Ultrasound-mediated delivery of nanomedicine across biological barriers - for improved treatment of cancer and diseases in the brain
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- Institutt for fysikk 
Despite major progress in the field of cancer research during the last decades, cancer remains a leading cause of death worldwide. Treatment with conventional chemotherapy is limited by inadequate delivery to the tumor and severe side-effects due to accumulation in healthy tissues. Encapsulation of drugs in nanoparticles can enable a more targeted delivery, for improved efficacy and reduced toxicity. However, delivery of nanoparticles is often insufficient and heterogeneous, due to various biological barriers in the tumor microenvironment. Ultrasound in combination with microbubbles has emerged as a promising method to enhance delivery of nanomedicines to tumor tissue. It can also facilitate non-invasive and localized opening of the blood-brain barrier for drug delivery to the brain. A unique microbubble-platform was investigated, which demonstrated great potential for controlled drug delivery. It consisted of a shell of polymeric nanoparticles, encapsulating drugs and contrast agents. Various payloads demonstrated different degree of stability in the nanoparticles, and also affected nanoparticle-cell interactions. Depending on the payload, the nanoparticles could effectively deliver hydrophobic dyes and drugs to cells by either contact-mediated delivery directly to cytosol, or uptake by endocytosis followed by intracellular release. Cellular uptake and toxicity of the nanoparticles, as well as in vivo circulation and biodistribution were determined. Ultrasound treatment caused cavitation and collapse of the microbubbles, resulting in significantly improved accumulation and distribution of nanoparticles in solid tumors. Too low pressures, or short pulses did not enhance uptake, whereas too high pressures combined with long pulses resulted in tissue damage. In a proof-of-principle therapy study, the enhanced delivery resulted in complete and stable remission in all animals. Furthermore, it was shown that this platform could be used in combination with ultrasound to open the blood-brain barrier and successfully deliver and distribute nanoparticles in the brain. Another highly interesting microbubble-platform was also explored, based on clusters of microdroplets and microbubbles, which upon activation by ultrasound form large bubbles that deposit in the microvasculature. They were previously shown to enhance therapeutic efficacy of co-injected drugs to tumors in mice. Herein, we demonstrated that the same platform could be used to transiently and safely open the blood-brain barrier for delivery of macromolecules to the brain. These results provide an important fundament for future studies, and indicate that ultrasound-mediated delivery of nanomedicines across biological barriers can significantly improve treatment of cancer and diseases in the brain.