Ultrasound (US) has an ever-increasing role in the delivery of therapeutic agents including genetic material, proteins, and chemotherapeutic agents. Cavitating gas bodies such as microbubbles are the mediators through which the energy of relatively non-interactive pressure waves is concentrated to produce forces that permeabilize cell membranes and disrupt the vesicles that carry drugs. Thus the presence of microbubbles enormously enhances delivery of genetic material, proteins and smaller chemical agents. Delivery of genetic material is greatly enhanced by ultrasound in the presence of microbubbles. Attaching the DNA directly to the microbubbles or to gas-containing liposomes enhances gene uptake even further. US-enhanced gene delivery has been studied in various tissues including cardiac, vascular, skeletal muscle, tumor and even fetal tissue. US-enhanced delivery of proteins has found most application in transdermal delivery of insulin. Cavitation events reversibly disrupt the structure of the stratus corneum to allow transport of these large molecules. Other hormones and small proteins could also be delivered transdermally. Small chemotherapeutic molecules are delivered in research settings from micelles and liposomes exposed to ultrasound. Cavitation appears to play two roles: it disrupts the structure of the carrier vesicle and releases the drug; it also makes the cell membranes and capillaries more permeable to drugs. There remains a need to better understand the physics of cavitation of microbubbles and the impact that such cavitation has upon cells and drug-carrying vesicles.
Application of ultrasound in combination with drug therapy was effective in reducing tumor growth rate, irrespective of which frequency was employed.
Ultrasound increases efficacy of drugs delivered from micelles, but the pharmacokinetics have not been studied previously. In this study, ultrasound was used to deliver doxorubicin sequestered in micelles in an in vivo rat model with bilateral leg tumors. One of two frequencies with identical mechanical index and intensity was delivered for 15 minutes to one tumor immediately after systemic injection of micellar doxorubicin. Pharmacokinetics in myocardium, liver, skeletal muscle, and tumors were measured for one week. When applied in combination with micellar doxorubicin, the ultrasoincated tumor had higher doxorubicin concentrations at 30 minutes, compared to bilateral noninsonated controls. Initially, concentrations were highest in heart and liver, but within 24 hours they decreased significantly. From 24 hours to 7 days, concentrations remained highest in tumors, regardless of whether they received ultrasound or not. Comparison of insonated and noninsonated tumors showed 50% more doxorubicin in the insonated tumor at 30 minutes post-treatment. Four weekly treatment produced additional doxorubicin accumulation in the myocardium but not in liver, skeletal leg muscle, or tumors compared to single treatment. Controls showed that neither ultrasound nor the empty carrier impacted tumor growth. This study shows that US causes more release of drug at the targeted tumor.
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