Novel Preparation Methods of 52Mn for ImmunoPET Imaging

Stephen A. Graves, Reinier Hernandez, Jesper Fonslet, Christopher G. England, Hector F. Valdovinos, Paul A. Ellison, Todd E. Barnhart, Dennis Ringkjøbing Elema, Charles P. Theuer, Weibo Cai, Robert J. Nickles, Gregory Severin

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Abstract

52Mn (t1/2 =5.59 d, ß+ = 29.6%, Eßave = 0.24 MeV) shows promise in positron emission tomography (PET) and in dual-modality manganese-enhanced magnetic resonance imaging (MEMRI) applications including neural tractography, stem cell tracking, and biological toxicity studies. The extension to bioconjugate application requires high specific activity 52Mn in a state suitable for macromolecule labeling. To that end a 52Mn production, purification, and labeling system is presented, and its applicability in preclinical, macromolecule PET is shown using the conjugate 52Mn-DOTA-TRC105. 52Mn is produced by 60 µA, 16 MeV proton irradiation of natural chromium metal pressed into a silver disc support. Radiochemical separation proceeds by strong anion exchange chromatography of the dissolved Cr target, employing a semi-organic mobile phase, 97:3 (v:v) ethanol: HCl (11M, aqueous). The method is 62 ± 14% efficient (n=7) in 52Mn recovery, leading to a separation factor from Cr of (1.6 ± 1.0) x106 (n = 4), and an average effective specific activity of 0.8 GBq/µmol (n = 4) in titration against DOTA. 52Mn-DOTA-TRC105 conjugation and labeling demonstrate the potential for chelation applications. In vivo images acquired using PET/CT in mice bearing 4T1 xenograft tumors are presented. Peak tumor uptake is 18.7 ± 2.7 %ID/g at 24 hours post injection and ex vivo 52Mn biodistribution validates the in vivo PET data. Free 52Mn2+(as chloride or acetate) is used as a control in additional mice to evaluate the non-targeted biodistribution in the tumor model.
Original languageEnglish
JournalBioconjugate Chemistry
Volume26
Issue number10
Pages (from-to)2118–2124
ISSN1043-1802
DOIs
Publication statusPublished - 2015

Keywords

  • Positron emission tomography (PET)
  • ImmunoPET
  • Manganese-52 (Mn-52, 52Mn)
  • CD105/Endoglin
  • Tumor angiogenesis
  • TRC105
  • Molecular imaging
  • DOTA chelation
  • Organic anion exchange
  • Trace metal analysis (MP-AES, ICP-OES)

