We aim to produce emulsions that can act as contrast agents and drug carriers for cancer imaging and therapy. To increase tumor detection and decrease drug side effects, it is desirable to take advantage of the enhanced permeability and retention effect that allows nanoparticles to accumulate in tumor tissues.To do so, the emulsion droplets need to be small enough and stable over time in addition to enhancing image contrast and carrying a drug payload. In the present study, we have investigated the properties and potentiality as theranostic agents of perfluorocarbon emulsions stabilized by a biocompatible fluorinated surfactant called FTAC. To obtain better control of our system, the synthesis of those surfactants was studied and their physico-chemical properties were explored in different configurations such as micelles, in the perfluorocarbon droplet shell and at water/air and water/perfluorocarbon interfaces. The originality of this work lies in the determination of numerous characteristics of emulsions and fluorinated surfactants including surface tension, interfacial tension, critical micelle concentration, adiabatic compressibility, density, size distribution (aging studies), and ultrasonic echogenicity. These characterization studies were conducted using different types of FTAC and several perfluorocarbons (perfluoropentane, perfluorohexane, and perfluorooctyl bromide). We have also shown that a hydrophobic drug could be encapsulated in the FTAC-stabilized perfluorocarbon droplets thanks to triacetin addition. Finally, the perfluorocarbon emulsions were detectable in vitro by a clinical 3 T MRI scanner, equipped with a double frequency 19 F/ 1 H transmit-receive coil.

The purpose of this study was to define and validate an inertial cavitation dose (CD) based on the detection of broadband noise, designed to monitor ultrasound-mediated drug release from liposomes. The validation consists of using the terephthalate dosimeter to quantify by fluorescence measurements the extent of hydroxyl radical (()OH) production during inertial cavitation. Sonication of samples was performed using tone bursts (pulse repetition frequency (PRF): 10 Hz(-1) kHz, duty cycle (dc): 5-25%, Isppa: 4100-12,200 W/cm(2)) generated by a 1 MHz focused transducer. Three sets of ultrasound parameters with different PRF and dc were selected to be more precisely compared. Results demonstrated an excellent correlation between *OH radical production and CD for each set of parameters, but significant differences in hydroxyl radical levels were observed among the sets of parameters. The results were compared with other studies, and the same tendency of variation with pulse duration was demonstrated. Results also showed that the CD was not distorted by peak intensity variations and was a much more reliable indicator than sonication time. Consequently, one validated parameter was selected to monitor drug release from two liposome formulations, and compare their ultrasound sensitivity.

Polymeric nanoparticles are being intensively investigated as drug carriers. Their efficiency could be enhanced if the drug release can be triggered using an external stimulus such as ultrasound. This approach is possible using current commercial apparatus that combine focused ultrasound with MRI to perform ultrasonic surgery. In this approach, nanoparticles made of a perfluoro-octyl bromide core and a thick polymeric (PLGA-PEG) shell may represent suitable drug carriers. Indeed, their perfluorocarbon core are detectable by 19 F MRI, while their polymeric shell can encapsulate drugs. However, their applicability in ultrasound-triggered drug delivery remains to be proven. To do so, we used Nile red as a model drug and we measured its release from the polymeric shell by spectrofluorometry. In the absence of ultrasound, only a small amount of Nile red release was measured (<5%). Insonations were performed in a controlled environment using a 1.1 MHz transducer emitting tone bursts for a few minutes, whereas a focused broadband hydrophone was used to detect the occurrence of cavitation. In the absence of detectable inertial cavitation, less than 5% of Nile red was released. In the presence of detectable inertial cavitation, Nile red release was ranging from 10 to 100%, depending of the duty cycle, acoustic pressure, and tank temperature (25 or 37℃). Highest releases were obtained only for duty cycles of 25% at 37℃ and 50% at 25℃ and for a peak-to-peak acoustic pressure above 12.7 MPa. Electron microscopy and light scattering measurements showed a slight modification in the nanoparticle morphology only at high release contents. The occurrence of strong inertial cavitation is thus a prerequisite to induce drug release for these nanoparticles. Since strong inertial cavitation can lead to many unwanted biological effects, these nanoparticles may not be suitable for a therapeutic application using ultrasound-triggered drug delivery.