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Open Access Publications from the University of California

Ultrasound-responsive particles for cancer diagnostics and therapeutics

  • Author(s): Benchimol, Michael Jerome
  • et al.

Ultrasound is a toolbox for interacting with the human body and especially cancer where there is a need for precision and deep tissue access. Practiced medicinal applications of ultrasound are limited to depositing mechanical energy or probing mechanical properties of tissue. However, when particles capable of harnessing ultrasound energy are interfaced with complex systems, the capabilities of ultrasound become multidimensional and virtually limitless. One such potential investigated in this work is the ability to direct the exposure of encapsulated therapeutic agents to specific tissues. The incorporation of an ultrasound-sensitizing particle into a liposome yields a carrier which can circulate throughout the body and rupture to release its contents when and where ultrasound is applied. Tissues adjacent to the ultrasound focus do not experience a high enough pressure to cause drug release, since the acoustic energy is concentrated in all 3 dimensions. In vitro experiments have visually and quantitatively demonstrated the rapid fragmentation of liposome membranes as well as the localized release of entrapped molecules. Localized deposition of fluorescent molecules in mice has been demonstrated by intravenous administration of liposomes and application of focused ultrasound to the site of interest. Foreign enzyme has been hidden and incorporated in liposome membranes so that focused ultrasound can expose the enzyme to its substrate. This ability could be used for enzyme prodrug therapy, where immune evasion and delivery specificity are key challenges needing to be addressed. Another approach described here aims to break physical barriers to effective delivery. Engineered microstructures can direct concentrated acoustic energy, producing a powerful impulse which allows them to penetrate tissues for efficient delivery. The resulting "microbullet" is 100 times faster than current micromotors and does not rely on the presence of external fuel. The final portion of this dissertation presents a new fluorescent microbubble contrast agent capable of being tagged by ultrasound for precise localization. Radial oscillations of the microbubble modulate the fluorophore separation and fluorescence emission through a physical mechanism only theorized in the past. By directly attacking the biggest challenges in the field, these new directions for cancer therapeutics and diagnostics promise to evolve into game-changing technologies

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