Time of Flight Secondary Ion Mass Spectrometry imaging for precise localization of zirconium-labelled trastuzumab in xenograft cancer tumour tissues

The human epidermal growth factor receptor 2 (HER2) specific radiotracer zirconium-Desferrioxamine(DFO)-trastuzumab was visualized ex-vivo by Time of Flight Secondary Ion Mass Spectrometry (ToF-SIMS) imaging in ovarian and breast cancer xenograft tumor sections. Heterogeneous spatial distribution of [90Zr+] ions re-flected the heterogeneous localization of trastuzumab, observed in parallel by immunohistochemistry staining in HER2+ tumors. Our results show that ToF-SIMS imaging is a quick and sensitive technique to image zirconium labelled biologics at microscale in tissues

Elucidating the Influence of Tumor Presence on the Polymersome Circulation Time in Mice

The use of nanoparticles as tumor-targeting agents is steadily increasing, and the influence of nanoparticle characteristics such as size and stealthiness have been established for a large number of nanocarrier systems. However, not much is known about the impact of tumor presence on nanocarrier circulation times. This paper reports on the influence of tumor presence on the in vivo circulation time and biodistribution of polybutadiene-polyethylene oxide (PBd-PEO) polymersomes. For thi

Preventing overuse of laboratory diagnostics: a case study into diagnosing anaemia in Dutch general practice

BACKGROUND: More information is often thought to improve medical decision-making, which may lead to test overuse. This study assesses which out of 15 laboratory tests contribute to diagnosing the underlying cause of anaemia by general practitioners (GPs) and determines a potentially more efficient subset of tests for setting the correct diagnosis. METHODS: Logistic regression was performed to determine the impact of individual tests on the (correct) diagnosis. The statistically optimal test subset for diagnosing a (correct) underlying cause of anaemia by GPs was determined using data from a previous survey including cases of real-world anaemia patients. RESULTS: Only 9 (60%) of the laboratory tests, and patient age, contributed significantly to the GPs' ability to diagnose an underlying cause of anaemia (CRP, ESR, ferritin, folic acid, haemoglobin, leukocytes, eGFR/MDRD, reticulocytes and serum iron). Diagnosing the correct underlying cause may require just five (33%) tests (CRP, ferritin, folic acid, MCV and transferrin), and patient age. CONCLUSIONS: In diagnosing the underlying cause of anaemia a subset of five tests has most added value. The real-world impact of using only this subset should be further investigated. As illustrated in this case study, a statistical approach to assessing the added value of tests may reduce test overuse

Imaging and photodynamic therapy of prostate cancer using a theranostic PSMA-targeting ligand

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 111In 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

Preventing overuse of laboratory diagnostics: a case study into diagnosing anaemia in Dutch general practice

BACKGROUND: More information is often thought to improve medical decision-making, which may lead to test overuse. This study assesses which out of 15 laboratory tests contribute to diagnosing the underlying cause of anaemia by general practitioners (GPs) and determines a potentially more efficient subset of tests for setting the correct diagnosis. METHODS: Logistic regression was performed to determine the impact of individual tests on the (correct) diagnosis. The statistically optimal test subset for diagnosing a (correct) underlying cause of anaemia by GPs was determined using data from a previous survey including cases of real-world anaemia patients. RESULTS: Only 9 (60%) of the laboratory tests, and patient age, contributed significantly to the GPs' ability to diagnose an underlying cause of anaemia (CRP, ESR, ferritin, folic acid, haemoglobin, leukocytes, eGFR/MDRD, reticulocytes and serum iron). Diagnosing the correct underlying cause may require just five (33%) tests (CRP, ferritin, folic acid, MCV and transferrin), and patient age. CONCLUSIONS: In diagnosing the underlying cause of anaemia a subset of five tests has most added value. The real-world impact of using only this subset should be further investigated. As illustrated in this case study, a statistical approach to assessing the added value of tests may reduce test overuse

The in vivo fate of 225Ac daughter nuclides using polymersomes as a model carrier

