3 mm) than that by (68)Ga-PSMA PET/CT (6.0 mm; P = 0.006). The median level of suspicion did not differ significantly. Both modalities identified suspicious LNs in all anatomic regions of the pelvis. Conclusion: Both modalities identified suspicious LNs that were missed by the other. Both modalities identified suspicious LNs in all

Contains fulltext : 237688.pdf (Publisher’s version ) (Open Access), PURPOSE: In this phase I study, we evaluated the safety, biodistribution and dosimetry of [(89)Zr]Zr-DFO-girentuximab ((89)Zr-girentuximab) PET/CT imaging in patients with suspicion of clear cell renal cell carcinoma (ccRCC). METHODS: Ten eligible patients received an intravenous administration of 37 MBq (± 10%) of (89)Zr-girentuximab at mass doses of 5 mg or 10 mg. Safety was evaluated according to the NCI CTCAE (version 4.03). Biodistribution and normal organ dosimetry was performed based on PET/CT images acquired at 0.5, 4, 24, 72 and 168 h post-administration. Additionally, tumour dosimetry was performed in patients with confirmed ccRCC and visible tumour uptake on PET/CT imaging. RESULTS: (89)Zr-girentuximab was administered in ten patients as per protocol. No treatment-related adverse events ≥ grade 3 were reported. (89)Zr-girentuximab imaging allowed successful differentiation between ccRCC and non-ccRCC lesions in all patients, as confirmed with histological data. Dosimetry analysis using OLINDA/EXM 2.1 showed that the organs receiving the highest doses (mean ± SD) were the liver (1.86 ± 0.40 mGy/MBq), the kidneys (1.50 ± 0.22 mGy/MBq) and the heart wall (1.45 ± 0.19 mGy/MBq), with a mean whole body effective dose of 0.57 ± 0.08 mSv/MBq. Tumour dosimetry was performed in the 6 patients with histologically confirmed ccRCC resulting in a median tumour-absorbed dose of 4.03 mGy/MBq (range 1.90-11.6 mGy/MBq). CONCLUSIONS: This study demonstrates that (89)Zr-girentuximab is safe and well tolerated for the administered activities and mass doses and allows quantitative assessment of (89)Zr-girentuximab PET/CT imaging in patients with suspicion of ccRCC. TRIAL REGISTRATION: NCT03556046-14th of June, 2018.

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Contains fulltext : 225124.pdf (Publisher’s version ) (Open Access), PURPOSE: Angiogenesis plays an important role in the growth and metastatic spread of solid tumours and is characterised by the expression of integrins on the cell surface of endothelial cells. Radiolabelled RGD peptides specifically target angiogenesis-related α(v)β(3) integrins, expressed on the activated endothelial cells of sprouting blood vessels. Here, we validated the feasibility of (68)Ga[Ga]-DOTA-E-[c(RGDfK)](2) ((68)Ga-RGD) PET/CT to visualise angiogenesis in patients with oral squamous cell carcinoma (OSCC). METHODS: Ten patients with OSCC and scheduled for surgical resection including elective neck dissection received an intravenously administration of (68)Ga-RGD (42 ± 8 μg; 214 ± 9 MBq). All patients subsequently underwent dynamic (n = 5) or static PET/CT imaging (n = 5) for 60 min or for 4 min/bed position at 30, 60 and 90 min after injection, respectively. Quantitative tracer uptake in tumour lesions was expressed as standardised uptake values (SUV). Additionally, tumour tissue was immunohistochemically stained for α(v)β(3) integrin to assess the expression pattern. RESULTS: (68)Ga-RGD tumour accumulation was observed in all patients. At 60 min post injection, tumour SUV(max) ranged between 4.0 and 12.7. Tracer accumulation in tumour tissue plateaued at 10 min after injection. Uptake in background tissue did not change over time, resulting in tumour-to-muscle tissue of 6.4 ± 0.7 at 60 min post injection. CONCLUSIONS: (68)Ga-RGD PET/CT of α(v)β(3) integrin expression in OSCC patients is feasible with adequate tumour-to-background ratios. It will provide more insight in angiogenesis as a hallmark of the head and neck squamous cell carcinomas' tumour microenvironment. TRIAL REGISTRATION: https://eudract.ema.europa.eu no. 2015-000917-31.