Cite this

Graves, S. A., Hernandez, R., Fonslet, J., England, C. G., Valdovinos, H. F., Ellison, P. A., ... Severin, G. (2015). Novel Preparation Methods of 52Mn for ImmunoPET Imaging. Bioconjugate Chemistry, 26(10), 2118–2124. https://doi.org/10.1021/acs.bioconjchem.5b00414
Graves, Stephen A. ; Hernandez, Reinier ; Fonslet, Jesper ; England, Christopher G. ; Valdovinos, Hector F. ; Ellison, Paul A. ; Barnhart, Todd E. ; Elema, Dennis Ringkjøbing ; Theuer, Charles P. ; Cai, Weibo ; Nickles, Robert J. ; Severin, Gregory. / Novel Preparation Methods of 52Mn for ImmunoPET Imaging. In: Bioconjugate Chemistry. 2015 ; Vol. 26, No. 10. pp. 2118–2124.
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title = "Novel Preparation Methods of 52Mn for ImmunoPET Imaging",
abstract = "52Mn (t1/2 =5.59 d, {\ss}+ = 29.6{\%}, E{\ss}ave = 0.24 MeV) shows promise in positron emission tomography (PET) and in dual-modality manganese-enhanced magnetic resonance imaging (MEMRI) applications including neural tractography, stem cell tracking, and biological toxicity studies. The extension to bioconjugate application requires high specific activity 52Mn in a state suitable for macromolecule labeling. To that end a 52Mn production, purification, and labeling system is presented, and its applicability in preclinical, macromolecule PET is shown using the conjugate 52Mn-DOTA-TRC105. 52Mn is produced by 60 µA, 16 MeV proton irradiation of natural chromium metal pressed into a silver disc support. Radiochemical separation proceeds by strong anion exchange chromatography of the dissolved Cr target, employing a semi-organic mobile phase, 97:3 (v:v) ethanol: HCl (11M, aqueous). The method is 62 ± 14{\%} efficient (n=7) in 52Mn recovery, leading to a separation factor from Cr of (1.6 ± 1.0) x106 (n = 4), and an average effective specific activity of 0.8 GBq/µmol (n = 4) in titration against DOTA. 52Mn-DOTA-TRC105 conjugation and labeling demonstrate the potential for chelation applications. In vivo images acquired using PET/CT in mice bearing 4T1 xenograft tumors are presented. Peak tumor uptake is 18.7 ± 2.7 {\%}ID/g at 24 hours post injection and ex vivo 52Mn biodistribution validates the in vivo PET data. Free 52Mn2+(as chloride or acetate) is used as a control in additional mice to evaluate the non-targeted biodistribution in the tumor model.",
keywords = "Positron emission tomography (PET), ImmunoPET, Manganese-52 (Mn-52, 52Mn), CD105/Endoglin, Tumor angiogenesis, TRC105, Molecular imaging, DOTA chelation, Organic anion exchange, Trace metal analysis (MP-AES, ICP-OES)",
author = "Graves, {Stephen A.} and Reinier Hernandez and Jesper Fonslet and England, {Christopher G.} and Valdovinos, {Hector F.} and Ellison, {Paul A.} and Barnhart, {Todd E.} and Elema, {Dennis Ringkj{\o}bing} and Theuer, {Charles P.} and Weibo Cai and Nickles, {Robert J.} and Gregory Severin",
year = "2015",
doi = "10.1021/acs.bioconjchem.5b00414",
language = "English",
volume = "26",
pages = "2118–2124",
journal = "Bioconjugate Chemistry",
issn = "1043-1802",
publisher = "American Chemical Society",
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}

Graves, SA, Hernandez, R, Fonslet, J, England, CG, Valdovinos, HF, Ellison, PA, Barnhart, TE, Elema, DR, Theuer, CP, Cai, W, Nickles, RJ & Severin, G 2015, 'Novel Preparation Methods of 52Mn for ImmunoPET Imaging', Bioconjugate Chemistry, vol. 26, no. 10, pp. 2118–2124. https://doi.org/10.1021/acs.bioconjchem.5b00414

Novel Preparation Methods of 52Mn for ImmunoPET Imaging. / Graves, Stephen A.; Hernandez, Reinier; Fonslet, Jesper; England, Christopher G.; Valdovinos, Hector F.; Ellison, Paul A.; Barnhart, Todd E.; Elema, Dennis Ringkjøbing; Theuer, Charles P.; Cai, Weibo; Nickles, Robert J.; Severin, Gregory.

In: Bioconjugate Chemistry, Vol. 26, No. 10, 2015, p. 2118–2124.

Research output: Contribution to journalJournal articleResearchpeer-review

TY - JOUR

T1 - Novel Preparation Methods of 52Mn for ImmunoPET Imaging

AU - Graves, Stephen A.

AU - Hernandez, Reinier

AU - Fonslet, Jesper

AU - England, Christopher G.

AU - Valdovinos, Hector F.

AU - Ellison, Paul A.

AU - Barnhart, Todd E.

AU - Elema, Dennis Ringkjøbing

AU - Theuer, Charles P.

AU - Cai, Weibo

AU - Nickles, Robert J.

