UC San Diego

The small size of early stage tumors makes them difficult to detect and treat given current techniques that are applied at a systemic level. Addressing these challenges requires a shift from whole-body approaches to localized strategies. Localized light generation within a small tissue volume can yield spatially-resolved chemical information about the tissue microenvironment. This could help differentiate small cancerous lesions from benign masses enabling the detection of smaller, earlier-stage tumors. The detection of this locally-generated light is made difficult by the highly-scattering nature of biological tissue. A process was developed here to create fluorescent microbubbles that generate light in the small focal zone of an ultrasound beam by consistently modulating their fluorescence intensity. By amplifying these characteristic intensity modulations with a lock-in amplifier, the fluorescence from these locally-activated microbubbles was detected in a light-scattering environment. It was shown that these microbubbles also displayed harmonic oscillations beyond the ultrasound driving frequency which could be used to further improve the signal to noise ratio for detection. Once a tumor is detected, localizing treatment to just the tumor volume can reduce systemic side effects. Localized drug deposition can be achieved by using ultrasound to damage the tumor microcapillaries. Fluid jets that are formed through the inertial cavitation of microbubbles in the ultrasound focal zone can increase the level of damage, especially if they are directed horizontally along the capillary surface. Data presented here shows that shorter distances between microbubble pairs at the time of ultrasound exposure significantly increased the chances of this horizontally-oriented jet formation. Another localized treatment technique uses locally-delivered light to activate a photocleavable prodrug. Manufacturing techniques developed here created nanoparticles that consisted entirely of photocleavable prodrug monomers. The particles were 30 times less toxic than the pure active drug. Pure active chemotherapy drug was released from the particles only when exposed to the light and was shown to kill tumor cells. The nanoparticle form of the chemotherapy prodrug monomers will increase their circulation time and allow tumor accumulation by extravasation