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Radboud University, 16 september 2020, Promotores : Boerman, O.C., Oyen, W.J.G. Co-promotores : Rijpkema, M.J.P., Aarntzen, E.H.J.G., Contains fulltext : 220328 .pdf (publisher's version ) (Open Access)

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Contains fulltext : 220791pub.pdf (publisher's version ) (Open Access), INTRODUCTION: Tumor-targeted imaging is a promising technique for the detection of lymph node metastases (LNM) and primary tumors. It remains unclear which biomarker is the most suitable target to distinguish malignant from healthy tissue in esophageal adenocarcinoma (EAC). OBJECTIVE: We performed an immunohistochemistry study to identify viable tumor markers for tumor-targeted imaging of EAC. METHODS: We used samples from 72 patients with EAC to determine the immunohistochemical expression of ten potential tumor biomarkers for EAC (carbonic anhydrase IX [CA-IX], carcinoembryonic antigen [CEA], hepatic growth factor receptor, epidermal growth factor receptor, epithelial membrane antigen [EMA], epithelial cell adhesion molecule [EpCAM], human epidermal growth factor receptor 2 [HER-2], urokinase plasminogen activator receptor, vascular endothelial growth factor-A [VEGF-A], and VEGF receptor 2). Immunohistochemistry was performed on tissue microarrays of LNM (n = 48), primary EACs (n = 62), fibrotic tissues (n = 11), nonmalignant lymph nodes (n = 24), and normal esophageal and gastric tissues (n = 40). Tumor marker staining was scored on intensity and percentage of positive cells. RESULTS: EMA and EpCAM showed strong expression in LNM (> 95%) and primary EACs (> 95%). Significant expression was also observed for LNM and EAC using VEGF-A (85 and 92%), CEA (68 and 54%), and CA-IX (4 and 34%). The other tumor biomarkers showed expression of 0-15% for LNM and primary EAC. Except for VEGF-A, nonmalignant lymph node staining was scored as slight or absent. CONCLUSIONS: High expression rates and correlation between LNM in EAC combined with low expression rates in healthy lymph nodes and esophagus tissues were observed for EpCAM and CEA, meaning these are promising targets for tumor-targeted imaging approaches for lymph nodes in patients with EAC.

Contains fulltext : 219699.pdf (publisher's version ) (Open Access), Huntington's disease (HD) is a fatal neurodegenerative disease caused by a CAG expansion mutation in the huntingtin gene. As a result, intranuclear inclusions of mutant huntingtin protein are formed, which damage striatal medium spiny neurons (MSNs). A review of Positron Emission Tomography (PET) studies relating to HD was performed, including clinical and preclinical data. PET is a powerful tool for visualisation of the HD pathology by non-invasive imaging of specific radiopharmaceuticals, which provide a detailed molecular snapshot of complex mechanistic pathways within the brain. Nowadays, radiochemists are equipped with an impressive arsenal of radioligands to accurately recognise particular receptors of interest. These include key biomarkers of HD: adenosine, cannabinoid, dopaminergic and glutamateric receptors, microglial activation, phosphodiesterase 10 A and synaptic vesicle proteins. This review aims to provide a radiochemical picture of the recent developments in the field of HD PET, with significant attention devoted to radiosynthetic routes towards the tracers relevant to this disease.

