Therapeutic Applications of Microbubbles with Nanoparticle Encapsulation

Abstract

E-mail: [email protected] New developments in imaging physics have found promising biomedical applications. One example is the combination of ultrasound and photoacoustics that has demonstrated new opportunities in both imaging and therapeutic applications with functionalized microbubbles playing a pivotal role. The microbubbles typically used in ultrasonic imaging as the contrast agent present unique mechanical properties and the associated acoustic cavitation has been exploited for therapeutic purposes. Similarly, gold nanoparticles (AuNPs) are found to be a good contrast agent for photoacoustic imaging for its bioconjugation capabilities. The efficient light absorption of AuNPs and abilities to tune their optical properties have also led to new photothermal therapy methods. New development in combined diagnosis with therapy for both modalities have also been introduced. AuNPs encapsulated with microbubbles (AuMBs) have been introduced as a photoacoustic and ultrasound dual-modality contrast agent. Applications can be extended to theranosis purpose. In a previous study, an enhanced delivery method of AuNPs is proposed by using microbubbles as a targeted carrier and by inducing acoustic cavitation to enhance permeability. At least 10 times improvement in AuNP delivery and twenty degrees of temperature elevation were achieved. An optical microscope which collects the two photon fluorescence emitted by AuNPs further confirms the enhanced delivery. Finally, in vivo delivery of AuNPs was demonstrated with laser-induced thermotherapy that showed hyperthermia (>45°C) with sonoporation. Therefore, controlled release of AuNPs is feasible with acoustic cavitation and the procedure can further improve therapeutic effects of the AuNPs. Such functionalized microbubbles can also be used by exploiting the radiosensitization effect of gold nanoparticles (AuNPs) to enhance the cell-killing of ionization on tumor cells. In our research, we utilized AuMBs together with ultrasound as a radiosensitizer. Pre-radiotherapy cavitation carried out by acoustic stimulation increased the permeability of cell membrane and intracellular uptake of AuNPs. Simultaneous measurement of cavitation during ultrasound treatment also confirmed the production of cavitation. After combined treatment of AuMBs and ultrasound, Huh7 cells, a notoriously radioresistant cancer cells, was exposed to various dose of irradiation by a 6-MV linear accelerator. Cologenic assay showed a significant radiosensitization with AuMB+US, especially with high-dose irradiation (10 Gy). A dose modifying factor at 60% survival fraction (DMF60%) of 0.74 was obtained with AuMB and ultrasound treatment.