Investigations of the effect of pulsed focused ultrasound (pFUS) induced changes in tumor interstitial fluid pressure and enhanced delivery of therapeutic agents

Abstract

In this study, we hypothesized that using a pulsed focused ultrasound (pFUS) pretreatment lowers the IFP and enhances the delivery of therapeutics. We designed and conducted a set of ex vivo and in vivo experiments to test and evaluate the validity of our hypothesis. This dissertations is a summary of investigations on the enhanced delivery of agents using pFUS. In the first chapter, we provided background information about the research projects of this dissertations. Chapter two described a custom and automated image processing procedure based on the Otsu thresholding method. We developed this procedure to quantify the distribution of administered NPs after an MRgFUS treatment. It was shown that the distribution of 70 nm, 200 nm, and 700 nm NPs was enhanced with an MRgFUS pretreatment for 21%, 47%, and 39%, respectively. Chapter three covers the development and validation of the LgFUS system. We designed and fabricated a portable and low-cost laser guiding apparatus, which helps to target the desired locations accurately. As a proof of concept of its suitability, we evaluated the LgFUS for opening of the Brain-Blood Barrier (BBB) in rats. Enhancement of gadolinium and blue dye is evident in MRI images as well as digital images of sliced brain tissue. In chapter four, we evaluated the custom LgFUS system to enhance the delivery of TPNs in treating head and neck solid tumors. The average epifluorescence signals were found to be 49% greater in the pFUS treated tumors than that in the control group. Possible mechanisms of the enhancement may be explained by the measured IFPs in the experimental group, which is 28% smaller than that in the control group. Chapter five describes an ongoing therapeutic study using cisplatin loaded TPNs. We evaluated the biodistribution and toxicity of cisplatin loaded TPNs and free drug to find out the maximum tolerated dose in mice In conclusion, we demonstrated that pFUS pretreatment of solid tumors could noninvasively and nondestructively lower IFP and improved penetration and overall delivery of NPs in a solid tumor xenograft model. Further investigations will be required to understand better how pFUS can specifically be employed to mitigate the effects of high levels of IFP and fibrillar collagen individually, and in combination, to maximize its potential for improving cancer treatment.