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Contains fulltext : 218875.pdf (publisher's version ) (Open Access), Myxofibrosarcoma(MFS) is the most common soft tissue sarcoma(STS) in elderly patients. Surgical resection remains the main treatment modality but tumor borders can be difficult to delineate with conventional clinical methods. Incomplete resections are a common problem and local recurrence remains a clinical issue. A technique that has shown great potential in improving surgical treatment of solid tumors is tumor targeted imaging and image-guided surgery with near-infrared fluorescence. To facilitate this technique, it is essential to identify a biomarker that is highly and homogenously expressed on tumor cells, while being absent on healthy non-malignant tissue. The purpose of this study was to identify suitable molecular targets for tumor-targeted imaging of myxofibrosarcoma. Ten potential molecular targets for tumor targeted imaging were investigated with immunohistochemical analysis in myxofibrosarcoma tissue (n = 34). Results were quantified according to the immunoreactive score(IRS). Moderate expression rates were found for uPAR, PDGFRa and EMA/MUC1. High expression rates of VEGF and TEM1 were seen. Strong expression was most common for TEM1 (88.2%). These results confirms that TEM1 is a suitable target for tumor-targeted imaging of myxofibrosarcoma. Keywords Image-guided surgery; Immunohistochemistry; Molecular imaging; Myxofibrosarcoma; Soft tissue sarcoma; Tumor endothelial marker 1(TEM1), Vascular endothelial growth factor (VEGF).

Radboud University, 12 november 2020, Promotores : Boerman, O.C., Wilt, J.H.W. de Co-promotores : Rijpkema, M.J.P., Bremers, A.J.A., Contains fulltext : 225375.pdf (publisher's version ) (Open Access)

Contains fulltext : 229511.pdf (Publisher’s version ) (Open Access), OBJECTIVE: In RA, synovial fibroblasts become activated. These cells express fibroblast activation protein (FAP) and contribute to the pathogenesis by producing cytokines, chemokines and proteases. Selective depletion in inflamed joints could therefore constitute a viable treatment option. To this end, we developed and tested a new therapeutic strategy based on the selective destruction of FAP-positive cells by targeted photodynamic therapy (tPDT) using the anti-FAP antibody 28H1 coupled to the photosensitizer IRDye700DX. METHODS: After conjugation of IRDye700DX to 28H1, the immunoreactive binding and specificity of the conjugate were determined. Subsequently, tPDT efficiency was established in vitro using a 3T3 cell line stably transfected with FAP. The biodistribution of [111In]In-DTPA-28H1 with and without IRDye700DX was assessed in healthy C57BL/6N mice and in C57BL/6N mice with antigen-induced arthritis. The potential of FAP-tPDT to induce targeted damage was determined ex vivo by treating knee joints from C57BL/6N mice with antigen-induced arthritis 24 h after injection of the conjugate. Finally, the effect of FAP-tPDT on arthritis development was determined in mice with collagen-induced arthritis. RESULTS: 28H1-700DX was able to efficiently induce FAP-specific cell death in vitro. Accumulation of the anti-FAP antibody in arthritic knee joints was not affected by conjugation with the photosensitizer. Arthritis development was moderately delayed in mice with collagen-induced arthritis after FAP-tPDT. CONCLUSION: Here we demonstrate the feasibility of tPDT to selectively target and kill FAP-positive fibroblasts in vitro and modulate arthritis in vivo using a mouse model of RA. This approach may have therapeutic potential in (refractory) arthritis.

