Synthesis and characterization of 68Ga-labeled curcumin and curcuminoid complexes as potential radiotracers for imaging of cancer and alzheimers disease

Mattia Asti, Erika Ferrari, Stefania Croci, Giulia Atti, Sara Rubagotti, Michele Iori, Pier C. Capponi, Alessandro Zerbini, Monica Saladini, Annibale Versari

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Abstract

Curcumin (CUR) and curcuminoids complexes labeled with fluorine-18 or technetium-99m have recently shown their potential as diagnostic tools for Alzheimers disease. Gallium-68 is a positron-emitting, generator-produced radionuclide, and its properties can be exploited in situ in medical facilities without a cyclotron. Moreover, CUR showed a higher uptake in tumor cells compared to normal cells, suggesting potential diagnostic applications in this field. In spite of this, no studies using labeled CUR have been performed in this direction, so far. Herein, 68Ga-labeled complexes with CUR and two curcuminoids, namely diacetyl-curcumin (DAC) and bis(dehydroxy)curcumin (bDHC), were synthesized and characterized by means of experimental and theoretical approaches. Moreover, a first evaluation of their affinity to synthetic β-amyloid fibrils and uptake by A549 lung cancer cells was performed to show the potential application of these new labeled curcuminoids in these diagnostic fields. The radiotracers were prepared by reacting 68Ga3+ obtained from a 68Ge/68Ga generator with 1 mg/mL curcuminoids solutions. Reaction parameters (precursor amount, reaction temperature, and pH) were optimized to obtain high and reproducible radiochemical yield and purity. Stoichiometry and formation of the curcuminoid complexes were investigated by matrix-assisted laser desorption ionization time-of-flight mass spectrometry, NMR, ultraviolet-visible, and fluorescence spectroscopy on the equivalent natGa-curcuminoids (nat = natural) complexes, and their structure was computed by theoretical density functional theory calculations. The analyses evidenced that CUR, DAC, and bDHC were predominantly in the keto-enol form and attested to Ga(L)2 + species formation. Identity of the 68Ga(L) 2 + complexes was confirmed by coelution with the equivalent natGa(L)2 + complexes in ultrahigh-performance liquid chromatography analyses.68Ga(CUR) 2 +, 68Ga(DAC)2 +, and 68Ga(bDHC)2 + were highly (87 ± 4, 90 ± 1%) and moderately (48 ± 2%), respectively, retained by synthetic β-amyloid fibrils in vitro. All the Ga-curcuminoid complexes showed an uptake in A549 lung cancer cells, at least equivalent to the respective free curcuminoids, confirming potential applications as cancer-detecting radiotracers.

Original languageEnglish
Pages (from-to)4922-4933
Number of pages12
JournalInorganic Chemistry
Volume53
Issue number10
DOIs
Publication statusPublished - May 19 2014

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Curcumin
Alzheimer Disease
cancer
Imaging techniques
synthesis
Diacetyl
lungs
Neoplasms
generators
technetium
Cells
liquid chromatography
Amyloid
radioactive isotopes
gallium
cyclotrons
fluorine
affinity
stoichiometry
positrons

ASJC Scopus subject areas

  • Inorganic Chemistry
  • Physical and Theoretical Chemistry
  • Medicine(all)

Cite this

Synthesis and characterization of 68Ga-labeled curcumin and curcuminoid complexes as potential radiotracers for imaging of cancer and alzheimers disease. / Asti, Mattia; Ferrari, Erika; Croci, Stefania; Atti, Giulia; Rubagotti, Sara; Iori, Michele; Capponi, Pier C.; Zerbini, Alessandro; Saladini, Monica; Versari, Annibale.

In: Inorganic Chemistry, Vol. 53, No. 10, 19.05.2014, p. 4922-4933.

