Future directions for ultrasound drug targeting

The wide and established application of ultrasound contrast agents has provided a solid foundation for research into ultrasound drug targeting. Since the US Food and Drug Administration published safety recommendations for the use of diagnostic ultrasound in 1976, a considerable amount of data has been collected and evaluated. Researchers now must bridge the gap between diagnostic and therapeutic applications.

More than 20 years of clinical experience with contrast imaging has helped scientists map the body organs most accessible to ultrasound. These organs represent suitable targets for microbubble targeting.

Several safety concerns with regard to microbubbles still pose open questions to the authorities. In 2008, FDA issued an alert about Optison (GE Healthcare, Waukesha, WI) and Definity (Bristol-Myers Squibb, New York), the two microbubble contrast agents approved in the US. The authorities revised the contraindications and warnings for these products after several cases of severe cardiopulmonary reactions occurred in patients with pulmonary hypertension shortly after the contrast agents were applied. Recent postmarketing observations, however, provided reassurance about the safety of ultrasound contrast agents (26).

Those safety incidents relate to microbubbles' ability to pass through narrow lung capillaries. Third-generation microbubbles are smaller than red blood cells and pass through the lung capillaries without impeding circulation. Severe adverse effects after microbubble administration have been observed in patients with multiple morbidities and large cardiopulmonary disturbances. Nevertheless, these concerns may potentially affect microbubble applications such as drug administration, where fairly enhanced dosages may be needed to reach therapeutic concentrations at the target site.

One question relevant to all drug-targeting approaches in general is how to estimate a drug's pharmacokinetic therapeutic window. In a targeting approach, the active drug must be enriched at the disease site, and the therapeutic window must be reached there rather than in the systemic circulation.

An important milestone on the way toward creating a successful product is the establishment of a lean and scalable manufacturing process that conforms to good manufacturing practice. The formulator should bear regulatory requirements in mind as early as in the prepatent stage of product development. If a production process is not designed to allow terminal sterile filtration, for example, during a drug's preformulation stage, it is problematic to redesign the process during the production of clinical batches.

With their dimensions of between several hundred nanometers and 5–6 µm, UCA cannot be subjected to sterile filtration. Their sensitivity to pressure excursions is also a hurdle to terminal steam sterilization. Sterilization through gamma irradiation is, in most cases, not an option because of the sensitivity of glass and most active ingredients to gamma rays. A sterile filtration of the contrast agent Definity is possible before the fill–finish step because the microbubbles are formed at the patient's bed side by mechanical agitation in the final container. If the product is supposed to include preformed microbubbles, however, some aseptic processing steps seem to be inevitable.

The development of techniques for safe and precise ultrasound focusing in sensitive areas such as behind the cranial wall remains a vital need. The ultrasound cycle should correspond to the maximal tissue replenishment achieved with microbubbles (e.g., by using electrocardiographic triggering to target the myocardium and the coronary vessels).

Finally, microbubbles pose a serious challenge for establishing methods for quality control and particle characterization. The final product often does not contain a single particle species; it includes at least two. Phospholipid microbubbles, for example, are always accompanied by liposomes. Furthermore, depending on their diameter, microbubbles rise upwards at various speeds. This feature requires scientists to consider the analytical approach for particle sizing and determining Zeta potential.

Conclusion

Undoubtedly, many aspects of UACs still must be sufficiently explored before an advanced drug-targeting strategy can be developed. Nevertheless, the industry has witnessed the emergence of the first fully established and marketed approach for active drug targeting: antibody drug conjugates. Inevitably, this approach will be followed by other, even more sophisticated means to guide the drug through the body to the desired site of action. The field of ultrasound drug targeting will remain active and exciting.

Acknowledgments

This article was funded by the BioFuture grant of Germany's Federal Ministry of Education and Research (Raffi Bekeredjian, Heidelberg, Germany).

Steliyan Tinkov* is an alumnus, Conrad Coester is an associate professor of pharmaceutical technology and biopharmaceutics, and Gerhard Winter is a professor of pharmaceutical technology and biopharmaceutics, all at Ludwig-Maximilians University Munich, Butenandtstr. 5-13, D-81377 Munich, Germany, stelijan.tinkov@cup.uni-muenchen.de
. Raffi Bekeredjian is an associate professor of cardiology at Ruprecht-Karls University in Heidelberg, Germany.

*To whom all correspondence should be addressed.