Contains fulltext : 204875.pdf (publisher's version ) (Open Access), Introduction: Evidence indicates a bidirectional relationship between poor sleep and Alzheimer’s disease (AD). While AD may lead to disruption of normal sleep, poor sleep in itself may play a causal role in the development of AD by influencing the production and/or clearance of the amyloid-beta (Aβ) protein. This led to the hypothesis that extended periods (>10 years) of sleep loss could lead to Aβ accumulation with subsequent cognitive AD-related decline. This manuscript describes the methodology of the SCHIP study, a cohort study in maritime pilots that aims at investigating the relationship between prolonged work-related sleep loss, cognitive function and amyloid accumulation among healthy middle-aged maritime pilots, to test the hypothesis that prolonged sleep loss increases the risk of AD-related cognitive decline. Methods: Our study sample consists of a group of healthy middle-aged maritime pilots (n=20), who have been exposed to highly irregular work schedules for more than 15 years. The maritime pilots will be compared to a group of healthy, age and education-matched controls (n=20) with normal sleep. Participants will complete 10 days of actigraphy (Actiwatch 2, Philips Respironics) combined with a sleep-wake diary. They will undergo one night of polysomnography, followed by comprehensive assessment of cognitive function. Additionally, participants will undergo amyloid positron emission tomography-CT to measure brain amyloid accumulation and MRI to investigate atrophy and vascular changes. Analysis: All analyses will be performed using IBM SPSS V.20.0 (SPSS). We will perform independent samples t-tests to compare all outcome parameters. Ethics and dissemination The study protocol was approved by our institutional ethical review board (NL55712.091.16, file number 2016-2337) and will be performed according to Good Clinical Practice rules. Data and results will be published in 2020.

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Contains fulltext : 215222.pdf (publisher's version ) (Open Access), Despite recent improvements in imaging and therapy, prostate cancer (PCa) still causes substantial morbidity and mortality. In surgical treatment, incomplete resection of PCa and understaging of possible undetected metastases may lead to disease recurrence and consequently poor patient outcome. To increase the chance of accurate staging and subsequently complete removal of all cancerous tissue, prostate specific membrane antigen (PSMA) targeting agents may provide the surgeon an aid for the intraoperative detection and resection of PCa lesions. Two modalities suitable for this purpose are radionuclide detection, which allows sensitive intraoperative localization of tumor lesions with a gamma probe, and fluorescence imaging, allowing tumor visualization and delineation. Next to fluorescence, use of photosensitizers may enable intraoperative targeted photodynamic therapy to eradicate remaining tumor lesions. Since radiodetection and optical imaging techniques each have their own strengths and weaknesses, a combination of both modalities could be of additional value. Here, we provide an overview of recent preclinical and clinical advances in PSMA-targeted radio- and fluorescence-guided surgery of PCa.

Contains fulltext : 215195.pdf (publisher's version ) (Open Access), BACKGROUND: In colorectal cancer, survival of patients is drastically reduced when complete resection is hampered by involvement of critical structures. Targeted photodynamic therapy (tPDT) is a local and targeted therapy which could play a role in eradicating residual tumor cells after incomplete resection. Since carcinoembryonic antigen (CEA; CEACAM5) is abundantly overexpressed in colorectal cancer, it is a potential target for tPDT of colorectal cancer. METHODS: To address the potential of CEA-targeted PDT, we compared colorectal cancer cell lines with different CEA-expression levels (SW-48, SW-480, SW-620, SW-1222, WiDr, HT-29, DLD-1, LS174T, and LoVo) under identical experimental conditions. We evaluated the susceptibility to tPDT by varying radiant exposure and concentration of our antibody conjugate (DTPA-hMN-14-IRDye700DX). Finally, we assessed the efficacy of tPDT in vivo in 18 mice (BALB/cAnNRj-Foxn1(nu/nu)) with subcutaneously xenografted LoVo tumors. RESULTS: In vitro, the treatment effect of tPDT varied per cell line and was dependent on both radiant exposure and antibody concentration. Under standardized conditions (94.5 J/cm(2) and 0.5 mug/muL antibody conjugate concentration), the effect of tPDT was higher in cells with higher CEA availability: SW-1222, LS174T, LoVo, and SW-48 (22.8%, 52.8%, 49.9%, and 51.9% reduction of viable cells, respectively) compared to cells with lower CEA availability. Compared to control groups (light or antibody conjugate only), tumor growth rate was reduced in mice with s.c. LoVo tumors receiving tPDT. CONCLUSION: Our findings suggest cells (and tumors) have different levels of susceptibility for tPDT even though they all express CEA. Furthermore, tPDT can effectively reduce tumor growth in vivo.