Research output: Contribution to journalArticle

Asti, Mattia ; Ferrari, Erika ; Croci, Stefania ; Atti, Giulia ; Rubagotti, Sara ; Iori, Michele ; Capponi, Pier C. ; Zerbini, Alessandro ; Saladini, Monica ; Versari, Annibale. / Synthesis and characterization of 68Ga-labeled curcumin and curcuminoid complexes as potential radiotracers for imaging of cancer and alzheimers disease. In: Inorganic Chemistry. 2014 ; Vol. 53, No. 10. pp. 4922-4933.
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abstract = "Curcumin (CUR) and curcuminoids complexes labeled with fluorine-18 or technetium-99m have recently shown their potential as diagnostic tools for Alzheimers disease. Gallium-68 is a positron-emitting, generator-produced radionuclide, and its properties can be exploited in situ in medical facilities without a cyclotron. Moreover, CUR showed a higher uptake in tumor cells compared to normal cells, suggesting potential diagnostic applications in this field. In spite of this, no studies using labeled CUR have been performed in this direction, so far. Herein, 68Ga-labeled complexes with CUR and two curcuminoids, namely diacetyl-curcumin (DAC) and bis(dehydroxy)curcumin (bDHC), were synthesized and characterized by means of experimental and theoretical approaches. Moreover, a first evaluation of their affinity to synthetic β-amyloid fibrils and uptake by A549 lung cancer cells was performed to show the potential application of these new labeled curcuminoids in these diagnostic fields. The radiotracers were prepared by reacting 68Ga3+ obtained from a 68Ge/68Ga generator with 1 mg/mL curcuminoids solutions. Reaction parameters (precursor amount, reaction temperature, and pH) were optimized to obtain high and reproducible radiochemical yield and purity. Stoichiometry and formation of the curcuminoid complexes were investigated by matrix-assisted laser desorption ionization time-of-flight mass spectrometry, NMR, ultraviolet-visible, and fluorescence spectroscopy on the equivalent natGa-curcuminoids (nat = natural) complexes, and their structure was computed by theoretical density functional theory calculations. The analyses evidenced that CUR, DAC, and bDHC were predominantly in the keto-enol form and attested to Ga(L)2 + species formation. Identity of the 68Ga(L) 2 + complexes was confirmed by coelution with the equivalent natGa(L)2 + complexes in ultrahigh-performance liquid chromatography analyses.68Ga(CUR) 2 +, 68Ga(DAC)2 +, and 68Ga(bDHC)2 + were highly (87 ± 4, 90 ± 1{\%}) and moderately (48 ± 2{\%}), respectively, retained by synthetic β-amyloid fibrils in vitro. All the Ga-curcuminoid complexes showed an uptake in A549 lung cancer cells, at least equivalent to the respective free curcuminoids, confirming potential applications as cancer-detecting radiotracers.",
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AU - Atti, Giulia

AU - Rubagotti, Sara

AU - Iori, Michele

AU - Capponi, Pier C.

AU - Zerbini, Alessandro

AU - Saladini, Monica

AU - Versari, Annibale

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N2 - Curcumin (CUR) and curcuminoids complexes labeled with fluorine-18 or technetium-99m have recently shown their potential as diagnostic tools for Alzheimers disease. Gallium-68 is a positron-emitting, generator-produced radionuclide, and its properties can be exploited in situ in medical facilities without a cyclotron. Moreover, CUR showed a higher uptake in tumor cells compared to normal cells, suggesting potential diagnostic applications in this field. In spite of this, no studies using labeled CUR have been performed in this direction, so far. Herein, 68Ga-labeled complexes with CUR and two curcuminoids, namely diacetyl-curcumin (DAC) and bis(dehydroxy)curcumin (bDHC), were synthesized and characterized by means of experimental and theoretical approaches. Moreover, a first evaluation of their affinity to synthetic β-amyloid fibrils and uptake by A549 lung cancer cells was performed to show the potential application of these new labeled curcuminoids in these diagnostic fields. The radiotracers were prepared by reacting 68Ga3+ obtained from a 68Ge/68Ga generator with 1 mg/mL curcuminoids solutions. Reaction parameters (precursor amount, reaction temperature, and pH) were optimized to obtain high and reproducible radiochemical yield and purity. Stoichiometry and formation of the curcuminoid complexes were investigated by matrix-assisted laser desorption ionization time-of-flight mass spectrometry, NMR, ultraviolet-visible, and fluorescence spectroscopy on the equivalent natGa-curcuminoids (nat = natural) complexes, and their structure was computed by theoretical density functional theory calculations. The analyses evidenced that CUR, DAC, and bDHC were predominantly in the keto-enol form and attested to Ga(L)2 + species formation. Identity of the 68Ga(L) 2 + complexes was confirmed by coelution with the equivalent natGa(L)2 + complexes in ultrahigh-performance liquid chromatography analyses.68Ga(CUR) 2 +, 68Ga(DAC)2 +, and 68Ga(bDHC)2 + were highly (87 ± 4, 90 ± 1%) and moderately (48 ± 2%), respectively, retained by synthetic β-amyloid fibrils in vitro. All the Ga-curcuminoid complexes showed an uptake in A549 lung cancer cells, at least equivalent to the respective free curcuminoids, confirming potential applications as cancer-detecting radiotracers.

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