Sir Peter MacCallum Department of Oncology - Research Publications
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ItemNo Preview AvailableDevelopment of Highly Potent Clinical Candidates for Theranostic Applications against Cholecystokinin-2 Receptor Positive Cancers(AMER CHEMICAL SOC, 2023-07-26)Peptide receptor radionuclide therapy (PRRT) is a promising form of systemic radiation therapy designed to eradicate cancer. Cholecystokinin-2 receptor (CCK2R) is an important molecular target that is highly expressed in a range of cancers. This study describes the synthesis and in vivo characterization of a novel series of 177Lu-labeled peptides ([177Lu]Lu-2b-4b) in comparison with the reference CCK2R-targeting peptide CP04 ([177Lu]Lu-1b). [177Lu]Lu-1b-4b showed high chemical purity (HPLC ≥ 94%), low Log D7.4 (-4.09 to -4.55) with strong binding affinity to CCK2R (KD 0.097-1.61 nM), and relatively high protein binding (55.6-80.2%) and internalization (40-67%). Biodistribution studies of the novel 177Lu-labeled peptides in tumors (AR42J and A431-CCK2R) showed uptake one- to eight-fold greater than the reference compound CP04 at 1, 24, and 48 h. Rapid clearance and high tumor uptake and retention were established for [177Lu]Lu-2b-4b, making these compounds excellent candidates for theranostic applications against CCK2R-expressing tumors.
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ItemImmunoPET: IMaging of cancer imMUNOtherapy targets with positron Emission Tomography: a phase 0/1 study characterising PD-L1 with 89Zr-durvalumab (MEDI4736) PET/CT in stage III NSCLC patients receiving chemoradiation study protocol.(BMJ Publishing Group, 2022-11-18)BACKGROUND: ImmunoPET is a multicentre, single arm, phase 0-1 study that aims to establish if 89Zr-durvalumab PET/CT can be used to interrogate the expression of PD-L1 in larger, multicentre clinical trials. METHODS: The phase 0 study recruited 5 PD-L1+ patients with metastatic non-small cell lung cancer (NSCLC). Patients received 60MBq/70 kg 89Zr-durva up to a maximum of 74 MBq, with scan acquisition at days 0, 1, 3 or 5±1 day. Data on (1) Percentage of injected 89Zr-durva dose found in organs of interest (2) Absorbed organ doses (µSv/MBq of administered 89Zr-durva) and (3) whole-body dose expressed as mSv/100MBq of administered dose was collected to characterise biodistribution.The phase 1 study will recruit 20 patients undergoing concurrent chemoradiotherapy for stage III NSCLC. Patients will have 89Zr-durva and FDG-PET/CT before, during and after chemoradiation. In order to establish the feasibility of 89Zr-durva PET/CT for larger multicentre trials, we will collect both imaging and toxicity data. Feasibility will be deemed to have been met if more than 80% of patients are able complete all trial requirements with no significant toxicity. ETHICS AND DISSEMINATION: This phase 0 study has ethics approval (HREC/65450/PMCC 20/100) and is registered on the Australian Clinical Trials Network (ACTRN12621000171819). The protocol, technical and clinical data will be disseminated by conference presentations and publications. Any modifications to the protocol will be formally documented by administrative letters and must be submitted to the approving HREC for review and approval. TRIAL REGISTRATION NUMBER: Australian Clinical Trials Network ACTRN12621000171819.
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ItemImaging immunity in patients with cancer using positron emission tomography(NATURE PORTFOLIO, 2022-04-07)Immune checkpoint inhibitors and related molecules can achieve tumour regression, and even prolonged survival, for a subset of cancer patients with an otherwise dire prognosis. However, it remains unclear why some patients respond to immunotherapy and others do not. PET imaging has the potential to characterise the spatial and temporal heterogeneity of both immunotherapy target molecules and the tumor immune microenvironment, suggesting a tantalising vision of personally-adapted immunomodulatory treatment regimens. Personalised combinations of immunotherapy with local therapies and other systemic therapies, would be informed by immune imaging and subsequently modified in accordance with therapeutically induced immune environmental changes. An ideal PET imaging biomarker would facilitate the choice of initial therapy and would permit sequential imaging in time-frames that could provide actionable information to guide subsequent therapy. Such imaging should provide either prognostic or predictive measures of responsiveness relevant to key immunotherapy types but, most importantly, guide key decisions on initiation, continuation, change or cessation of treatment to reduce the cost and morbidity of treatment while enhancing survival outcomes. We survey the current literature, focusing on clinically relevant immune checkpoint immunotherapies, for which novel PET tracers are being developed, and discuss what steps are needed to make this vision a reality.
