Methods and techniques for in vitro subcellular localization of radiopharmaceuticals and radionuclides

Costa, Inês; Cheng, Jordan; Osytek, Katarzyna M.; Imberti, Cinzia; Terry, Samantha Y.A.

doi:10.1016/j.nucmedbio.2021.03.010

Cited by 6 publications

(9 citation statements)

References 103 publications

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“…ICP-MS is a very powerful multi-elemental analysis technique for quantitative assessment of metals at concentrations down to the sub-parts-per-trillion level in complex matrices. , Over the past years, more and more biomedical applications of the ICP-MS technology have emerged for the detection and quantification of proteins, biomolecules, or nanoparticles in specific assays. ,, The utilization of ICP-MS for the characterization of metal conjugates as an alternative to radiometal-based assays has only recently been proposed. ,, …”

Section: Discussionmentioning

confidence: 99%

“…Inductively coupled plasma mass spectrometry (ICP-MS) is a highly sensitive, quantitative, and multi-elemental analysis technique that enables the characterization of metal conjugates in conventional research laboratories . In the recent past, ICP-MS became increasingly important for biological research, for instance, for the quantitative analysis of metal-based nanoparticles in cell uptake experiments and biodistribution studies as well as in the context of metallomics. − ICP-MS has lately been proposed for the characterization of candidates for radiotheranostic application avoiding the use of radioactive metals. ,, …”

Section: Introductionmentioning

confidence: 99%

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Inductively Coupled Plasma Mass Spectrometry─A Valid Method for the Characterization of Metal Conjugates in View of the Development of Radiopharmaceuticals

et al. 2023

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This study addresses the question whether inductively coupled plasma mass spectrometry (ICP-MS) can be used as a method for the in vitro and in vivo characterization of non-radioactive metal conjugates to predict the properties of analogous radiopharmaceuticals. In a "proof-of-concept" study, the prostate-specific membrane antigen (PSMA)-targeting [ 175 Lu]Lu-PSMA-617 and [ 159 Tb]Tb-PSMA-617 were compared with their respective radiolabeled analogues, [ 177 Lu]Lu-PSMA-617 (PLU-VICTO, Novartis) and [ 161 Tb]Tb-PSMA-617. ICP-MS and conventional γ-counting of the cell samples revealed almost identical results (<6% absolute difference between the two technologies) for the in vitro uptake and internalization of the (radio)metal conjugates, irrespective of the employed methodology. In vivo, an equal uptake in PSMA-positive PC-3 PIP tumor xenografts was determined 1 h after the injection of [ 175 Lu]Lu-/[ 177 Lu]Lu-PSMA-617 (41 ± 6% ID/g and 44 ± 12% IA/g, respectively) and [ 159 Tb]Tb-/[ 161 Tb]Tb-PSMA-617 (44 ± 5% ID/g and 44 ± 5% IA/g, respectively). It was further revealed that it is crucial to use the same ratios of the (radio)metal-labeled and unlabeled ligands for both methodologies to obtain equal data in organs in which receptor saturation was reached such as the kidneys (12 ± 2% ID/g vs 10 ± 1% IA/g, 1 h after injection). The data of this study demonstrate that the use of high-sensitivity ICP-MS allows reliable and predictive quantification of compounds labeled with stable metal isotopes in cell and tissue samples obtained in preclinical studies. It can, hence, be employed as a valid alternative to the state-of-the-art γ-counting methodology to detect radioactive ligands.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Inductively Coupled Plasma Mass Spectrometry─A Valid Method for the Characterization of Metal Conjugates in View of the Development of Radiopharmaceuticals

et al. 2023

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“…Furthermore, the quantitative comparison of 68 Ga-MMC(IR800)-TOC to 68 Ga-DOTA-TOC in vivo strengthened our understanding of off-target uptake (i.e., blood half-life) and provides a rationale for optimization with some of the dyes discussed herein. Conversely, fluorescence imaging of a dual-labeled tumor targeting agent has been used to identify the sub-cellular distributions of radiopharmaceuticals [ 143 ]. Dual-modal imaging can also be used in translational studies by ex vivo staining of human tumor tissues and subsequent fluorescent imaging and autoradiography of the tissue section, as described by Rijpkema and coworkers [ 144 ].…”

Section: Future Directions Of Dual-modal Imagingmentioning

confidence: 99%

Targeted Dual-Modal PET/SPECT-NIR Imaging: From Building Blocks and Construction Strategies to Applications

