Imaging of Brain Tumors with Copper-64 Chloride: Early Experience and Results

Panichelli, P.; Villano, Carlo; Cistaro, Angelina; Bruno, Andrea; Barbato, Francesco; Piccardo, Arnoldo; Duatti, Adriano

doi:10.1089/cbr.2016.2028

Cited by 49 publications

(47 citation statements)

References 38 publications

(44 reference statements)

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“…Radioactive Cu 2+ injections are currently used in the clinic for tumor imaging . Accordingly, the administration of Cu 2+ was tested to alleviate Cu deficiency in the tissue and to enhance the anticancer activity of the formulation.…”

Section: Resultsmentioning

confidence: 99%

Paraptosis‐Inducing Nanomedicine Overcomes Cancer Drug Resistance for a Potent Cancer Therapy

Zhou

Huang

Yang

et al. 2018

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Most chemotherapeutic drugs and their nanomedicine formulations exert anticancer activity by inducing cancer cell apoptosis. However, cancer cells inherently have and acquire many antiapoptosis mechanisms, causing cancer drug resistance and poor prognoses in patients. Herein, a potent paraptosis‐inducing nanomedicine is reported that causes quick nonapoptotic death of cancer cells, overcoming apoptosis‐based resistance and effectively inhibiting drug‐resistant tumor growth. The nanomedicine is composed of micelles made from an amphiphilic 8‐hydroxyquinoline (HQ)‐conjugate block copolymer with polyethylene glycol. Cu2+ can catalyze the hydrolysis of the HQ conjugation linker and liberate HQ, and these molecules can form the complex Cu(HQ)2, a strong proteasome inhibitor effective at inducing cell paraptosis. In vivo, the Cu2+‐responsive HQ‐releasing micelles respond to elevated tumor Cu2+ levels or externally administered Cu2+ and effectively inhibit the growth of human breast adenocarcinoma doxorubicin‐resistant (MCF‐7/ADR) tumors. Compared with other nanomedicines that overcome drug resistance via delivering several agents or even siRNA, this paraptosis‐inducing nanomedicine provides a simple but potent approach to overcoming cancer drug resistance.

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Section: Resultsmentioning

confidence: 99%

Paraptosis‐Inducing Nanomedicine Overcomes Cancer Drug Resistance for a Potent Cancer Therapy

Zhou

Huang

Yang

et al. 2018

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“…One of the reasons these cancer types were chosen in the studies with [ * Cu][Cu(ATSM)] PET imaging is because of the difficulties to detect hypoxia due to the physical inaccessibility to use invasive methods [30][31][32][33]. Although the exact mechanism and relations to tissue hypoxia explaining the retention of either [ 64 [36,37], and imaging of brain tumors ([ 64 Cu]CuCl 2 ) [38]. A summary of clinical studies with either copper-labelled ATSM or ionic radiocopper is shown in Table 1.…”

Section: Clinical Studies With [ * Cu][cu(atsm)] and Ionic Copper-64mentioning

confidence: 99%

“…Cervical cancer 38 Patients were monitored through a period from 3 to 79 months. With a threshold of T/M = 3.5 the 3-year progression free and cause-specific survival rate of patients with normoxic tumors (T/M < 3.5, 71%) is significantly higher than that of hypoxic tumor (T/M > 3.5, 28%).…”

Section: Role Of Cu-64 In Therapeutic Applicationsmentioning

confidence: 99%

“…A similar dosimetry estimation was also reported by Panichelli et al in a clinical study of brain tumors involving 19 patients with [ 64 Cu]CuCl 2 PET. The highest dose-absorbing organ was the liver, with an absorbed dose of 0.321 mGy/MBq, while the full body dose was estimated to be 0.0312 mGy/MBq [38]. In a recent clinical study using [ 64 Cu]CuCl 2 to detect prostate cancer relapse involving 50 patients, Piccardo et al evaluated the absorbed dose to each organ.…”

Section: Dosimetrymentioning

confidence: 99%

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Hypoxia imaging and theranostic potential of [64Cu][Cu(ATSM)] and ionic Cu(II) salts: a review of current evidence and discussion of the retention mechanisms

