[64Cu]Cu-ATSM: an emerging theranostic agent for cancer and neuroinflammation

Xie, Fang; Wei, Weijun

doi:10.1007/s00259-022-05887-6

Cited by 11 publications

(4 citation statements)

References 81 publications

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“…Previously, [ 64 Cu][Cu(ATSM)] was considered a promising theranostic candidate for hypoxic tumors [ 12 – 14 , 52 – 54 ]. However, challenges and controversies regarding the retention mechanism of [ 64 Cu][Cu(ATSM)] has limited its use, especially as similar results have been obtained for ionic Cu-64 substances, such as [ 64 Cu]CuCl 2 and 64 Cu-acetate [ 10 , 11 , 55 ].…”

Section: Discussionmentioning

confidence: 99%

In vitro and in vivo characterization of [64Cu][Cu(elesclomol)] as a novel theranostic agent for hypoxic solid tumors

Liu,

Dahle,

Lystad

et al. 2023

Eur J Nucl Med Mol Imaging

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Purpose Hypoxic tumors are associated with therapy resistance and poor cancer prognosis, but methods to detect and counter tumor hypoxia remain insufficient. Our purpose was to investigate 64Cu(II)-elesclomol ([64Cu][Cu(ES)]) as a novel theranostic agent for hypoxic tumors, by implementing an improved production method and assessing its therapeutic and diagnostic potential compared to the established Cu-64 radiopharmaceuticals [64Cu]CuCl2 and [diacetyl-bis(N4-methylthiosemicarbazone) [64Cu][Cu(ATSM)]. Methods Cu-64 was produced using a biomedical cyclotron at 12 MeV with the reaction 64Ni(p,n)64Cu, followed by synthesis of [64Cu]CuCl2, [64Cu][Cu(ATSM)], and [64Cu][Cu(ES)]. In vitro therapeutic effects were assessed in both normoxic and hypoxic cells (22Rv1 and PC3 prostate cancer cells, and U-87MG glioblastoma cells) using the clonogenic assay and analyzing cellular uptake and internalization. In vivo therapeutic effects were assessed in 22Rv1 xenografts in BALB/cAnN-Foxn1nu/nu/Rj mice receiving a single or multiple doses of radiopharmaceutical, before their feasibility to detect tumor hypoxia was assessed by positron emission tomography (PET) in 22Rv1 and U-87MG xenografts. Results In vitro and in vivo studies demonstrated that [64Cu][Cu(ES)] reduced cell survival and inhibited tumor growth more effectively than [64Cu][Cu(ATSM)] and [64Cu]CuCl2. Hypoxia increased the cellular uptake and internalization of [64Cu][Cu(ES)] and [64Cu][Cu(ATSM)]. [64Cu][Cu(ES)]-PET tumor hypoxia detection was feasible and also revealed an unexpected finding of uptake in the brain. Conclusion To the best of our knowledge, this is the first time that ES is radiolabeled with [64Cu]CuCl2 to [64Cu][Cu(ES)]. We demonstrated superior therapeutic effects of [64Cu][Cu(ES)] compared to [64Cu][Cu(ATSM)] and [64Cu]CuCl2 and that [64Cu][Cu(ES)]-PET is feasible. [64Cu][Cu(ES)] is a promising theranostic agent for hypoxic solid tumors.

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Section: Discussionmentioning

confidence: 99%

In vitro and in vivo characterization of [64Cu][Cu(elesclomol)] as a novel theranostic agent for hypoxic solid tumors

Liu,

Dahle,

Lystad

et al. 2023

Eur J Nucl Med Mol Imaging

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“…Copper bis(thiosemicarbazones) (BTSCs), radiolabeled with either 64 Cu or 62 Cu, show promise as PET hypoxia imaging agents. They have been widely investigated for cancer imaging (12), but remain relatively underexplored in cardiology. The lead BTSC compound [ 64 Cu[CuATSM ( 64 Cu-2,3-butanedione bis(N4-methylthiosemicarbazone)) has been shown to deposit 64 Cu in hypoxic cardiac myocytes (13), isolated perfused hearts (14), and in regionally occluded canine myocardium in vivo (15).…”

Section: Introductionmentioning

confidence: 99%

Perfusion-Independent Tissue Hypoxia in Cardiac Hypertrophy in Mice Measured by⁶⁴Cu-CTS PET Imaging