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Contains fulltext : 205486.pdf (publisher's version ) (Closed access), The aim was to compare the prostate-specific membrane antigen (PSMA)-targeting characteristics of PSMA-11, radiolabeled on the basis of chelation of (18)F-AlF, with those of (68)Ga-PSMA-11 to image PSMA-expressing xenografts. Methods: Labeling of (18)F-AlF-PSMA-11 via (18)F-AlF-complexation was performed as described by Boschi et al. and Malik et al. with minor modifications. Several conditions for the quality control of the labeling of (18)F-AlF-PSMA-11 via (18)F-AlF-complexation were evaluated to characterize the influence of ethanol, acetonitrile, and trifluoroacetic acid on the stability of the labeled product. Internalization kinetics of (18)F-AlF-PSMA-11 were compared with those of (68)Ga-PSMA-11 using PSMA-expressing LNCaP tumor cells. Biodistribution of (18)F-AlF-PSMA-11 (0.26 nmol/mouse, 8-9 MBq/mouse) in male BALB/c nude mice with PSMA-expressing subcutaneous LS174T-PSMA tumors was compared with that of (68)Ga-PSMA-11 at 1 and 2 h after injection. In addition, (18)F-AlF-PSMA-11 PET/CT and (68)Ga-PSMA-11 PET/CT imaging were performed at 1 and 2 h after injection. Results: In contrast to (68)Ga-PSMA-11, (18)F-AlF-PSMA-11 was not stable in water (radiochemical purity was 64.5% immediately after purification and 52.7% at 120 min after purification). (18)F-AlF-PSMA-11 remained relatively stable in 25 mM NH4OAc, pH 6.9, and radiochemical purity decreased from 98.5% at purification to 96.3%, 94.7%, and 92.5% at 60, 120, and 180 min after purification. In vitro, the (18)F- and (68)Ga-labeled compounds showed rapid internalization in LS174T-PSMA cells. The highest tumor uptake (percentage injected dose [%ID]) was observed at 2 h after injection (10.8 +/- 2.3 %ID/g and 7.9 +/- 1.3 %ID/g for (18)F-AlF-PSMA-11 and (68)Ga-PSMA-11, respectively [P > 0.05]). Renal tracer uptake peaked at 2 h after injection (43.5 +/- 5.7 %ID/g and 105.8 +/- 13.8 %ID/g for (18)F-AlF-PSMA-11 and (68)Ga-PSMA-11, respectively, P < 0.05). Bone uptake of (18)F-AlF-PSMA-11 was 3.3 +/- 0.6 at 1

Radboud University, 7 december 2018, Promotores : Mulders, P.F.A., Boerman, O.C. Co-promotores : Rijpkema, M.J.P., Oosterwijk, E., Contains fulltext : 197559.pdf (publisher's version ) (Open Access)

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Contains fulltext : 193281.pdf (publisher's version ) (Open Access), Intraoperative imaging with antibodies labeled with both a radionuclide for initial guidance and a near-infrared dye for adequate tumor delineation may overcome the main limitation of fluorescence imaging: the limited penetration depth of light in biological tissue. In this study, we demonstrate the feasibility and safety of intraoperative dual-modality imaging with the carbonic anhydrase IX (CAIX)-targeting antibody (111)In-DOTA-girentuximab-IRDye800CW in clear cell renal cell carcinoma (ccRCC) patients. Methods: A phase I protein dose escalation study was performed in patients with a primary renal mass who were scheduled for surgery. (111)In-DOTA-girentuximab-IRDye800CW (5, 10, 30, or 50 mg, n=3 ccRCC patients per dose level) was administered intravenously and after 4 days SPECT/CT imaging was performed. Seven days after antibody injection, surgery was performed with the use of a gamma probe and near-infrared fluorescence camera. Results: In total, fifteen patients were included (12 ccRCC, 3 CAIX-negative tumors). No study-related serious adverse events were observed. All ccRCC were visualized by SPECT/CT and localized by intraoperative gamma probe detection (mean tumor-to-normal kidney (T:N) ratio 2.5 +/- 0.8), while the T:N ratio was 1.0 +/- 0.1 in CAIX-negative tumors. ccRCC were hyperfluorescent at all protein doses and fluorescence imaging could be used for intraoperative tumor delineation, assessment of the surgical cavity and detection of (positive) surgical margins. The radiosignal was crucial for tumor localization in case of overlying fat tissue. Conclusion: This first in man study shows that tumor-targeted dual-modality imaging using (111)In-DOTA-girentuximab-IRDye800CW is safe and can be used for intraoperative guidance of ccRCC resection.

