Advanced Ultrasound in Diagnosis and Therapy ›› 2026, Vol. 10 ›› Issue (4): 264-276.doi: 10.26599/AUDT.2026.260027
• REVIEW ARTICLE • Previous Articles Next Articles
Khatami Seyedeh Mohaddeseha, Rahmani Arashb, Liu Ji-Bina, Eisenbrey Johna,*(
)
Received:2026-07-31
Revised:2026-08-31
Accepted:2026-10-15
Online:2026-12-30
Published:2026-11-02
Contact:
Eisenbrey John,
E-mail:John.Eisenbrey@jefferson.edu
Khatami Seyedeh Mohaddeseh, Rahmani Arash, Liu Ji-Bin, Eisenbrey John. Ultrasound-Stimulated Microbubbles in Cancer Therapy: A Review of Clinical and Translational Evidence. Advanced Ultrasound in Diagnosis and Therapy, 2026, 10(4): 264-276.
Table 1
Clinically available second-generation microbubble contrast agents and their approved diagnostic indications [7,13,14]."
| Agent | Manufacturer | Shell | Gas Core | Mean diameter (μm) | Approved Indications | Regions of approval |
| Definity (Luminity in EU) | Lantheus | Lipid | Octafluoropropane (C3F8) | 1.1-3.3 | Echocardiography | US, Canada, EU, Australia |
| Lumason/SonoVue | Bracco | Phospholipid | Sulfur hexafluoride (SF6) | 1.5-2.5 | Echocardiography; focal liver lesions; vesicoureteral reflux | US, EU, China, |
| Optison | GE Healthcare | Albumin | Octafluoropropane (C3F8) | 3.0-4.5 | Echocardiography | US, EU |
| Sonazoid | GE Healthcare | Phospholipid | Perfluorobutane (C4F10) | 2-3 | Focal liver lesions; focal breast lesions (Japan) | Japan, South Korea, Taiwan, China, Norway |
Figure 1
UTMD performed during Y90-TARE treatment of hepatocellular carcinoma in a 70-year-old man with a 3.1 cm segment 4A HCC (arrows), who subsequently achieved complete radiologic response on long-term follow-up imaging. Dual-screen acquisition is shown in each panel, with nonlinear contrast-mode imaging on the left and corresponding B-mode imaging on the right for anatomic reference. (A) Pre-contrast baseline; (B) Peak intratumoral and parenchymal enhancement following intravenous microbubble infusion; (C) Application of the high-mechanical-index destructive pulse; (D) Immediate post-pulse image demonstrating absence of contrast within the tumor, confirming microbubble destruction."
Figure 2
In vivo assessment of tumour perfusion using 3D Power Doppler (PD) ultrasound imaging. Left panel: Representative volumetric reconstructions of tumour vasculature (orange) are shown for each treatment group. Vascularity is visualized in a 3D overlay on B-mode grayscale anatomical images. Scale bar: 2 mm. Right panel: Average Vascular index (VI) across control (C), microbubble-enhanced focused ultrasound (MB + FUS), single-dose radiation therapy (XRT, 8 Gy), and MB + FUS + XRT treatment groups. Data are presented as mean ± SD. p-values ranging from P < 0.05 (*), P < 0.01 (**), P < 0.001 (***). (Reproduced from Petchiny et al32 under the Creative Commons CC-BY 4.0 license)."
Figure 3
Schematic of intraoperative LIPU/MB procedure and time course of peritumoral brain biopsy. Photo from surgical microscope shows hyperfluorescent areas of dysfunctional BBB shortly after LIPU/MB and infusion of chemotherapy with fluorescein bolus as previously described (24). Blue arrows indicate sonicated peritumoral brain and pink arrows indicate nonsonicated peritumoral brain. Sonicated peritumoral brain biopsies were collected at early time points after LIPU/MB (within 15 minutes) and at later time points (at least 45 minutes after LIPU/MB). (Reproduced from Gould, A. et al.40 under the Creative Commons CC-BY 4.0 license)."