Baark,

Michaels,

Waters

et al. 2024

Preprint

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Background: Hypoxia is central to many cardiac pathologies, but clinically its presence can only be inferred by indirect biomarkers including hypoperfusion and energetic compromise. Imaging hypoxia directly could offer new opportunities for the diagnosis and sub-stratification of cardiovascular diseases. Objectives: To determine whether [64Cu]CuCTS Positron Emission Tomography (PET) can identify hypoxia in a murine model of cardiac hypertrophy. Methods: Male C57BL/6 mice underwent abdominal aortic constriction (AAC) to induce cardiac hypertrophy, quantified by echocardiography over 4 weeks. Hypoxia and perfusion were quantified in vivo using [64Cu]CuCTS and [64Cu]CuGTSM PET, respectively, and radiotracer biodistribution was quantified post-mortem. Cardiac radiotracer retention was correlated with contractile function (measured by echocardiography), cardiac hypertrophy (measured by histology), HIF-1a; stabilization and NMR-based metabolomics. The effect of anesthesia on [64Cu]CuCTS uptake was additionally investigated in a parallel cohort of mice injected with radiotracer while conscious. Results: Hearts showed increased LV wall thickness, reduced ejection fraction and fractional shortening following AAC. [64Cu]CuCTS retention was 317% higher in hypertrophic myocardium (p<0.001), despite there being no difference in perfusion measured by 64CuGTSM. Radiotracer retention correlated on an animal-by-animal basis with severity of hypertrophy, contractile dysfunction, HIF1a; stabilization and metabolic signatures of hypoxia. [64Cu]CuCTS uptake in hypertrophic hearts was significantly higher when administered to conscious animals. Conclusions: [64Cu]CuCTS PET can quantify cardiac hypoxia in hypertrophic myocardium, independent of perfusion, suggesting the hypoxia is caused by increased oxygen diffusion distances at the subcellular level. Alleviation of cardiac workload by anesthesia in preclinical models partially alleviates this effect.

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“…As copper-chelating scaffold, thiocarbahydrazone and thiosemicarbazone moieties were used, which were also successfully utilized in the design of amyloid-imaging drugs, as well as Сu-ATSM drugs. 27 The choice of allyl, benzyl, and phenylethyl moieties in molecular design was guided by our early studies of the antitumor activity of copper-containing coordination compounds. 28,29 BFCs based on benzothiazole scaffold with thiocarbahydrazone chelating moieties Alz-1 -Alz-3 were synthesised in six steps (Scheme S1, †), BFCs based on stilbene scaffold with thiosemicarbazone chelating moieties Alz-4, Alz-5 were synthesised in nine successful steps (Scheme S2, †).…”

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confidence: 99%

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confidence: 99%

Aβ-affine bifunctional copper chelators capable of Aβ-induced oxidative stress reduction and amyloid disaggregation

Krasnovskaya,

Abramchuk,

Vaneev

et al. 2023

Preprint

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Alz-5 acts as a bifunctional chelator that can interact with various Aβ aggregates and reduce their neurotoxicity. Single-cell ROS measurements provided by Pt-nanoelectrode technique revealed a significant antioxidant properties of Alz-5 in Aβ42- affected SH-SY5Y cell. AFM data obtained on Aβ42fibrils clearly indicate an anti-aggregating property of Alz-5. Young’s modulus mapping on living SH-SY5Y cells revealed an ability of Alz-5 to decrease cell rigidity in Aβ42- affected SH-SY5Y cells.

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[64Cu]Cu-ATSM: an emerging theranostic agent for cancer and neuroinflammation

Cited by 11 publications

References 81 publications

In vitro and in vivo characterization of [64Cu][Cu(elesclomol)] as a novel theranostic agent for hypoxic solid tumors

In vitro and in vivo characterization of [64Cu][Cu(elesclomol)] as a novel theranostic agent for hypoxic solid tumors

Perfusion-Independent Tissue Hypoxia in Cardiac Hypertrophy in Mice Measured by⁶⁴Cu-CTS PET Imaging

Aβ-affine bifunctional copper chelators capable of Aβ-induced oxidative stress reduction and amyloid disaggregation

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[64Cu]Cu-ATSM: an emerging theranostic agent for cancer and neuroinflammation

Cited by 11 publications

References 81 publications

In vitro and in vivo characterization of [64Cu][Cu(elesclomol)] as a novel theranostic agent for hypoxic solid tumors

In vitro and in vivo characterization of [64Cu][Cu(elesclomol)] as a novel theranostic agent for hypoxic solid tumors

Perfusion-Independent Tissue Hypoxia in Cardiac Hypertrophy in Mice Measured by64Cu-CTS PET Imaging

Aβ-affine bifunctional copper chelators capable of Aβ-induced oxidative stress reduction and amyloid disaggregation

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Perfusion-Independent Tissue Hypoxia in Cardiac Hypertrophy in Mice Measured by⁶⁴Cu-CTS PET Imaging