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Contains fulltext : 194444.pdf (publisher's version ) (Closed access)

Contains fulltext : 194513.pdf (publisher's version ) (Open Access)

Contains fulltext : 177772.pdf (publisher's version ) (Open Access), Complete resection of tumor lesions in advanced stage ovarian cancer patients is of utmost importance, since the extent of residual disease after surgery strongly affects survival. Intraoperative imaging may be useful to improve surgery in these patients. Farletuzumab is a humanized IgG1 antibody that specifically recognizes the folate receptor alpha (FRalpha). Labeled with a radiolabel and a fluorescent dye, farletuzumab may be used for the intraoperative detection of ovarian cancer lesions. The current aim is to demonstrate the feasibility of FRalpha-targeted dual-modality imaging using 111In-farletuzumab-IRDye800CW in an intraperitoneal ovarian cancer model. Biodistribution studies were performed 3 days after injection of 3, 10, 30, or 100 mug of 111In-farletuzumab-IRDye800CW in mice with subcutaneous IGROV-1 tumors (5 mice per group). In mice with intraperitoneal IGROV-1 tumors the nonspecific uptake of 111In-farletuzumab-IRDye800CW was determined by coinjecting an excess of unlabeled farletuzumab. MicroSPECT/CT and fluorescence imaging were performed 3 days after injection of 10 mug of 111In-farletuzumab-IRDye800CW. FRalpha expression in tumors was determined immunohistochemically. Optimal tumor-to-blood-ratios (3.4-3.7) were obtained at protein doses up to 30 mug. Multiple intra-abdominal tumor lesions were clearly visualized by microSPECT/CT, while uptake in normal tissues was limited. Fluorescence imaging was used to visualize and guide resection of superficial tumors. Coinjection of an excess of unlabeled farletuzumab significantly decreased tumor uptake of 111In-farletuzumab-IRDye800CW (69.4 +/- 27.6 versus 18.3 +/- 2.2% ID/g, p < 0.05). Immunohistochemical analyses demonstrated that the radioactive and fluorescent signal corresponded with FRalpha-expressing tumor lesions. FRalpha-targeted SPECT/fluorescence imaging using 111In-farletuzumab-IRDye800CW can be used to detect ovarian cancer in vivo and could be a valuable tool for enhanced intraoperative tumo