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ItemGallium Fluoride Complexes with Acyclic Bispicolinic Ligands as Potential New Fluorine-18 Labelled Imaging Agents(WILEY-V C H VERLAG GMBH, 2020-09-22)The positron‐emitting radionuclide, fluorine‐18, is used to radiolabel molecules to develop tracers for diagnostic imaging with positron‐emission tomography. There is growing interest in the potential of using strong coordinate bonds between electropositive Ga(III) and electronegative fluoride (≈ 557 kJ/mol) to provide new methods of incorporating fluorine‐18 into molecules. The potential of gallium(III) complexes with acyclic pentadentate bispicolinic acid containing ligands (H2L1–3) to form ternary complexes with fluoride, [GaL1–3F] was investigated with a view to developing new methods for fluorine‐18 radiolabelling. A solid‐phase peptide synthesis approach was used to produce a bispicolinic acid chelator with a lysine residue. Characterisation of [GaL1X] (X = OH, Cl, F) by X‐ray crystallography revealed that L1 acted as dianionic N2O2 donor to the Ga(III) with the fifth site occupied by a monodentate anion (OH–, Cl– or F–). Despite its high stability in aqueous mixture and [D6]DMSO and the straightforward synthesis of [GaL1F], it was only possible to form the radioactive analogue [18F][GaL1F] in low radiochemical yields.
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ItemSynthesis of [18F]F-γ-T-3, a Redox-Silent γ-Tocotrienol (γ-T-3) Vitamin E Analogue for Image-Based In Vivo Studies of Vitamin E Biodistribution and Dynamics(MDPI, 2020-12)Vitamin E, a natural antioxidant, is of interest to scientists, health care pundits and faddists; its nutritional and biomedical attributes may be validated, anecdotal or fantasy. Vitamin E is a mixture of tocopherols (TPs) and tocotrienols (T-3s), each class having four substitutional isomers (α-, β-, γ-, δ-). Vitamin E analogues attain only low concentrations in most tissues, necessitating exacting invasive techniques for analytical research. Quantitative positron emission tomography (PET) with an F-18-labeled molecular probe would expedite access to Vitamin E's biodistributions and pharmacokinetics via non-invasive temporal imaging. (R)-6-(3-[18F]Fluoropropoxy)-2,7,8-trimethyl-2-(4,8,12-trimethyltrideca-3,7,11-trien-1-yl)-chromane ([18F]F-γ-T-3) was prepared for this purpose. [18F]F-γ-T-3 was synthesized from γ-T-3 in two steps: (i) 1,3-di-O-tosylpropane was introduced at C6-O to form TsO-γ-T-3, and (ii) reaction of this tosylate with [18F]fluoride in DMF/K222. Non-radioactive F-γ-T-3 was synthesized by reaction of γ-T-3 with 3-fluoropropyl methanesulfonate. [18F]F-γ-T-3 biodistribution in a murine tumor model was imaged using a small-animal PET scanner. F-γ-T-3 was prepared in 61% chemical yield. [18F]F-γ-T-3 was synthesized in acceptable radiochemical yield (RCY 12%) with high radiochemical purity (>99% RCP) in 45 min. Preliminary F-18 PET images in mice showed upper abdominal accumulation with evidence of renal clearance, only low concentrations in the thorax (lung/heart) and head, and rapid clearance from blood. [18F]F-γ-T-3 shows promise as an F-18 PET tracer for detailed in vivo studies of Vitamin E. The labeling procedure provides acceptable RCY, high RCP and pertinence to all eight Vitamin E analogues.
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Item4-Nitrophenyl activated esters are superior synthons for indirect radiofluorination of biomolecules(ROYAL SOC CHEMISTRY, 2020-08-01)Indirect radiolabelling has for a long time been the mainstay strategy for radiofluorination of biomolecules. Acylation of biomolecules through the use of an 18F-labelled activated ester is a standard method for indirect radiolabelling. However, the preparation of 18F-labelled activated esters is typically a complex and multistep procedure. Herein, we describe the use of 4-nitrophenyl (PNP) activated esters to rapidly prepare 18F-labelled acylation synthons in one step. Furthermore, we present a comparative study of PNP activated esters and the commonly utilised 2,3,5,6-tetrafluorphenyl (TFP) activated esters under direct radiofluorination conditions and demonstrate their relative acylation behaviour. We demonstrate the superiority of PNP esters under direct radiofluorination conditions with favourable acylation kinetics.