NIBIB - Targeted Drug Delivery with Microbubbles

							National Institute of Biomedical Imaging and Bioengineering

Targeted Drug Delivery with Microbubbles


     Treating malignant brain tumors can be difficult. The protective blood-brain barrier blocks many drugs from
     acting on brain cells. Now, a new method for delivering drugs directly to the affected area may increase the
     effectiveness of chemotherapy in brain tumors and reduce its toxic effect on healthy cells.

     Researchers at the University of California, Davis, and ImaRx Therapeutics in Tucson, Arizona, are
     developing an innovative technique that uses ultrasound and drug-laden “microbubbles” to deliver
     concentrated chemotherapy drugs to the inner lining of blood vessels. Doctors already use ultrasound to
     identify tumors and guide biopsy procedures. Ultrasound pulse sequences can also guide micro-packaged
     medications to specific parts of the body.

     Ultrasound as a Guide
     NIBIB grantee Dr. Katherine Ferrara, professor of
     biomedical engineering at the University of California,
     Davis, and her student, Michaelann Shortencarier, have
     shown that ultrasound can guide tiny gas bubbles filled with
     fluorescent dye to a particular site, and then bursts of
     ultrasound can fragment the bubbles and spray their
     contents onto diseased tissue. Pre-clinical studies are under
     way.

     Ferrara, Shortencarier, and colleagues use acoustically
     active lipospheres (AALs) – microscopic bubbles with a gas
     center that’s surrounded by a thick oil shell and encased by
     an outer layer of fatty substances known as lipids. The outer
     lipid coating of the microbubble encloses the drug while it
     circulates throughout the body, preventing systemic toxicity
     while providing concentrated drug delivery to a specific          Fluorescently labeled lipospheres circulate in blood
     region.                                                           vessels within a transparent membrane. The top left
                                                                       microscope image shows a vessel before an
     In their experiments, the researchers filled the lipospheres      ultrasound pulse train fragments the lipospheres. Top
                                                                       right shows the vessels 3 minutes after ultrasound.
     with a fluorescent dye and guided them to a target site using     The two lower images were acquired using the
     a specially devised pattern of ultrasound pulses. Applying        fluorescent signal given off by the lipospheres. The
     ultrasound to the lipospheres causes the gas bubbles inside       lower left image shows the vessel prior to
     them to expand and contract. A series of ultrasound pulses        fragmentation and the lower right 3 minutes after
                                                                       ultrasound delivery. In current studies, the ultrasound
     is tailored specifically to increase the close contact between    pulse sequence shatters the lipospheres releasing a
     the lipospheres and their target. Once the lipospheres are in     dye which then adheres to the vessel wall. This
     place, a high-intensity ultrasound pulse breaks the bubbles       approach provides greater accuracy for targeted drug
     into tiny fragments, releasing the dye. The researchers are       delivery. Future studies will include a drug rather than
     currently focusing on delivering the lipospheres to blood         a dye.
                                                                       Image courtesy of Dr. Katherine Ferrara, University of
     vessel walls, because blood vessels provide nourishment to        California – Davis.
     tumors.

     From Lab to Clinic
     The liposphere/ultrasound approach offers several advantages over existing drug delivery methods. Ultrasound
     can selectively deliver drug-laden lipospheres to a tumor or organ and then release the drug at a particular site.
     The force used to propel the drug ensures that it is delivered specifically to the endothelial or surface cells of
     blood vessels in the target area and not simply released to flow downstream. “The idea is that you can use
     ultrasound pressure to prevent the drug delivery vehicle from being uniformly distributed throughout the
     body,” Dr. Ferrara says.
Ferrara hopes this technology will aid in managing brain cancer. To be beneficial, drugs used to treat brain
tumors must cross the blood-brain barrier. However, this protective defense blocks the therapeutic action of
many drugs and often renders chemotherapy ineffective. When the barrier is crossed, the entire brain, not just
the affected site, is subject to the toxic effects of chemotherapy. Although human clinical trials are still several
years away, Ferrara says that delivering drugs via ultrasound may produce fewer side effects and improve
patient outcomes.

The researchers’ goal is to have the pulse patterns used for guiding and then rupturing microbubbles integrated
into conventional ultrasound machines, thereby linking diagnostic and therapeutic work. The team wants to
develop a wider range of pulse sequences and drug-delivery vehicles to treat other diseases as well. “We’re
exploring the use of these techniques in a broad range of clinical applications,” says Ferrera.

Funding for the research was provided by the National Institute of Biomedical Imaging and Bioengineering
and the National Cancer Institute.

Reference
Shortencarier M, et al., A method for radiation-force localized drug delivery using gas-filled lipospheres, IEEE
Transactions on Ultrasonics, Ferroelectrics, and Frequency Control 51, 821-830, 2004.




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