3.2.5. Targeted MB in The Clinics

Although there are many successful pre-clinical studies using targeted MB, the translation to the clinics is slow. Most of the targeted MB used in research have been functionalized using biotin-avidin or covalent coupling. As discussed before, avidin can cause severe allergic reactions in patients and thus its use should be avoided [141–145]. However, free chemical groups sticking out of the MB shell can as well cause an immune response. Thus, it is not surprising that the only two targeted MB (Sonazoid™ and BR55) currently in clinical trials have the ligand incorporated in the shell layer.

Sonazoid™ (Daiichi Sankyo Company Ltd.) is not specifically advertised as a targeted MB. However, due to phosphatidylserine in the shell layer, these MB circulate for a longer time in the blood and accumulate in Kupffer cells and macrophages of the liver. These MB are clinically approved in Japan for CEUS imaging of hepatic tumors. They are also in phase I clinical trial in the United States (ClinicalTrials.gov identifier: NCT02968680) for detecting sentinel lymph nodes in patients with melanoma and in phase III clinical trial in China (NCT03335566) for liver lesion detection.

The second targeted MB in the clinical translation is BR55 (Bracco Suisse SA, Geneva, Switzerland). These MB contain VEGFR2-binding phospholipid-heteropeptides. The first clinical trials in women

with ovarian or breast cancer showed that BR55 is safe to use in patients, and the CEUS signal correlated with the VEGFR2 amount in tumor lesions [146]. Further clinical trials are ongoing to evaluate its specificity and sensitivity in the prostate (NCT02142608 and NCT01253213), ovarian cancer (NCT03493464 and NCT04248153) and pancreatic lesions (NCT03486327).
