DESCRIPTION (provided by applicant): Many promising studies indicate that ultrasound-enhanced drug delivery vehicles can be used to locally deliver a drug to a region of interest, with ultrasound imaging used to define the region to be treated and to monitor the inflow of the delivery vehicle. We have developed radiation force pulse sequences that first deflect a drug delivery vehicle to a vessel wall and then rupture the vehicle at that site. Drug delivery vehicles can be engineered to be manipulated by this ultrasonic radiation force, through the incorporation of a small volume of gas. We refer to the engineered vehicles as acoustically-active lipospheres (AALs) in that they have properties similar to ultrasound contrast agents, but are also designed to carry a significant drug payload. In addition, the vehicles can be designed such that ultrasound pressure produces fragmentation of a micron-sized sphere into particles on the order of tens to hundreds of nanometers, and these particles may be taken up readily. In the proposed studies, we will specifically explore the development of ultrasound techniques to locally concentrate a chemotherapeutic drug within the brain, crossing the blood-brain barrier (BBB). This is a unique problem and is critically important as the survival time with primary and metastatic brain tumors is low. Chemotherapy has been unsuccessful in general, and surgical debulking of the tumor and radiotherapy extend the patient survival only by 6-12 months. New research studies have demonstrated that BBB permeability can be greatly increased for both hydrophilic and hydrophobic drugs through the application of systemic compounds that include bradykinin analogs and P-glycoprotein (P-gp) modulators. The disadvantage of the global increase in BBB permeability produced by these compounds is that the simultaneous application of chemotherapy at the desired concentrations can result in a severe neurotoxicity. Our new technique may address this problem since the drug will be concentrated on the luminal surface of the endothelial cells in the desired region, and this increased concentration when combined with P-gp modulation should locally increase the drug concentration in the tumor and brain-surrounding tumor region. Thus, ultimately, by combining increased BBB permeability with local delivery of a chemotherapeutic to endothelial cells in a region of interest, we hope to significantly increase the effectiveness of chemotherapy in brain tumors. Our proposal includes the following goals designed to develop and validate ultrasound-enhanced local drug delivery of a hydrophilic drug to the brain. We will develop and evaluate a model for the displacement produced by ultrasonic radiation forces applied to AALs. Next, the transfer of fluorescently-labeled paclitaxel to endothelial cells will be assessed. Finally, we will evaluate the ability of local drug delivery vehicles containing F18-labelled paclitaxel to concentrate the drug within the brain with and without co-administration of a P-glycoprotein blocker.
|Effective start/end date||9/2/03 → 8/31/06|
- National Institutes of Health: $37,456.00
- National Institutes of Health: $175,646.00
- National Institutes of Health: $264,193.00
- Biochemistry, Genetics and Molecular Biology(all)