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Investigation of the mechanisms and applications of
ultrasound-induced intracellular molecular delivery (sonoporation)
Investigation of the mechanisms of ultrasound-induced apoptosis
Investigation of the mechanisms and applications of porphyrin-induced
sonodynamic effect
Ultrasound enhanced glomerular filtration rate of kidney
Objectives: To demonstrate the cavitation events during sonication in the glomerular capillary wall. To demonstrate the increasing filtration fraction during sonication. To investigate the optimal sonication parameters to produce the desired physiological or histological end points using in vivo rabbit kidney studies.
This method would open an alternative way for dialysis and further its effectiveness in the treatment of chronic kidney diseases (progrediating towards End Stage Renal Disease).
Background:
It is a histological fact that during the progression of chronic renal diseases the glomerular part of the kidney goes though mesangial proliferation. Parts of the capillary wall, such as the epithelial layer (podocyte flake) increases in thickness and become heterogonous, while the glomerular space shrinks. The filtration function of the kidney deteriorates by these processes leading to renal failure.
Laboratory experiments have shown that focused ultrasound beams can non-invasively destroy tissue, close blood vessels and increase the cell membrane permeability to molecules. It has also been shown that focused ultrasound can enhance transportation of molecules through the blood-brain barrier with the use of microbubbles. Based on these facts, we hypothesize that focus ultrasound exposures could increase the glomerular filtration rate of kidney.
Targeted Drug Delivery to the Brain by MRI-guided Focused Ultrasound
The clinical application of chemotherapy to brain tumors has been severely limited because antitumor agents are typically unable to penetrate an intact blood-brain barrier (BBB). Although doxorubicin has been named as a strong candidate for chemotherapy of the central nervous system, the BBB often prevents cytotoxic levels from being achieved in glioma tissue. Non-localized, diffuse opening of the BBB permits drugs to reach the brain but can have dose-limiting side effects due to the spread of neurologically active agents within the central nervous system. MRI-guided focused ultrasound (FUS) can be applied to the brain to disrupt the BBB in a transient and targeted manner. We are developing a drug delivery technique using MRI-guided focused ultrasound to enable the noninvasive treatment of primary and metastatic brain tumors.
By applying focused ultrasound in the presence of microbubble ultrasound contrast agent, we have achieved targeted drug delivery to the brain in vivo. Drug concentrations measured in sonicated brain tissue corresponded with cytotoxic levels measured in vivo in various human tumors. A strong correlation between MRI signal enhancement and drug absorption may indicate the capacity of MRI to be used as an indicator of BBB permeability during treatment. These results suggest the potential of MRI-guided focused ultrasound as an alternative to ionizing radiation therapy or invasive surgical resection, for use in the treatment of primary or metastatic brain tumors. Further investigation is required to evaluate the efficacy of this technique and to optimize its parameters for clinical application.
Immunoelectron microscopic investigation of tight junctional proteins after ultrasound-evoked opening of the blood-brain barrier:
a). To determine the involvement of tight-junction specific proteins (occludin, claudin-1 and 5, ZO-1 protein) in intercellular pathway opening by ultrasound.
b). To determine the reversibility of the ultrastructural changes and the time for restoration of the BBB to small (lanthanum nitrate, m.w. 433 Da) and large (horseradish peroxidase, m.w. 40,000 Da) tracer molecules, i.e. to estimate the duration of the therapeutic window for tight-junction-based drug delivery to the brain.
Transcranial sonications (ac.power 0.6 W, 1.5 MHz) on rats are used. Immunolabeling of the proteins and morphometrical evaluation of immunosignals are performed.