**4. Conclusions**

Molecular US has broadened the application spectrum of standard US. Multiple effective endovascular targeting strategies have been explored using MB, and are now complemented by NB that open access to extravascular targets. Unfortunately, of the many pre-clinically explored actively targeted MB, only few meet the criteria for clinical translation. Furthermore, important questions about MB pharmacokinetics and the fate of shell components, but also about upscaling of MB production, batch reproducibility, storage stability, and sterilization, often remain open. Without these questions being answered by our scientific community, it will be difficult to convince investors or pharmaceutical industry to consider these agents as potential clinical products. In addition, the clinical indications must be very carefully chosen. High comfort to the patient, lack of radiation, excellent availability of US devices, and low costs are arguments speaking for the clinical implementation of molecular US imaging. However, to have a chance for broad acceptance, the molecular US methods need to be at least equivalent to or able to provide a clear added value over the clinical diagnostic standard methods. This can be reflected in higher sensitivity and specificity in disease detection, classification, and therapy response monitoring. Taking these arguments into consideration, indications in the fields of angiogenesis in cancer, inflammatory diseases, and arteriosclerosis/thrombosis appear highly meaningful. Ideally, the chosen applications should already use US in the clinical diagnostic routine. The molecular US examination then increases the power and expressiveness of the routine examination, enables faster therapeutic decision making, and reduces the need for further diagnostic analyses. Unfortunately, often, the most promising indications do not address huge markets, and thus are financially not interesting for big pharmaceutical companies. In addition, academia faces the dilemma that third-party funding is often only available for basic research and clinical phase II/III studies, but hard to get for closing the critical translational gap in between. Nonetheless, to move this exciting technology into clinical application, in our opinion, the translational process must be actively promoted by academia together with spin offs and small and medium enterprises, for which smaller markets are still attractive. Then, molecular US imaging could evolve to its full potential as a highly sensitive, specific, and real-time molecular imaging tool to the benefit of patients suffering from various diseases.

**Author Contributions:** G.K. and M.D. researched the data for the article and wrote the manuscript. F.K. reviewed and edited the manuscript. All authors have read and agreed to the published version of the manuscript.

**Funding:** This research was supported by the Deutsche Forschungsgemeinschaft (DFG) in the framework of the Research Training Group 2375 "Tumor-targeted Drug Delivery" grant 331065168, DFG FOR 2591 to F.K. grant No. 321137804 and grant No. KI 1072/11-3.

**Conflicts of Interest:** The authors declare no conflict of interest.
