Multimodal Perfluorocarbon Nanoemulsions for ~(19)F MRI, Ultrasonography, and Catalysis of MRgFUS-Mediated Drug Delivery

摘要

Perfluorocarbon nanoemulsions can target lipophilic therapeutic agents to solid tumors and simultaneously provide for monitoring nanocarrier biodistribution via ultrasonography and/or ~(19)F MRI. In the first generation of block copolymer stabilized perfluorocarbon nanoemulsions, perfluoropentane (PFP) was used as the droplet forming compound. Although manifesting excellent therapeutic and ultrasound imaging properties, PFP nanoemulsions were unstable at storage, difficult to handle, and underwent droplet-to-bubble transition upon injection that was hard to control. To solve the above problems, perfluoro-15-crown-5-ether (PFCE) was used as a core forming compound in the second generation of block copolymer stabilized perfluorocarbon nanoemulsions. In the present paper, acoustic, imaging, and therapeutic properties of unloaded and paclitaxel (PTX) loaded PFCE nanoemulsions are reported. The size of paclitaxel-loaded PFCE nanodroplets (300 nm to 500 nm depending on emulsification conditions) favors their passive accumulation in tumor tissue. PFCE nanodroplets manifest both ultrasound and ~(19)F MR contrast properties, which allows the use of multimodal imaging to monitor nanodroplet biodistribution. Ultrasonography and ~(19)F MRI produced consistent results on nanodroplet biodistribution. Sonication with 1-MHz therapeutic ultrasound triggered reversible droplet-to-bubble transition in PFCE nanoemulsions. Microbubbles formed by acoustic vaporization underwent stable cavitation. In a pilot study on ultrasound-mediated therapy of a large breast cancer tumor, paclitaxel-loaded PFCE nanoemulsions combined with 1-MHz ultrasound (MI >= 1.75) showed excellent therapeutic properties. Anticipated mechanisms of the observed effects are discussed.