Synthesis and biodistribution studies of 3H- and 64Cu-labeled dendritic polyglycerol and dendritic polyglycerol sulfate

Kritee Pant, Dominic Groger, Ralf Bergmann, Jens Pietzsch, Jorg Steinbach, Bim Graham, Leone Spiccia, Fannely Berthon, Bertrand Czarny, Laurent Devel, Vincent Dive, Holger Stephan, Rainer Haag

Research output: Contribution to journalArticleResearchpeer-review

Abstract

Dendritic polyglycerol sulfate (dPGS) is a biocompatible, bioactive polymer which exhibits anti-inflammatory activity in vivo and thus represents a promising candidate for therapeutic and diagnostic applications. To investigate the in vivo pharmacokinetics in detail, dPGS with a molecular weight of approx. 10 kDa was radiolabeled with 3H and 64Cu, and evaluated by performing biodistribution studies and small animal positron emission tomography (PET). 3H-labeling was accomplished by an oxidation-reduction process with sodium periodate and [3H]-borohydride. 64Cu-labeling was achieved by conjugation of isothiocyanate- or maleimide-functionalized copper(II)-chelating ligands based on 1,4-bis(2-pyridinylmethyl)-1,4,7-triazacyclononane (DMPTACN) to an amino functionalized dPGS scaffold, followed by reaction with an aqueous solution containing 64CuCl2. Independent biodistribution by radioimaging and PET imaging studies with healthy mice and rats showed that the neutral dPG was quantitatively renally eliminated, whereas the polysulfated analogues accumulated mainly in the liver and spleen. Small amounts of the dPGS derivatives were slowly excreted via the kidneys. The degree of uptake by the reticuloendothelial system (RES) was similar for dPGS with 40% or 85% sulfation, and surface modification of the scaffold with the DMPTACN chelator did not appear to significantly affect the biodistribution profile. On the basis of our data, the applicability of bioactive dPGS as a therapeutic agent might be limited due to organ accumulation even after 3 weeks. The inert characteristics and clearance of the neutral polymer, however, emphasizes the potential of dPG as a multifunctional scaffold for various nanomedical applications.
Original languageEnglish
Pages (from-to)906-918
Number of pages13
JournalBioconjugate Chemistry
Volume26
Issue number5
DOIs
Publication statusPublished - 2015

Cite this

Pant, Kritee ; Groger, Dominic ; Bergmann, Ralf ; Pietzsch, Jens ; Steinbach, Jorg ; Graham, Bim ; Spiccia, Leone ; Berthon, Fannely ; Czarny, Bertrand ; Devel, Laurent ; Dive, Vincent ; Stephan, Holger ; Haag, Rainer. / Synthesis and biodistribution studies of 3H- and 64Cu-labeled dendritic polyglycerol and dendritic polyglycerol sulfate. In: Bioconjugate Chemistry. 2015 ; Vol. 26, No. 5. pp. 906-918.
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title = "Synthesis and biodistribution studies of 3H- and 64Cu-labeled dendritic polyglycerol and dendritic polyglycerol sulfate",
abstract = "Dendritic polyglycerol sulfate (dPGS) is a biocompatible, bioactive polymer which exhibits anti-inflammatory activity in vivo and thus represents a promising candidate for therapeutic and diagnostic applications. To investigate the in vivo pharmacokinetics in detail, dPGS with a molecular weight of approx. 10 kDa was radiolabeled with 3H and 64Cu, and evaluated by performing biodistribution studies and small animal positron emission tomography (PET). 3H-labeling was accomplished by an oxidation-reduction process with sodium periodate and [3H]-borohydride. 64Cu-labeling was achieved by conjugation of isothiocyanate- or maleimide-functionalized copper(II)-chelating ligands based on 1,4-bis(2-pyridinylmethyl)-1,4,7-triazacyclononane (DMPTACN) to an amino functionalized dPGS scaffold, followed by reaction with an aqueous solution containing 64CuCl2. Independent biodistribution by radioimaging and PET imaging studies with healthy mice and rats showed that the neutral dPG was quantitatively renally eliminated, whereas the polysulfated analogues accumulated mainly in the liver and spleen. Small amounts of the dPGS derivatives were slowly excreted via the kidneys. The degree of uptake by the reticuloendothelial system (RES) was similar for dPGS with 40{\%} or 85{\%} sulfation, and surface modification of the scaffold with the DMPTACN chelator did not appear to significantly affect the biodistribution profile. On the basis of our data, the applicability of bioactive dPGS as a therapeutic agent might be limited due to organ accumulation even after 3 weeks. The inert characteristics and clearance of the neutral polymer, however, emphasizes the potential of dPG as a multifunctional scaffold for various nanomedical applications.",
author = "Kritee Pant and Dominic Groger and Ralf Bergmann and Jens Pietzsch and Jorg Steinbach and Bim Graham and Leone Spiccia and Fannely Berthon and Bertrand Czarny and Laurent Devel and Vincent Dive and Holger Stephan and Rainer Haag",
year = "2015",
doi = "10.1021/acs.bioconjchem.5b00127",
language = "English",
volume = "26",
pages = "906--918",
journal = "Bioconjugate Chemistry",
issn = "1043-1802",
publisher = "American Chemical Society",
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Pant, K, Groger, D, Bergmann, R, Pietzsch, J, Steinbach, J, Graham, B, Spiccia, L, Berthon, F, Czarny, B, Devel, L, Dive, V, Stephan, H & Haag, R 2015, 'Synthesis and biodistribution studies of 3H- and 64Cu-labeled dendritic polyglycerol and dendritic polyglycerol sulfate', Bioconjugate Chemistry, vol. 26, no. 5, pp. 906-918. https://doi.org/10.1021/acs.bioconjchem.5b00127