Usama

Marker

Vargas

et al. 2022

Cancers

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Molecular imaging is an emerging non-invasive method to qualitatively and quantitively visualize and characterize biological processes. Among the imaging modalities, PET/SPECT and near-infrared (NIR) imaging provide synergistic properties that result in deep tissue penetration and up to cell-level resolution. Dual-modal PET/SPECT-NIR agents are commonly combined with a targeting ligand (e.g., antibody or small molecule) to engage biomolecules overexpressed in cancer, thereby enabling selective multimodal visualization of primary and metastatic tumors. The use of such agents for (i) preoperative patient selection and surgical planning and (ii) intraoperative FGS could improve surgical workflow and patient outcomes. However, the development of targeted dual-modal agents is a chemical challenge and a topic of ongoing research. In this review, we define key design considerations of targeted dual-modal imaging from a topological perspective, list targeted dual-modal probes disclosed in the last decade, review recent progress in the field of NIR fluorescent probe development, and highlight future directions in this rapidly developing field.

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“…Although activity uptake in the cell nucleus is limited for most vectors [ 19 , 32 ], Falzone et al have shown that even little uptake in the nucleus can induce a substantial increase in TCP, especially for particles with a short range, such as Auger electrons [ 72 ]. The available methods and techniques to access the subcellular activity distribution in vitro were recently reviewed by Costa et al [ 73 ]. The most common method by far is fractionation, in which the different physiochemical properties of the cell organelles of interest are exploited to obtain separated fractions, which subsequently can be measured with a gamma counter.…”

Section: Preclinical Dosimetrymentioning

confidence: 99%

“…The most common method by far is fractionation, in which the different physiochemical properties of the cell organelles of interest are exploited to obtain separated fractions, which subsequently can be measured with a gamma counter. Although fractionation is a fast, relatively easy and low-cost method, it provides only a population-averaged distribution [ 73 ]. In all 27 studies using dosimetry methods in this review, the activity is assumed to be uniformly distributed within the cells.…”

Section: Preclinical Dosimetrymentioning

confidence: 99%

A Review on Tumor Control Probability (TCP) and Preclinical Dosimetry in Targeted Radionuclide Therapy (TRT)

et al. 2022

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Targeted radionuclide therapy (TRT) uses radiopharmaceuticals to specifically irradiate tumor cells while sparing healthy tissue. Response to this treatment highly depends on the absorbed dose. Tumor control probability (TCP) models aim to predict the tumor response based on the absorbed dose by taking into account the different characteristics of TRT. For instance, TRT employs radiation with a high linear energy transfer (LET), which results in an increased effectiveness. Furthermore, a heterogeneous radiopharmaceutical distribution could result in a heterogeneous dose distribution at a tissue, cellular as well as subcellular level, which will generally reduce the tumor response. Finally, the dose rate in TRT is protracted, relatively low, and variable over time. This allows cells to repair more DNA damage, which may reduce the effectiveness of TRT. Within this review, an overview is given on how these characteristics can be included in TCP models, while some experimental findings are also discussed. Many parameters in TCP models are preclinically determined and TCP models also play a role in the preclinical stage of radiopharmaceutical development; however, this all depends critically on the calculated absorbed dose. Accordingly, an overview of the existing preclinical dosimetry methods is given, together with their limitation and applications. It can be concluded that although the theoretical extension of TCP models from external beam radiotherapy towards TRT has been established quite well, the experimental confirmation is lacking. Thus, requiring additional comprehensive studies at the sub-cellular, cellular, and organ level, which should be provided with accurate preclinical dosimetry.

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Methods and techniques for in vitro subcellular localization of radiopharmaceuticals and radionuclides

Cited by 6 publications

References 103 publications

Inductively Coupled Plasma Mass Spectrometry─A Valid Method for the Characterization of Metal Conjugates in View of the Development of Radiopharmaceuticals

Inductively Coupled Plasma Mass Spectrometry─A Valid Method for the Characterization of Metal Conjugates in View of the Development of Radiopharmaceuticals

Targeted Dual-Modal PET/SPECT-NIR Imaging: From Building Blocks and Construction Strategies to Applications

A Review on Tumor Control Probability (TCP) and Preclinical Dosimetry in Targeted Radionuclide Therapy (TRT)

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