et al. 2020

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Background: Tumor hypoxia (low tissue oxygenation) is an adverse condition of the solid tumor environment, associated with malignant progression, radiotherapy resistance, and poor prognosis. One method to detect tumor hypoxia is by positron emission tomography (PET) with the tracer [ 64 Cu][Cu-diacetyl-bis(N(4)methylthiosemicarbazone)] ([ 64 Cu][Cu(ATSM)]), as demonstrated in both preclinical and clinical studies. In addition, emerging studies suggest using [ 64 Cu][Cu(ATSM)] for molecular radiotherapy, mainly due to the release of therapeutic Auger electrons from copper-64, making [ 64 Cu][Cu(ATSM)] a "theranostic" agent. However, the radiocopper retention based on a metal-ligand dissociation mechanism under hypoxia has long been controversial. Recent studies using ionic Cu(II) salts as tracers have raised further questions on the original mechanism and proposed a potential role of copper itself in the tracer uptake. We have reviewed the evidence of using the copper radiopharmaceuticals [ 60/61/62/64 Cu][Cu(ATSM)]/ionic copper salts for PET imaging of tumor hypoxia, their possible therapeutic applications, issues related to the metal-ligand dissociation mechanism, and possible explanations of copper trapping based on studies of the copper metabolism under hypoxia. Results:We found that hypoxia selectivity of [ 64 Cu][Cu(ATSM)] has been clearly demonstrated in both preclinical and clinical studies. Preclinical therapeutic studies in mice have also demonstrated promising results, recently reporting significant tumor volume reductions and improved survival in a dose-dependent manner. Cu(II)-[Cu(ATSM)] appears to be accumulated in regions with substantially higher CD133 + expression, a marker for cancer stem cells. This, combined with the reported requirement of copper for activation of the hypoxia inducible factor 1 (HIF-1), provides a possible explanation for the therapeutic effects of [ 64 Cu][Cu(ATSM)]. Comparisons between [ 64 Cu][Cu(ATSM)] and ionic Cu(II) salts have showed similar results in both imaging and therapeutic studies, supporting the argument for the central role of copper itself in the retention mechanism.Conclusions: We found promising evidence of using copper-64 radiopharmaceuticals for both PET imaging and treatment of hypoxic tumors. The Cu(II)-[Cu(ATSM)] retention mechanism remains controversial and future mechanistic studies should be focused on understanding the role of copper itself in the hypoxic tumor metabolism.

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“…Age-dependent changes of brain copper fluxes in Atp7b −/− knockout WD mice was demonstrated by a longitudinal PET study using orally administered 64 CuCl 2 as a radiotracer [64]. Moreover, 64 CuCl 2 was successfully used as a radiotracer for diagnostic imaging of prostate cancer [65] and brain tumors [66] in humans with PET, based on previous use of 64 CuCl 2 as a tracer for localization of human prostate cancer xenograft tumors in rodents [67]. The findings from these studies support use of 64 CuCl 2 as a radiotracer for quantitative analysis of age-dependent changes of copper fluxes in brain aging and pathophysiology of AD with PET [68–70].…”

Section: Coppermentioning

confidence: 99%

Radiopharmaceuticals for Assessment of Altered Metabolism and Biometal Fluxes in Brain Aging and Alzheimer’s Disease with Positron Emission Tomography

Xie

Peng

2017

JAD

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Aging is a risk factor for Alzheimer’s disease (AD). There are changes of brain metabolism and biometal fluxes due to brain aging, which may play a role in pathogenesis of AD. Positron emission tomography (PET) is a versatile tool for tracking alteration of metabolism and biometal fluxes due to brain aging and AD. Age-dependent changes in cerebral glucose metabolism can be tracked with PET using 2-deoxy-2-[18F]-fluoro-D-glucose (18F-FDG), a radiolabeled glucose analogue, as a radiotracer. Based on different patterns of altered cerebral glucose metabolism, 18F-FDG PET was clinically used for differential diagnosis of AD and Frontotemporal dementia (FTD). There are continued efforts to develop additional radiopharmaceuticals or radiotracers for assessment of age-dependent changes of various metabolic pathways and biometal fluxes due to brain aging and AD with PET. Elucidation of age-dependent changes of brain metabolism and altered biometal fluxes is not only significant for a better mechanistic understanding of brain aging and the pathophysiology of AD, but also significant for identification of new targets for the prevention, early diagnosis and treatment of AD.

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Imaging of Brain Tumors with Copper-64 Chloride: Early Experience and Results

Abstract: Copper-64 chloride has favorable biological properties for brain imaging and warrants further investigation as a diagnostic tracer for GBM.

Cited by 49 publications

References 38 publications

Paraptosis‐Inducing Nanomedicine Overcomes Cancer Drug Resistance for a Potent Cancer Therapy

Paraptosis‐Inducing Nanomedicine Overcomes Cancer Drug Resistance for a Potent Cancer Therapy

Hypoxia imaging and theranostic potential of [64Cu][Cu(ATSM)] and ionic Cu(II) salts: a review of current evidence and discussion of the retention mechanisms

Radiopharmaceuticals for Assessment of Altered Metabolism and Biometal Fluxes in Brain Aging and Alzheimer’s Disease with Positron Emission Tomography

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