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1.
EJNMMI Res ; 13(1): 73, 2023 Aug 08.
Artigo em Inglês | MEDLINE | ID: mdl-37552341

RESUMO

BACKGROUND: In vivo monitoring of cell biodistribution using positron emission tomography (PET) provides a quantitative non-invasive method to further optimize cell therapies and related new developments in the field. Our group has earlier optimized and evaluated the in vitro properties of two radiotracers,[89Zr]Zr-(oxinate)4 and [89Zr]Zr-DFO-NCS, for the radiolabelling of different cell types. Here, we performed a microPET study to assess the in vivo biodistribution of cells in rats using these two radiotracers. Human decidual stromal cells (hDSC) and rat macrophages (rMac) were radiolabelled with [89Zr]Zr-(oxinate)4 or [89Zr]Zr-DFO-NCS. Rats were intravenously injected with radiolabelled cells, and the in vivo biodistribution was monitored with microPET/CT imaging for up to day 7. Organ uptake was evaluated and presented as a percentage of injected activity per gram tissue (%IA/g) and total absorbed organ doses (mSv/MBq). RESULTS: The biodistribution in vivo showed an immediate uptake in the lungs. Thereafter, [89Zr]Zr-(oxinate)4 labelled cells migrated to the liver, while the signal from [89Zr]Zr-DFO-NCS labelled cells lingered in the lungs. The differences in the in vivo behaviour for the same cell type appeared related to the radiotracer labelling. After 24 h, [89Zr]Zr-(oxinate)4 labelled cells had over 70% higher liver uptake for both hDSC and rMac compared to [89Zr]Zr-DFO-NCS labelled cells, whereas [89Zr]Zr-DFO-NCS labelled cells showed over 60% higher uptake in the lungs compared to [89Zr]Zr-(oxinate)4 labelled cells. This difference in both lung and liver uptake continued until day 7. Dosimetry calculations showed a higher effective dose (mSv/MBq) for [89Zr]Zr-DFO-NCS compared to [89Zr]Zr-(oxinate)4, for both cell types. Although the bone uptake was higher for [89Zr]Zr-(oxinate)4 labelled cells, the prolonged uptake in the lungs contributed to a significant crossfire to bone marrow resulting in a higher bone dose. CONCLUSION: The [89Zr]Zr-DFO-NCS labelled cells suggest a prolonged accumulation in the lungs, while [89Zr]Zr-(oxinate)4 suggests quicker clearance of the lungs followed by accumulation in the liver. Accumulation of radiolabelled cells in the liver corresponds to other cell-tracking methods. Further studies are required to determine the actual location of the [89Zr]Zr-DFO-NCS labelled cell.

2.
Nucleic Acid Ther ; 32(3): 221-233, 2022 06.
Artigo em Inglês | MEDLINE | ID: mdl-35238623

RESUMO

2'-O-(N-(Aminoethyl)carbamoyl)methyl (2'-O-AECM)-modified oligonucleotides (ONs) and their mixmers with 2'-O-methyl oligonucleotides (2'-OMe ONs) with phosphodiester linkers as well as with partial and full phosphorothioate (PS) inclusion were synthesized and functionally evaluated as splice-switching oligonucleotides in several different reporter cell lines originating from different tissues. This was enabled by first preparing the AECM-modified A, C, G and U, which required a different strategy for each building block. The AECM modification has previously been shown to provide high resistance to enzymatic degradation, even without PS linkages. It is therefore particularly interesting and unprecedented that the 2'-O-AECM ONs are shown to have efficient splice-switching activity even without inclusion of PS linkages and found to be as effective as 2'-OMe PS ONs. Importantly, the PS linkages can be partially included, without any significant reduction in splice-switching efficacy. This suggests that AECM modification has the potential to be used in balancing the PS content of ONs. Furthermore, conjugation of 2'-O-AECM ONs to an endosomal escape peptide significantly increased splice-switching suggesting that this effect could possibly be due to an increase in uptake of ON to the site of action.


Assuntos
Oligonucleotídeos Antissenso , Oligonucleotídeos Fosforotioatos , Linhagem Celular , Oligonucleotídeos Antissenso/química , Oligonucleotídeos Antissenso/genética , Oligonucleotídeos Fosforotioatos/química , Oligonucleotídeos Fosforotioatos/genética
3.
Biomolecules ; 11(8)2021 07 29.
Artigo em Inglês | MEDLINE | ID: mdl-34439784