Contains fulltext : 173129.pdf (publisher's version ) (Open Access), Despite the large interest in nuclear/optical multimodality imaging, the effect of radiation on the fluorescence of fluorophores remains largely unexplored. Herein, we report on the radiobleaching of cyanine fluorophores and describe conditions to provide robust radioprotection under practical (pre)clinical settings. We determined the radiosensitivity of several cyanine fluorescent compounds, including IRDye 800CW (800CW) and a dual modality imaging tetrapeptide containing DOTA as chelator and Dylight 800 as fluorophore, exposed to increasing activities of 111In, 68Ga, or 213Bi (gamma, EC/beta, and alpha emitter, respectively). An activity and type of radiation-dependent radiation-induced loss of fluorescence, radiobleaching, of 800CW was observed upon incubation with escalating activities of 111In, 68Ga, or 213Bi. 68Ga showed the largest radiolytic effect, followed by 111In and 213Bi. The addition of oxygen radical scavengers including ethanol, gentisic acid, and ascorbic acid (AA), provided a concentration dependent radioprotective effect. These results supported the hypothesis of a free radical-mediated radiobleaching mechanism. AA provided the most robust radioprotection over a wide range of concentrations and preserved fluorescence at much higher radioactivity levels. Overall, both near-infrared fluorescent compounds displayed similar sensitivity, except for 213Bi-irradiated solutions, where the dual modality construct exhibited enhanced radiolysis, presumably due to direct radiation damage from alpha particles. Concurrently, AA was not able to preserve fluorescence of the dual-modality molecule labeled with 213Bi. Our findings have important consequences for several research areas including ROS sensing, radiation-mediated drug release (uncaging), fluorescent dosimetry, and in the preparation of dual-modality radiopharmaceuticals.

Item does not contain fulltext, Intraoperative dual-modality imaging can help the surgeon distinguish tumor from normal tissue. This technique may prove particularly valuable if small tumors need to be removed that are difficult to detect with the naked eye. The humanized anticarcinoembryonic antigen (anti-CEA) monoclonal antibody, labetuzumab, can be used as a tumor-targeting agent in colorectal cancer, since CEA is overexpressed in approximately 95% of colorectal cancer. Dual-labeled labetuzumab, labeled with both a near-infrared fluorescent dye (IRDye800CW) and a radioactive label (111In), can be used as a tracer for dual-modality imaging. This study aimed to assess whether dual-modality imaging using 111In-diethylenetriaminepentaacetic acid (DTPA)-labetuzumab-IRDye800CW can detect pulmonary micrometastases in a mouse model. Methods: Pulmonary GW-39 human colonic carcinoma microcolonies were induced in athymic BALB/c mice by intravenous injection of 100 muL of a GW-39 cell suspension. After 1, 2, 3, and 4 wk of tumor growth, dual-modality imaging was performed 3 d after intravenous injection of 111In-DTPA-labetuzumab-IRDye800CW (10 mug, 25 MBq). Small-animal SPECT images and optical images were acquired, and image-guided surgery was performed. Finally, the biodistribution of the dual-labeled tracer was determined. Formalin-fixed sections of the lungs were analyzed using fluorescence imaging, autoradiography, and immunohistochemistry. Results: Submillimeter pulmonary tumor colonies could be visualized with both small-animal SPECT and fluorescence imaging from the first week of tumor growth, before they became visible to the naked eye. Furthermore, dual-modality imaging could be used to guide resection of tumors. Mean uptake (percentage injected dose per gram) of the dual-labeled tracer in tumors was 17.2 +/- 5.4 and 16.5 +/- 4.4 at weeks 3 and 4, respectively. Immunohistochemical analysis of the tumorous lungs showed that the distribution of the radioactive and fluorescent signal colocalized wit

Contains fulltext : 181624.pdf (Publisher’s version ) (Open Access), Immuno-positron emission tomography (immunoPET) with (89)Zr-labeled antibodies has shown great potential in cancer imaging. It can provide important information about the pharmacokinetics and tumor-targeting properties of monoclonal antibodies and may help in anticipating on toxicity. Furthermore, it allows accurate dose planning for individualized radioimmunotherapy and may aid in patient selection and early-response monitoring for targeted therapies. The most commonly used chelator for (89)Zr is desferrioxamine (DFO). Preclinical studies have shown that DFO is not an ideal chelator because the (89)Zr-DFO complex is partly unstable in vivo, which results in the release of (89)Zr from the chelator and the subsequent accumulation of (89)Zr in bone. This bone accumulation interferes with accurate interpretation and quantification of bone uptake on PET images. Therefore, there is a need for novel chelators that allow more stable complexation of (89)Zr. In this Review, we will describe the most recent developments in (89)Zr radiochemistry, including novel chelators and site-specific conjugation methods.