Synthesis and biodistribution studies of 3H- and 64Cu-labeled dendritic polyglycerol and dendritic polyglycerol sulfate. / Pant, Kritee; Groger, Dominic; Bergmann, Ralf; Pietzsch, Jens; Steinbach, Jorg; Graham, Bim; Spiccia, Leone; Berthon, Fannely; Czarny, Bertrand; Devel, Laurent; Dive, Vincent; Stephan, Holger; Haag, Rainer.

In: Bioconjugate Chemistry, Vol. 26, No. 5, 2015, p. 906-918.

Research output: Contribution to journalArticleResearchpeer-review

TY - JOUR

T1 - Synthesis and biodistribution studies of 3H- and 64Cu-labeled dendritic polyglycerol and dendritic polyglycerol sulfate

AU - Pant, Kritee

AU - Groger, Dominic

AU - Bergmann, Ralf

AU - Pietzsch, Jens

AU - Steinbach, Jorg

AU - Graham, Bim

AU - Spiccia, Leone

AU - Berthon, Fannely

AU - Czarny, Bertrand

AU - Devel, Laurent

AU - Dive, Vincent

AU - Stephan, Holger

AU - Haag, Rainer

PY - 2015

Y1 - 2015

N2 - Dendritic polyglycerol sulfate (dPGS) is a biocompatible, bioactive polymer which exhibits anti-inflammatory activity in vivo and thus represents a promising candidate for therapeutic and diagnostic applications. To investigate the in vivo pharmacokinetics in detail, dPGS with a molecular weight of approx. 10 kDa was radiolabeled with 3H and 64Cu, and evaluated by performing biodistribution studies and small animal positron emission tomography (PET). 3H-labeling was accomplished by an oxidation-reduction process with sodium periodate and [3H]-borohydride. 64Cu-labeling was achieved by conjugation of isothiocyanate- or maleimide-functionalized copper(II)-chelating ligands based on 1,4-bis(2-pyridinylmethyl)-1,4,7-triazacyclononane (DMPTACN) to an amino functionalized dPGS scaffold, followed by reaction with an aqueous solution containing 64CuCl2. Independent biodistribution by radioimaging and PET imaging studies with healthy mice and rats showed that the neutral dPG was quantitatively renally eliminated, whereas the polysulfated analogues accumulated mainly in the liver and spleen. Small amounts of the dPGS derivatives were slowly excreted via the kidneys. The degree of uptake by the reticuloendothelial system (RES) was similar for dPGS with 40% or 85% sulfation, and surface modification of the scaffold with the DMPTACN chelator did not appear to significantly affect the biodistribution profile. On the basis of our data, the applicability of bioactive dPGS as a therapeutic agent might be limited due to organ accumulation even after 3 weeks. The inert characteristics and clearance of the neutral polymer, however, emphasizes the potential of dPG as a multifunctional scaffold for various nanomedical applications.

AB - Dendritic polyglycerol sulfate (dPGS) is a biocompatible, bioactive polymer which exhibits anti-inflammatory activity in vivo and thus represents a promising candidate for therapeutic and diagnostic applications. To investigate the in vivo pharmacokinetics in detail, dPGS with a molecular weight of approx. 10 kDa was radiolabeled with 3H and 64Cu, and evaluated by performing biodistribution studies and small animal positron emission tomography (PET). 3H-labeling was accomplished by an oxidation-reduction process with sodium periodate and [3H]-borohydride. 64Cu-labeling was achieved by conjugation of isothiocyanate- or maleimide-functionalized copper(II)-chelating ligands based on 1,4-bis(2-pyridinylmethyl)-1,4,7-triazacyclononane (DMPTACN) to an amino functionalized dPGS scaffold, followed by reaction with an aqueous solution containing 64CuCl2. Independent biodistribution by radioimaging and PET imaging studies with healthy mice and rats showed that the neutral dPG was quantitatively renally eliminated, whereas the polysulfated analogues accumulated mainly in the liver and spleen. Small amounts of the dPGS derivatives were slowly excreted via the kidneys. The degree of uptake by the reticuloendothelial system (RES) was similar for dPGS with 40% or 85% sulfation, and surface modification of the scaffold with the DMPTACN chelator did not appear to significantly affect the biodistribution profile. On the basis of our data, the applicability of bioactive dPGS as a therapeutic agent might be limited due to organ accumulation even after 3 weeks. The inert characteristics and clearance of the neutral polymer, however, emphasizes the potential of dPG as a multifunctional scaffold for various nanomedical applications.

UR - http://pubs.acs.org.ezproxy.lib.monash.edu.au/doi/pdf/10.1021/acs.bioconjchem.5b00127

U2 - 10.1021/acs.bioconjchem.5b00127

DO - 10.1021/acs.bioconjchem.5b00127

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EP - 918

JO - Bioconjugate Chemistry

JF - Bioconjugate Chemistry

SN - 1043-1802

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ER -