RESUMO

By using solid targets in medical cyclotrons, it is possible to produce large amounts of 68GaCl3. Purification of Ga3+ from metal ion impurities is a critical step, as these metals compete with Ga3+ in the complexation with different chelators, which negatively affects the radiolabeling yields. In this work, we significantly lowered the level of iron (Fe) impurities by adding ascorbate in the purification, and the resulting 68GaCl3could be utilized for high-yield radiolabeling of clinically relevant DOTA-based tracers. 68GaCl3 was cyclotron-produced and purified with ascorbate added in the wash solutions through the UTEVA resins. The 68Ga eluate was analyzed for radionuclidic purity (RNP) by gamma spectroscopy, metal content by ICP-MS, and by titrations with the chelators DOTA, NOTA, and HBED. The 68GaCl3eluate was utilized for GMP-radiolabeling of the DOTA-based tracers DOTATOC and FAPI-46 using an automated synthesis module. DOTA chelator titrations gave an apparent molar activity (AMA) of 491 ± 204 GBq/µmol. GMP-compliant syntheses yielded up to 7 GBq/batch [68Ga]Ga-DOTATOC and [68Ga]Ga-FAPI-46 (radiochemical yield, RCY ~ 60%, corresponding to ten times higher compared to generator-based productions). Full quality control (QC) of 68Ga-labelled tracers showed radiochemically pure and stable products at least four hours from end-of-synthesis.


Assuntos
Radioisótopos de Gálio/química , Gálio/química , Marcação por Isótopo/métodos , Octreotida/análogos & derivados , Quinolinas/síntese química , Radioquímica/métodos , Acetatos/química , Ácido Ascórbico/química , Quelantes/química , Ciclotrons , Etilenodiaminas/química , Gálio/isolamento & purificação , Compostos Heterocíclicos com 1 Anel/química , Humanos , Octreotida/síntese química , Tomografia por Emissão de Pósitrons/métodos
4.
Appl Radiat Isot ; 176: 109825, 2021 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-34157495

RESUMO

The growing need and limited availability of generator produced 68Ga (T1/2 = 68 min) for PET has provided the impetus for alternative, high output, 68Ga production routes such as charge particle activation of enriched 68Zn using PET cyclotrons. The work presents a rapid production method for clinically useful 68Ga for radiolabeling. The focus is also to expand the production capacity of cyclotron solid target-produced 68Ga over generator produced and liquid solutions targets by using enriched 68Zn-foils that minimizes target preparation.


Assuntos
Ciclotrons , Radioisótopos de Gálio/química , Isótopos de Zinco/química , Compostos Heterocíclicos com 1 Anel/química
5.
Chem Commun (Camb) ; 51(19): 4044-7, 2015 Mar 07.
Artigo em Inglês | MEDLINE | ID: mdl-25664358

RESUMO

2'-O-AECM modified oligonucleotides provide an unusual combination of remarkable properties. This includes the combination of high resistance towards enzymatic degradation and the spontaneous cellular uptake of AECM oligonucleotides.


Assuntos
Esterases/metabolismo , Oligonucleotídeos/química , Oligonucleotídeos/metabolismo , Transporte Biológico , Linhagem Celular Tumoral , Humanos
6.
Nucleosides Nucleotides Nucleic Acids ; 26(10-12): 1491-3, 2007.
Artigo em Inglês | MEDLINE | ID: mdl-18066812

RESUMO

Two different classes of protection for the uridine lactam function have been evaluated. These are benzoyl protections and different acetal functions. In particular the triisopropylsiloxymethyl protection is a most promising lactam protecting group for use in synthesis of 2'-O-alkyl-uridines.


Assuntos
Lactamas/química , Nucleosídeos de Pirimidina/síntese química , Uridina/análogos & derivados , Alquilação , Oligonucleotídeos/química
7.
Nucleosides Nucleotides Nucleic Acids ; 26(10-12): 1495-9, 2007.
Artigo em Inglês | MEDLINE | ID: mdl-18066813

RESUMO

In order to obtain higher quality 2'-O-carbamoylmethyl oligoribonucleotides we are conducting studies of this modification. Here we present synthesis of 2'-O-carbamoylmethyl containing H-phosphonate building blocks as well as synthesis of model dinucleotides needed for these studies.


Assuntos
Organofosfonatos/síntese química , Ribonucleosídeos/química , Oligorribonucleotídeos/química , Organofosfonatos/química , Ribonucleosídeos/síntese química
8.
Nucleic Acids Symp Ser (Oxf) ; (51): 149-50, 2007.
Artigo em Inglês | MEDLINE | ID: mdl-18029630

RESUMO

An efficient and selective synthesis of 2'-O-alkyl modified adenosine nucleosides carrying either a triple bond function or an azido group is reported. These nucleosides are thus armed for performing 1,3 dipolar cycloadditions (click chemistry)(1). Derivatives suitable for further conversion into different building blocks are reported.


Assuntos
Adenosina/análogos & derivados , Nucleotídeos de Adenina/química , Adenosina/síntese química , Adenosina/química , Oligonucleotídeos/síntese química , Oligonucleotídeos/química
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