Increasing attention is given to personalized tumour therapy, where alpha-emitters can potentially play an important role. Alpha particles are ideal for localized cell killing because of their high linear energy transfer and short ranges. However, upon the emission of an alpha particle the daughter nuclide experiences a recoil energy large enough to ensure decoupling from any chemical bond. These ‘free’ daughter nuclides are no longer targeted to the tumour and can accumulate in normal tissue. In this paper, we used polymersomes as model carrier to evaluate the retention of recoiling daughters of 225Ac in vivo, and assessed their suitability as therapeutic agents. Vesicles containing 225Ac were injected intravenously in healthy mice, and intratumourally in tumour-bearing mice, and the relocation of free 213Bi was assessed in different organs upon the injection [225Ac]Ac-polymersomes. The therapeutic effect of 225Ac-containing vesicles was studied upon intratumoural injection, where treatment groups experienced no tumour-related deaths over a 115 day period. While polymersomes containing 225Ac could be suitable agents for long-term irradiation of tumours without causing significant renal toxicity, there is still a significant re-distribution of daughter nuclides throughout the body, signifying the importance of careful evaluation of the effect of daughter nuclides in targeted alpha therapy.JRC.G.I.5-Advanced Nuclear Knowledg

Recoil retention and therapeutic efficacy of 225Ac-containing polymersomes

Alpha emitters can play an important role in cancer treatment. With their high linear energy transfer and short range, alpha particles are ideal for localized cell killing. However, upon emission of an alpha particle, the radioactive daughter nuclides experience a recoil energy of about 100-200 keV which is much larger than the energy of any chemical bond, resulting in the daughter nuclide breaking free from any targeting agent. These daughters can accumulate in healthy tissue as kidneys, resulting in toxicity. Here, we evaluate the retention of recoiling daughter 213Bi of 225Ac entrapped in polymersomes in vivo, both upon intravenous as well as intratumoral administration. Furthermore, the suitability of 225Ac-containing PBD-PEO (poly-butadiene-poly-ethylene oxide) polymersomes as therapeutic agents is assessed upon intratumoral injection.JRC.G.I.5-Advanced Nuclear Knowledg

Site-Specific Dual-Labeling of a VHH with a Chelator and a Photosensitizer for Nuclear Imaging and Targeted Photodynamic Therapy of EGFR-Positive Tumors

International audienceVariable domains of heavy chain only antibodies (VHHs) are valuable agents for application in tumor theranostics upon conjugation to both a diagnostic probe and a therapeutic compound. Here, we optimized site-specific conjugation of the chelator DTPA and the photosensitizer IRDye700DX to anti-epidermal growth factor receptor (EGFR) VHH 7D12, for applications in nuclear imaging and photodynamic therapy. 7D12 was site-specifically equipped with bimodal probe DTPA-tetrazine-IRDye700DX using the dichlorotetrazine conjugation platform. Binding, internalization and light-induced toxicity of DTPA-IRDye700DX-7D12 were determined using EGFR-overexpressing A431 cells. Finally, ex vivo biodistribution of DTPA-IRDye700DX-7D12 in A431 tumor-bearing mice was performed, and tumor homing was visualized with SPECT and fluorescence imaging. DTPA-IRDye700DX-7D12 was retrieved with a protein recovery of 43%, and a degree of labeling of 0.56. Spectral properties of the IRDye700DX were retained upon conjugation. 111In-labeled DTPA-IRDye700DX-7D12 bound specifically to A431 cells, and they were effectively killed upon illumination. DTPA-IRDye700DX-7D12 homed to A431 xenografts in vivo, and this could be visualized with both SPECT and fluorescence imaging. In conclusion, the dichlorotetrazine platform offers a feasible method for site-specific dual-labeling of VHH 7D12, retaining binding affinity and therapeutic efficacy. The flexibility of the described approach makes it easy to vary the nature of the probes for other combinations of diagnostic and therapeutic compounds