AU - Severin, Gregory

PY - 2015

Y1 - 2015

N2 - 52Mn (t1/2 =5.59 d, ß+ = 29.6%, Eßave = 0.24 MeV) shows promise in positron emission tomography (PET) and in dual-modality manganese-enhanced magnetic resonance imaging (MEMRI) applications including neural tractography, stem cell tracking, and biological toxicity studies. The extension to bioconjugate application requires high specific activity 52Mn in a state suitable for macromolecule labeling. To that end a 52Mn production, purification, and labeling system is presented, and its applicability in preclinical, macromolecule PET is shown using the conjugate 52Mn-DOTA-TRC105. 52Mn is produced by 60 µA, 16 MeV proton irradiation of natural chromium metal pressed into a silver disc support. Radiochemical separation proceeds by strong anion exchange chromatography of the dissolved Cr target, employing a semi-organic mobile phase, 97:3 (v:v) ethanol: HCl (11M, aqueous). The method is 62 ± 14% efficient (n=7) in 52Mn recovery, leading to a separation factor from Cr of (1.6 ± 1.0) x106 (n = 4), and an average effective specific activity of 0.8 GBq/µmol (n = 4) in titration against DOTA. 52Mn-DOTA-TRC105 conjugation and labeling demonstrate the potential for chelation applications. In vivo images acquired using PET/CT in mice bearing 4T1 xenograft tumors are presented. Peak tumor uptake is 18.7 ± 2.7 %ID/g at 24 hours post injection and ex vivo 52Mn biodistribution validates the in vivo PET data. Free 52Mn2+(as chloride or acetate) is used as a control in additional mice to evaluate the non-targeted biodistribution in the tumor model.

AB - 52Mn (t1/2 =5.59 d, ß+ = 29.6%, Eßave = 0.24 MeV) shows promise in positron emission tomography (PET) and in dual-modality manganese-enhanced magnetic resonance imaging (MEMRI) applications including neural tractography, stem cell tracking, and biological toxicity studies. The extension to bioconjugate application requires high specific activity 52Mn in a state suitable for macromolecule labeling. To that end a 52Mn production, purification, and labeling system is presented, and its applicability in preclinical, macromolecule PET is shown using the conjugate 52Mn-DOTA-TRC105. 52Mn is produced by 60 µA, 16 MeV proton irradiation of natural chromium metal pressed into a silver disc support. Radiochemical separation proceeds by strong anion exchange chromatography of the dissolved Cr target, employing a semi-organic mobile phase, 97:3 (v:v) ethanol: HCl (11M, aqueous). The method is 62 ± 14% efficient (n=7) in 52Mn recovery, leading to a separation factor from Cr of (1.6 ± 1.0) x106 (n = 4), and an average effective specific activity of 0.8 GBq/µmol (n = 4) in titration against DOTA. 52Mn-DOTA-TRC105 conjugation and labeling demonstrate the potential for chelation applications. In vivo images acquired using PET/CT in mice bearing 4T1 xenograft tumors are presented. Peak tumor uptake is 18.7 ± 2.7 %ID/g at 24 hours post injection and ex vivo 52Mn biodistribution validates the in vivo PET data. Free 52Mn2+(as chloride or acetate) is used as a control in additional mice to evaluate the non-targeted biodistribution in the tumor model.

KW - Positron emission tomography (PET)

KW - ImmunoPET

KW - Manganese-52 (Mn-52, 52Mn)

KW - CD105/Endoglin

KW - Tumor angiogenesis

KW - TRC105

KW - Molecular imaging

KW - DOTA chelation

KW - Organic anion exchange

KW - Trace metal analysis (MP-AES, ICP-OES)

U2 - 10.1021/acs.bioconjchem.5b00414

DO - 10.1021/acs.bioconjchem.5b00414

M3 - Journal article

VL - 26

SP - 2118

EP - 2124

JO - Bioconjugate Chemistry

JF - Bioconjugate Chemistry

SN - 1043-1802

IS - 10

ER -

Graves SA, Hernandez R, Fonslet J, England CG, Valdovinos HF, Ellison PA et al. Novel Preparation Methods of 52Mn for ImmunoPET Imaging. Bioconjugate Chemistry. 2015;26(10):2118–2124. https://doi.org/10.1021/acs.bioconjchem.5b00414