Table 2
Clinical trials of ultrasound-stimulated microbubbles in oncology (by year)."
| First author, year | Application | Tumor | Phase/design | n | Microbubble agent | US delivery | Ref |
| Reference numbers correspond to the bibliography of the current manuscript. Abbreviations: BBB, blood-brain barrier; CRC, colorectal cancer; DMG, diffuse midline glioma; FUS, focused ultrasound; GBM, glioblastoma; HCC, hepatocellular carcinoma; HIFU, high-intensity focused ultrasound; HNSCC, head and neck squamous cell carcinoma; ICC, intrahepatic cholangiocarcinoma; MB, microbubble; MDL, metastatic disease to liver; PDAC, pancreatic ductal adenocarcinoma; PK, pharmacokinetics; RT, radiotherapy; TARE, transarterial radioembolization; US, ultrasound; USMB, ultrasound-stimulated microbubbles; UTMD, ultrasound-triggered microbubble destruction. | |||||||
| Carpentier, 2016 | Drug delivery | Recurrent GBM | Phase 1/2a, single-arm | 15 | SonoVue | SonoCloud-1 implantable + carboplatin | [ |
| Dimcevski, 2016 | Drug delivery | Inoperable PDAC | Phase 1, single-arm | 10 | SonoVue | External US + gemcitabine | [ |
| Idbaih, 2019 | Drug delivery | Recurrent GBM | Phase 1/2a, single-arm | 21 enrolled/ 19 treated | SonoVue | SonoCloud-1 implantable + carboplatin | [ |
| Mainprize, 2019 | Drug delivery | Primary brain tumor | Phase 1, single-arm | 5 | Definity | Transcranial MR-guided FUS | [ |
| Eisenbrey, 2021 | Radiosensitization | HCC | Phase 1, randomized pilot | 28 | Optison | UTMD + 90Y-TARE | [ |
| Zhou, 2022 | Drug delivery | HER2-neg invasive breast | Prospective non-randomized | 26 (10 USMB/16 ctrl) | SonoVue | Diagnostic US + neoadjuvant chemo | [ |
| Dasgupta, 2023 | Radiosensitization | Breast | Phase 1 feasibility | 8 (9 tumors) | Definity | MR-guided FUS + RT | [ |
| Haram, 2023 | Drug delivery | CRC liver mets | First-in-human, lesion-randomized | 17 | SonoVue | External US + systemic chemo | [ |
| Sonabend, 2023 | Drug delivery | Recurrent GBM | Phase 1, single-arm | 17 | Definity | SonoCloud-9 + nab-paclitaxel | [ |
| Han, 2024 | Drug delivery | Inoperable pancreatic cancer | Multicenter, open-label, randomized phase 2 | 78 (38/40) | SonoVue | Diagnostic US + gemcitabine-based chemo | [ |
| Carpentier, 2024 | Drug delivery | Recurrent GBM | Multicenter phase 1/2 | 33 | Definity/ Luminity | SonoCloud-9 + carboplatin | [ |
| Moore-Palhares, 2024 (Breast) | Radiosensitization | Breast/chest wall | Phase 1 | 21 enrolled (18 analyzed/20 tumors) | Definity | MR-guided FUS + RT | [ |
| Moore-Palhares, 2024 (HNSCC) | Radiosensitization | HNSCC (newly dx + recurrent) | Phase 1 | 11 (8 with response data) | Definity | Focused US + RT | [ |
| Zhou, 2024 | Thermal ablation | Advanced primary/metastatic liver | Single-arm prospective feasibility | 17 | Sonazoid | HIFU + Sonazoid bolus | [ |
| Habashy, 2025 | Drug delivery | Recurrent GBM (PK substudy) | PK/microdialysis | 4 | Definity | SonoCloud-9 + carboplatin | [ |
| Wessner, 2025 (HCC) | Radiosensitization | HCC | Single-center phase 2 randomized | 98 (50/48) | Optison | 2D UTMD + 90Y-TARE | [ |
| Wessner, 2025 (ICC/MDL) | Radiosensitization | ICC + liver metastases | Single-center phase 2 | 30 (15/15 matched) | Optison | 3D volumetric UTMD + 90Y-TARE | [ |
| Wu, 2025 | Drug delivery | Pediatric relapsed DMG | First-in-pediatrics feasibility | 3 | Definity | Neuronavigation-guided FUS + oral panobinostat | [ |
| Woodworth, 2025 | Drug delivery | High-grade glioma | Multicenter phase 1/2 (BT008), single-arm | 34 | Definity | MR-guided transcranial FUS + temozolomide | [ |
| Dong, 2026 | Perfusion (drug-delivery rationale) | Invasive breast | Prospective controlled, non-randomized | 36 (18/18) | SonoVue | Diagnostic US + MB | [ |
Figure 4
Schematic diagram of ultrasound combined with targeted microvesicle therapy for PCa. (red arrow: BST-2-EGFR-STAT3/ERK1/2 pathway inhibition; green arrow: HIFU thermal effect activates immunogenic cell death (ICD); purple arrow: HIFU cavitation effect generates cellular debris; yellow arrow: apoptosis due to multiple effects of HIFU; blue arrow: activation of immune pathways). (Reproduced from Zhou. et al60 under the Creative Commons CC-BY 4.0 license)"
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