Pulsating ultrasound enhances gene therapy for tumors

High-intensity focused ultrasound emitted in short pulses is a promising, non-invasive procedure for enhancing gene delivery to cancerous cells without destroying healthy tissue, according to a study in the May issue of the journal Radiology.

High-intensity focused ultrasound (HIFU) is more powerful than standard ultrasound. HIFU can destroy tumors through long and continuous exposures that raise the temperature inside cancerous cells, effectively "cooking" them. Under a technique introduced by King C.P. Li, M.D., M.B.A., from the National Institutes of Health (NIH), short pulses of HIFU can be used to prevent exposed tissue from becoming too hot and damaged. Pulsed-HIFU instead renders tissues permeable and helps target them for taking up genes and other therapeutic substances injected into the body.

"Basically, we're using sound waves to open up the tissue by producing gaps between the cells, making it leakier and more prone to taking up various genes, agents and compounds," said Victor Frenkel, Ph.D., a staff scientist for the diagnostic radiology department at the NIH Clinical Center in Bethesda, Md.

Working with lead authors Kristin M. Dittmar, M.D., and Jianwu Xie, M.D., the researchers used pulsed-HIFU on tumors in mice, then immediately injected an easily measurable reporter gene into the vein in their tails. The reporter gene in this study--a fluorescent-green protein found in deep-sea invertebrates--was visible in all sections of the tumors exposed to pulsed-HIFU. Tumors not targeted with pulsed-HIFU showed negligible signs of the gene.

An analysis showed reporter gene levels to be nine times higher in tumors treated with pulsed-HIFU compared with tumors left unexposed.

Researchers were especially encouraged by the results because the type of cancer treated in the study--squamous cell carcinoma, found in head and neck tumors--is one of the least permeable cancers and does not respond well to chemotherapy or radiation. However, these types of tumors have responded to certain types of therapeutic genes.

"This procedure is hypothetically generic for enhancing delivery to all tissues," Dr. Frenkel said. "Previous studies by Dr. Li have shown that pulsed-HIFU increases the uptake of drugs. Now we've shown that it works for genes and we're making the case that there's a connection between the two."

Other methods currently being investigated for enhancing gene delivery, such as lasers and electric current, are limited to surface lesions or require needles to be inserted in the body. Pulsed-HIFU is non-invasive and can treat any area of the body accessible by ultrasound, the exceptions being the lungs and bones. Additional advantages of pulsed-HIFU include no scarring, limited blood loss and infections, reduced risk of other complications, shortened recovery time, significant reduction in costs and the potential for many procedures to be done on an outpatient basis.