(414c) Multimodal Phase-Shift Nanoemulsions for MRI, Ultrasonography, and Catalysis of Image-Guided Drug Delivery

The paper discusses imaging, acoustic, and therapeutic properties of block copolymer stabilized perfluorocarbon nanoemulsions used as anticancer drug carriers. Three physical factors that trigger droplet-to-bubble transition in liquid emulsions and gels have been identified, namely heat, ultrasound, and injections through fine-gauge needles. Among those listed, ultrasound irradiation was found to be the most efficient factor. Droplet-to-bubble transition and cavitation of formed microbubbles has been identified as a key step in drug release from nanodroplets. In gel matrices, ultrasound-induced droplet-to-bubble transition was catalyzed by pre-existing bubbles. Dependence of droplet vaporization temperatures on droplet size, surface properties, and pressure will be discussed in relation to therapeutic properties. Novel drug-loaded perfluorocarbon nanoemulsions with a unique combination of properties have been developed. Nanodroplets accumulated in tumor volume by passive targeting via extravasation through defective tumor microvasculature. Tumor accumulation of nanodroplets after systemic injections was confirmed by ultrasound and 19F MR imaging. Nanodroplets were susceptible to acoustic droplet vaporization (ADV) and cavitation as manifested by ultrasonography and generation of harmonics in FFT spectra of scattered ultrasound. Introduction of nanodroplets dramatically accelerated and enhanced focused ultrasound (FUS)-induced heating in gel phantoms and in vivo. In a case study, a large breast cancer tumor was completely resolved under the combined action of systemically injected paclitaxel loaded nanodroplets and 1-MHz FUS at 1.74 MPa rarefactional pressure. No tumor recurrence was observed. With the same therapeutic approach, pancreatic tumors were either resolved or substantially regressed. No therapeutic effect from the nanodroplet/ultrasound combination was observed without the drug, indicating that therapeutic effect was caused by the ultrasound-enhanced chemotherapeutic action of the tumor-targeted drug, rather than the mechanical or thermal action of ultrasound itself. The mechanism of drug release in the process of ultrasonically-activated droplet-to-bubble conversion will be discussed. Summarizing, the developed multimodal nanoemulsion drug formulations can be used for the MRI-guided, ultrasound-mediated, targeted tumor chemotherapy.