ORCID Profile
0000-0002-7623-2401
Current Organisations
Wolfson College, University of Oxford
,
University of Oxford
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Publications
Correlation between molar activity, injection mass and uptake of the PARP targeting radiotracer [18F]olaparib in mouse models of glioma
Publisher: Springer Science and Business Media LLC
Date: 09-10-2022
DOI: 10.1186/S13550-022-00940-9
Abstract: Radiopharmaceuticals targeting poly(ADP-ribose) polymerase (PARP) have emerged as promising agents for cancer diagnosis and therapy. PARP enzymes are expressed in both cancerous and normal tissue. Hence, the injected mass, molar activity and potential pharmacological effects are important considerations for the use of radiolabelled PARP inhibitors for diagnostic and radionuclide therapeutic applications. Here, we performed a systematic evaluation by varying the molar activity of [ 18 F]olaparib and the injected mass of [ Total F]olaparib to investigate the effects on tumour and normal tissue uptake in two subcutaneous human glioblastoma xenograft models. [ 18 F]Olaparib uptake was evaluated in the human glioblastoma models: in vitro on U251MG and U87MG cell lines, and in vivo on tumour xenograft-bearing mice, after administration of [ Total F]olaparib (varying injected mass: 0.04–8.0 µg, and molar activity: 1–320 GBq/μmol). Selective uptake of [ 18 F]olaparib was demonstrated in both models. Tumour uptake was found to be dependent on the injected mass of [ Total F]olaparib (µg) but not the molar activity. An injected mass of 1 μg resulted in the highest tumour uptake (up to 6.9 ± 1.3%ID/g), independent of the molar activity. In comparison, both the lower and higher injected masses of [ Total F]olaparib resulted in lower relative tumour uptake (%ID/g P 0.05). Ex vivo analysis of U87MG xenograft sections showed that the heterogeneity in [ 18 F]olaparib intratumoural uptake correlated with PARP1 expression. Substantial upregulation of PARP1-3 expression was observed after administration of [ Total F]olaparib ( 0.5 µg). Our findings show that the injected mass of [ Total F]olaparib has significant effects on tumour uptake. Moderate injected masses of PARP inhibitor-derived radiopharmaceuticals may lead to improved relative tumour uptake and tumour-to-background ratio for cancer diagnosis and radionuclide therapy.
Detection limit of 89Zr-labeled T cells for cellular tracking: an in vitro imaging approach using clinical PET/CT and PET/MRI
Publisher: Springer Science and Business Media LLC
Date: 14-07-2020
DOI: 10.1186/S13550-020-00667-5
Abstract: Tracking cells in vivo using imaging can provide non-invasive information to understand the pharmacology, efficacy, and safety of novel cell therapies. Zirconium-89 ( t 1/2 = 78.4 h) has recently been used to synthesize [ 89 Zr]Zr(oxinate) 4 for cell tracking using positron emission tomography (PET). This work presents an in vitro approach to estimate the detection limit for in vivo PET imaging of Jurkat T cells directly labeled with [ 89 Zr]Zr(oxinate) 4 utilizing clinical PET/CT and PET/MRI. Jurkat T cells were labeled with varying concentrations of [ 89 Zr]Zr(oxinate) 4 to generate different cell-specific activities (0.43–31.91 kBq/10 6 cells). Different concentrations of labeled cell suspensions (10 4 , 10 5 , and 10 6 cells) were seeded on 6-well plates and into a 3 × 3 cubic-well plate with 1 cm 3 cubic wells as a gel matrix. Plates were imaged on clinical PET/CT and PET/MRI scanners for 30 min. The total activity in each well was determined by drawing volumes of interest over each well on PET images. The total cell-associated activity was measured using a well counter and correlated with imaging data. Simulations for non-specific signal were performed to model the effect of non-specific radioactivity on detection. Using this in vitro model, the lowest cell number that could be visualized on 6-well plate images was 6.8 × 10 4 , when the specific activity was 27.8 kBq/10 6 cells. For the 3 × 3 cubic-well, a plate of 3.3 × 10 4 cells could be detected on images with a specific activity of 15.4 kBq/10 6 cells. The results show the feasibility of detecting [ 89 Zr]Zr(oxinate) 4 -labeled Jurkat T cells on clinical PET systems. The results provide a best-case scenario, as in vivo detection using PET/CT or PET/MRI will be affected by cell number, specific activity per cell, the density of cells within the target volume, and non-specific signal. This work has important implications for cell labeling studies in patients, particularly when using radiosensitive cells (e.g., T cells), which require detection of low cell numbers while minimizing radiation dose per cell.
