Quantification of extravasation and binding of PSMA-targeted nanobubbles by modelling the second-wave phenomenon
Purpose With about ten-fold smaller diameter than MBs, nanobubbles (NBs) were developed as new-generation ultrasound contrast agents (UCA) able to extravasate and target specific receptors expressed on extravascular cancer cells, such as the prostate-specific membrane antigen (PSMA). It has been shown that PSMA-targeted NBs (PSMA-NBs) can bind to specific prostate cancer (PCa) cells and exhibit a prolonged retention effect (PRE), observable by NB-based CEUS (NB-CEUS). However, previous analyses of PRE were mainly limited to the semi-quantitative assessment of the time-intensity curve (TIC) in an entire tumor ROI, possibly losing information on tumor spatial heterogeneity and local characteristics. When analyzing the pixel-level TICs of free NB-based CEUS, we observed a unique second-wave phenomenon: The first pass of the NB wave (bolus) is usually accompanied by a second wave in the time range of 3 to 15 min after the bolus injection. Such a phenomenon was shown to be potentially valuable in supporting the diagnostics of cancerous lesions. Procedures Seven male athymic nude mice were included and implanted with a tumor expressing PSMA (PSMA+) and tumors not expressing PSMA (PSMA-) on two flanks. Using either free NBs or PSMA-NBs, the characteristics of pixel-level TICs were estimated by a specialized model accounting for the two-wave phenomenon, compared with a conventional model describing only one wave. The estimated parameters by the two models were presented as parametric maps to visualize the PRE of PSMA-NBs in a dual-tumor mouse model. The effectiveness of the two models were also assessed by comparing the estimated parameters in the PSMA+ and PSMA- tumors through Mann-Whitney U test and quartile difference. Results Two parameters, the peak time and residual factor of the second wave, by the second-wave model were significantly different between PSMA+ and PSMA- tumors when using PSMA-NBs. Compared with the TICs of free NBs, TICs of PSMA-NBs present higher peak intensity and a more delayed second wave, especially in the PSMA+ tumor. Conclusions The estimation of parametric maps allows the estimation and visualization of specific binding of PSMA-NBs in PCa. The incorporation of the second-wave phenomenon enrich our understanding of NB kinetics in vivo and can possibly contribute to improved diagnostics of PCa in the future..
| Medienart: |
E-Artikel |
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| Erscheinungsjahr: |
2023 |
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| Erschienen: |
2023 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:26 |
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| Enthalten in: |
Molecular imaging & biology - 26(2023), 2 vom: 27. Dez., Seite 253-263 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Chen, Chuan [VerfasserIn] |
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| Links: |
Volltext [lizenzpflichtig] |
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| BKL: | |
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| Themen: |
Contrast-enhanced ultrasound |
| Anmerkungen: |
© The Author(s), under exclusive licence to World Molecular Imaging Society 2023. Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law. |
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| doi: |
10.1007/s11307-023-01891-w |
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| funding: |
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| Förderinstitution / Projekttitel: |
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| 520 | |a Purpose With about ten-fold smaller diameter than MBs, nanobubbles (NBs) were developed as new-generation ultrasound contrast agents (UCA) able to extravasate and target specific receptors expressed on extravascular cancer cells, such as the prostate-specific membrane antigen (PSMA). It has been shown that PSMA-targeted NBs (PSMA-NBs) can bind to specific prostate cancer (PCa) cells and exhibit a prolonged retention effect (PRE), observable by NB-based CEUS (NB-CEUS). However, previous analyses of PRE were mainly limited to the semi-quantitative assessment of the time-intensity curve (TIC) in an entire tumor ROI, possibly losing information on tumor spatial heterogeneity and local characteristics. When analyzing the pixel-level TICs of free NB-based CEUS, we observed a unique second-wave phenomenon: The first pass of the NB wave (bolus) is usually accompanied by a second wave in the time range of 3 to 15 min after the bolus injection. Such a phenomenon was shown to be potentially valuable in supporting the diagnostics of cancerous lesions. Procedures Seven male athymic nude mice were included and implanted with a tumor expressing PSMA (PSMA+) and tumors not expressing PSMA (PSMA-) on two flanks. Using either free NBs or PSMA-NBs, the characteristics of pixel-level TICs were estimated by a specialized model accounting for the two-wave phenomenon, compared with a conventional model describing only one wave. The estimated parameters by the two models were presented as parametric maps to visualize the PRE of PSMA-NBs in a dual-tumor mouse model. The effectiveness of the two models were also assessed by comparing the estimated parameters in the PSMA+ and PSMA- tumors through Mann-Whitney U test and quartile difference. Results Two parameters, the peak time and residual factor of the second wave, by the second-wave model were significantly different between PSMA+ and PSMA- tumors when using PSMA-NBs. Compared with the TICs of free NBs, TICs of PSMA-NBs present higher peak intensity and a more delayed second wave, especially in the PSMA+ tumor. Conclusions The estimation of parametric maps allows the estimation and visualization of specific binding of PSMA-NBs in PCa. The incorporation of the second-wave phenomenon enrich our understanding of NB kinetics in vivo and can possibly contribute to improved diagnostics of PCa in the future. | ||
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