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Evolution of a Polymer-shelled Ultrasound Contrast Agent

Wednesday, April 11, 2018

4:00 PM-5:30 PM

BIOMED Seminar

Evolution of a Polymer-shelled Ultrasound Contrast Agent

Margaret A. Wheatley, PhD
John M. Reid Professor
School of Biomedical Engineering, Science and Health Systems
Drexel University

The use of ultrasound (US) to produce diagnostic images in cancer detection has many advantages because it is safe compared with X-rays and is inexpensive when compared with MRI. However, the images are not sensitive enough to detect very small features. We have. developed biocompatible agents (stabilized microbubbles of different gases) that a physician can inject intravenously just prior to an US scan, that are small enough to enter the tumor blood vessels and are excellent at reflecting US, leading to high contrast images. Shell properties of US contrast microbubbles (MB) play a pivotal role, not only in determining acoustic properties, but also determining in vivo behavior.

There are complex interactions among the ultrasound, the encapsulated gas, blood components, vasculature and normal and malignant tissue. The predominant shell components used in ultrasound contrast agents are comprised of either phospholipids/surfactants or polymers. Both forms possess a shell that can house and protect a drug or multimodal species such as iron oxide, and both can be modified with a targeting ligand specific for a given cell surface receptor. However, any changes to the shell will impact the acoustic properties, and a balance must be achieved between acoustic and clinical requirements.

Polymer based agents differ from phospholipid agents both in the capacity of the shell to house foreign species, and their acoustic behavior, reflecting different shell elasticities. Our group has developed polymeric MB based on polylactic acid (PLA) shells, and modified the designs to address different needs. We have found that the acoustic properties are extremely sensitive to any adaptations to the shell, but the basic structure offers many opportunities in imaging and theranostics.

We have also found that insonation at frequencies within the medical imaging range produces a significant size reduction, resulting in production of drug-loaded fragments, which we term nano shards. uniform, spherical capsules are produced into which a drug, imaging agent or targeting ligand can be incorporated. The agents are air-filled, with average diameters of 1.7 ± 0.8µm. They show a tight size distribution (PDI of 0.21 ± 0.0), and demonstrate excellent echogenicity (> 20 dB) at doses of less than 6 µg/mL in vitro. The MB have a negative surface charge, reflecting the carboxylate end group of PLA. This inhibits aggregation and clumping in suspension, a key requirement for injectables to prevent vascular blockage during administration. Shell thickness of 140 nm have been measured on a freeze fractured sample. Shell volume is roughly 3.5 μm3. Confocal fluorescence microscopy detected the drug doxorubicin (Dox) (3 wt% loading) in the shell, confirming both incorporation, and the hollow nature of the platform.

The seminar will trace the arc from development of a hollow polymeric capsule through drug incorporation, addition of a targeting ligand, and evolution into multi-modal imagng agents.

Margaret A. Wheatley, PhD, is head of the Microencapsulation lab and a John M. Reid Professor of Biomedical Engineering at the School of Biomedical Engineering, Science and Health Systems at Drexel University, Philadelphia, USA. Graduating with BS (Hons) in Chemistry and an MS in biochemistry from Oxford, UK, she obtained her PhD in Chemical Engineering from the University of Toronto, Canada, and followed with a post-doctoral at MIT USA.

After three years in industry at Glaxo Smith Kline, Professor Wheatley joined the Department of Chemical Engineering at Drexel, and then joined Drexel's School of Biomedical Engineering, Science and Health Systems at its inception.

Professor Wheatley’s research is at the interface of biotechnology and materials science. Her interests are ultrasound contrast agent development (tumor targeting and triggered drug delivery), controlled release technology triggered by ultrasound (bioactive compounds), and microencapsulated allografts (ex vivo gene therapy) for spinal cord injury. She holds several patents on polymer ultrasound contrast agents. Current research projects are aimed at investigating the mechanism of release from polymeric drug delivery systems by ultrasound with concomitant microstructural analysis and mathematical modeling, studying applications of the polymeric drug delivery systems including the development of effective long-term delivery systems for insulin, anti-cancer drugs, growth factors, gene therapy agents, and vaccines.

Contact Information

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Papadakis Integrated Sciences Building (PISB), Room 120


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