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Quantification of extravasation and binding of PSMA-targeted nanobubbles by modelling the second-wave phenomenon

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Abstract

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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Funding

This work was funded by the National Institutes of Health (R01EB028144), 1S10OD021635-01, the CWRU Coulter Translational Research Partnership, and the 4TU. Precision Medicine grant.

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Author notes

  1. Chuan Chen and Reshani Perera contributed equally to this article.

Authors and Affiliations

  1. Southeast University, Nanjing, People’s Republic of China

    Chuan Chen

  2. Eindhoven University of Technology, Eindhoven, The Netherlands

    Chuan Chen, Massimo Mischi & Simona Turco

  3. Case Western Reserve University, Cleveland, OH, USA

    Reshani Perera & Agata Exner

  4. Toronto Metropolitan University, Toronto, Canada

    Michael Kolios

Authors
  1. Chuan Chen
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  2. Reshani Perera
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  3. Massimo Mischi
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  4. Michael Kolios
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  6. Simona Turco
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Correspondence to Chuan Chen.

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Chen, C., Perera, R., Mischi, M. et al. Quantification of extravasation and binding of PSMA-targeted nanobubbles by modelling the second-wave phenomenon. Mol Imaging Biol 26, 253–263 (2024). https://doi.org/10.1007/s11307-023-01891-w

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