Imaging PARP with [18F]rucaparib in pancreatic cancer models
Publisher: Springer Science and Business Media LLC
Date: 26-05-2022
DOI: 10.1007/S00259-022-05835-4
Abstract: Rucaparib, an FDA-approved PARP inhibitor, is used as a single agent in maintenance therapy to provide promising treatment efficacy with an acceptable safety profile in various types of BRCA -mutated cancers. However, not all patients receive the same benefit from rucaparib-maintenance therapy. A predictive biomarker to help with patient selection for rucaparib treatment and predict clinical benefit is therefore warranted. With this aim, we developed [ 18 F]rucaparib, an 18 F-labelled isotopologue of rucaparib, and employed it as a PARP-targeting agent for cancer imaging with PET. Here, we report the in vitro and in vivo evaluation of [ 18 F]rucaparib in human pancreatic cancer models. We incorporated the positron-emitting 18 F isotope into rucaparib, enabling its use as a PET imaging agent. [ 18 F]rucaparib binds to the DNA damage repair enzyme, PARP, allowing direct visualisation and measurement of PARP in cancerous models before and after PARP inhibition or other genotoxic cancer therapies, providing critical information for cancer diagnosis and therapy. Proof-of-concept evaluations were determined in pancreatic cancer models. Uptake of [ 18 F]rucaparib was found to be mainly dependent on PARP1 expression. Induction of DNA damage increased PARP expression, thereby increasing uptake of [ 18 F]rucaparib. In vivo studies revealed relatively fast blood clearance of [ 18 F]rucaparib in PSN1 tumour-bearing mice, with a tumour uptake of 5.5 ± 0.5%ID/g (1 h after i.v. administration). In vitro and in vivo studies showed significant reduction of [ 18 F]rucaparib uptake by addition of different PARP inhibitors, indicating PARP-selective binding. Taken together, we demonstrate the potential of [ 18 F]rucaparib as a non-invasive PARP-targeting imaging agent for pancreatic cancers.
The emerging role of cell surface receptor and protein binding radiopharmaceuticals in cancer diagnostics and therapy
Publisher: Elsevier BV
Date: 2021
Radiofluorination of a highly potent ATM inhibitor as a potential PET imaging agent
Publisher: Springer Science and Business Media LLC
Date: 13-08-2022
DOI: 10.1186/S13550-022-00920-Z
Abstract: Ataxia telangiectasia mutated (ATM) is a key mediator of the DNA damage response, and several ATM inhibitors (ATMi) are currently undergoing early phase clinical trials for the treatment of cancer. A radiolabelled ATMi to determine drug pharmacokinetics could assist patient selection in a move towards more personalised medicine. The aim of this study was to synthesise and investigate the first 18 F-labelled ATM inhibitor [ 18 F] 1 for non-invasive imaging of ATM protein and ATMi pharmacokinetics. Radiofluorination of a confirmed selective ATM inhibitor ( 1 ) was achieved through substitution of a nitro-precursor with [ 18 F]fluoride. Uptake of [ 18 F] 1 was assessed in vitro in H1299 lung cancer cells stably transfected with shRNA to reduce expression of ATM. Blocking studies using several non-radioactive ATM inhibitors assessed binding specificity to ATM. In vivo biodistribution studies were performed in wild-type and ATM-knockout C57BL/6 mice using PET/CT and ex vivo analysis. Uptake of [ 18 F] 1 in H1299 tumour xenografts was assessed in BALB/c nu / nu mice. Nitro-precursor 2 was synthesised with an overall yield of 12%. Radiofluorination of 2 achieved radiochemically pure [ 18 F] 1 in 80 ± 13 min with a radiochemical yield of 20 ± 13% (decay-corrected) and molar activities up to 79.5 GBq/μmol ( n = 11). In vitro, cell-associated activity of [ 18 F] 1 increased over 1 h, and retention of [ 18 F] 1 dropped to 50% over 2 h. [ 18 F] 1 uptake did not correlate with ATM expression, but could be reduced significantly with an excess of known ATM inhibitors, demonstrating specific binding of [ 18 F] 1 to ATM. In vivo, fast hepatobiliary clearance was observed with tumour uptake ranging 0.13–0.90%ID/g after 1 h. Here, we report the first radiofluorination of an ATM inhibitor and its in vitro and in vivo biological evaluations, revealing the benefits but also some limitations of 18 F-labelled ATM inhibitors.
[123I]CC1: A PARP-Targeting, Auger Electron–Emitting Radiopharmaceutical for Radionuclide Therapy of Cancer
Publisher: Society of Nuclear Medicine
Date: 28-09-2023
In Vivo Cell Tracking Using PET: Opportunities and Challenges for Clinical Translation in Oncology
Publisher: MDPI AG
Date: 11-08-2021
Abstract: Cell therapy is a rapidly evolving field involving a wide spectrum of therapeutic cells for personalised medicine in cancer. In vivo imaging and tracking of cells can provide useful information for improving the accuracy, efficacy, and safety of cell therapies. This review focuses on radiopharmaceuticals for the non-invasive detection and tracking of therapeutic cells using positron emission tomography (PET). A range of approaches for imaging therapeutic cells is discussed: Direct ex vivo labelling of cells, in vivo indirect labelling of cells by utilising gene reporters, and detection of specific antigens expressed on the target cells using antibody-based radiopharmaceuticals (immuno-PET). This review examines the evaluation of PET imaging methods for therapeutic cell tracking in preclinical cancer models, their role in the translation into patients, first-in-human studies, as well as the translational challenges involved and how they can be overcome.
Intravital Imaging of Adoptive T-Cell Morphology, Mobility and Trafficking Following Immune Checkpoint Inhibition in a Mouse Melanoma Model
Publisher: Frontiers Media SA
Date: 22-07-2020
Related Organisations
Agency For Science Technology And Research (A*Star)
Location: Singapore
Imperial College London
Location: United Kingdom of Great Britain and Northern Ireland
University Of Cambridge
Location: United Kingdom of Great Britain and Northern Ireland
Wolfson College, University Of Oxford
Location: United Kingdom of Great Britain and Northern Ireland
University Of Oxford
Location: United Kingdom of Great Britain and Northern Ireland
Related Funding Activities
No related grants have been discovered for Doreen Lau.