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This precludes the differentiation of viable tumor tissue, necrotic tissue, and margin-associated disease. We investigate the use of prostate-specific membrane antigen (PSMA)-targeted lipid-shelled perfluorocarbon nanobubbles (PSMA-NBs) in an orthotopic rabbit model using a clinical CEUS system. We implanted PSMA-positive PC3pip-GFP tumors into the prostates of immunosuppressed New Zealand White rabbits and performed transabdominal imaging with PSMA-NBs, MBs, and untargeted nanobubbles (Plain-NB) using the same imaging and analysis protocols. To address tumor heterogeneity and ultrasound boundary ambiguity, ROIs were defined from baseline B-mode images and segmented into the tumor core, rim, and a surrounding peritumoral area. Pixel-wise parametric and decorrelation time (DT) maps were generated and correlated with whole-slide histology (H&amp;E) and PSMA IHC. Compared to MBs, PSMA-NBs exhibited higher peak intensities in the tumor core and rim (1.60-fold and 1.50-fold, respectively) and improved retention (mean transit time: 4.20 to 4.50-fold higher) for up to 10 minutes in the tumor and peritumoral areas. PSMA-NB kinetic and DT parameters also correlated with histology-defined tumor viability and PSMA expression. Compared to Plain-NBs, PSMA-NBs also exhibited improved retention (MTT +21%; AUCwo) in the rim and peritumoral areas. This study demonstrates the capability of PSMA-NBs to characterize prostate cancer by molecular CEUS beyond what is possible with conventional MBs.<\/jats:p>","DOI":"10.1101\/2025.08.07.668901","type":"posted-content","created":{"date-parts":[[2025,8,11]],"date-time":"2025-08-11T06:45:10Z","timestamp":1754894710000},"source":"Crossref","is-referenced-by-count":2,"title":["Preclinical Evaluation of PSMA-Targeted Ultrasound Contrast Agents in an Orthotopic Model of Prostate Cancer in Rabbits"],"prefix":"10.64898","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-6028-2503","authenticated-orcid":false,"given":"Felipe M.","family":"Berg","sequence":"first","affiliation":[{"name":"Department of Radiology, Case Western Reserve University, Cleveland, OH, United States"},{"name":"Hospital Israelita Albert Einstein, S\u00e3o Paulo, SP, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2733-4006","authenticated-orcid":false,"given":"Eric 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