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Focused Ultrasound for Enhancement of Drug Delivery into Malignant Tissues Open Access

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Focused Ultrasound (FUS) has drawn much attention in recent years because of its capability of providing localized therapeutic effects non-invasively at targeted regions. Traditionally, FUS exposures have been utilized at high rates of energy deposition for thermal ablations of benign and malignant tumors. More recently, FUS exposures have also been evaluated in a pulsed mode, which reduces the rate of energy deposition (for thermal effects) and generates mechanical effects resulting in enhanced tissue permeability. These exposures can also be modified for low-level hyperthermia (39 - 44°C) as an adjuvant therapy for drug delivery applications. Due to the relatively small size of the FUS focal zone, however, this type of treatment may require clinically unrealistic procedure times. Therefore, obtaining optimal FUS exposures is of great interest to both researchers and clinicians to reduce the treatment duration. Until now, the optimal exposure parameter selection and experimental demonstration of these parameters have not been reported for FUS-induced hyperthermia applications. In this dissertation, procedures to obtain optimal FUS exposures were proposed based on theoretical simulations. Initial simulations were carried out for the commonly used FUS tissue-mimicking phantoms, while subsequent measurements with thermocouples allowed for validation (18.4% difference) of the theoretical model. Once this was accomplished, the exposure optimization protocol was demonstrated for a murine xenograft flank tumor model. The evaluated FUS parameters included total acoustic power (TAP), duty cycle (DC), pulse repetition frequency (PRF), and blood perfusion. Preliminary in vivo studies of FUS mediated anti-tumor drug delivery via heat sensitive liposomes were conducted, and qualitative results were presented. The optimal FUS exposure for this particular in vivo setup was determined to be TAP of 4 W, DC of 50% and PRF of 5 Hz. The proposed protocol was then applied to a human tumor model (retinoblastoma) to explore the feasibility of using FUS and heat sensitive liposomes to achieve targeted chemotherapy. It was concluded that FUS frequency between 2 - 3.5 MHz may be best suited for such ocular tumor treatments.In addition to hyperthermia, FUS-induced mechanical effects were evaluated for monoclonal antibody delivery via in vivo experiments. Tissue processing and image based quantitative analysis techniques were developed to examine antibody penetration from the blood vessel walls and tumor periphery. It was observed that antibody intensities were doubled with FUS treatments in the proximity of both tumor periphery and blood vessel walls. Finally, the effects of temperature dependent micro-vascular perfusion (capillary network) and the effects of macro-vascular perfusion (large blood vessels) on FUS-induced hyperthermia were discussed. Micro-vascular perfusion was found to have a greater impact at long treatment times (i.e. 5 min or longer). The effects of macro-vascular perfusion (when treatment time was 2 min or longer) were observed to be confined within 2 - 4 mm from blood vessel surfaces.In summary, both FUS-induced thermal and mechanical effects can be utilized for targeted delivery into malignant tissues. Careful selection of FUS parameters would allow researchers and clinicians to conduct treatments in a more effective manner.

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