Ultrasonically activated chemotherapeutic drug delivery in a rat model

Systemic delivery of anticancer agents is accompanied by many unwanted side effects that can be mitigated by encapsulation of antineoplastic agents. However, encapsulation necessitates a technique for controlled delivery to the cancerous tissue. We have developed a novel drug delivery system that releases drug from stabilized micelles upon application of low-frequency ultrasound and that demonstrates efficacy using doxorubicin (Dox) to treat tumors in vivo. Forty-two BDIX rats were inoculated in each hind leg with a DHD/K12/TRb tumor cell line. Dox was encapsulated within stabilized Pluronic micelles and administered weekly i.v. to the rats starting 6 weeks after the tumor inoculations. One of the two tumors was exposed to low-frequency ultrasound for 1 h. Dox concentrations of 1.33, 2.67, and 8 mg/kg and ultrasound frequencies of 20 and 70 kHz were used for treatment. Tumor volume was measured with calipers and observed over the treatment time. Administration of encapsulated Dox at concentrations of 1.33 and 2.67 mg/kg was not lethal to the rats. Application of low-frequency ultrasound (both 20 and 70 kHz) significantly reduced the tumor size when compared with noninsonated controls (P = 0.0062) in the other leg for rats receiving encapsulated Dox. Significant tumor reduction was also noted for those rats receiving ultrasound and encapsulated Dox at 2.67 mg/kg (P = 0.017) and rats receiving Dox and ultrasound at 70 kHz (P = 0.029). We postulate that ultrasound releases the Dox from the micelles as they enter the insonated volume, and ultrasound could also assist the drug and/or carriers to extravasate and enter the tumor cells. Encapsulation of Dox using stabilized Pluronic micelles and localized release using low-frequency ultrasound show promise in offering controlled drug delivery in the treatment of tumors in a rat model.