Phase Change Ultrasound Contrast Agents with a Photopolymerized Diacetylene Shell.

Phase change contrast agents for ultrasound (US) imaging consist of nanodroplets (NDs) with a perfluorocarbon (PFC) liquid core stabilized with a lipid or a polymer shell. Liquid ↔ gas transition, occurring in the core, can be triggered by US to produce acoustically active microbubbles (MBs) in a process named acoustic droplet vaporization (ADV). MB shells containing polymerized diacetylene moiety were considered as a good trade off between the lipid MBs, showing optimal attenuation, and the polymeric ones, displaying enhanced stability. This work reports on novel perfluoropentane and perfluorobutane NDs stabilized with a monolayer of an amphiphilic fatty acid, i.e. 10,12-pentacosadiynoic acid (PCDA), cured with ultraviolet (UV) irradiation. The photopolymerization of the diacetylene groups, evidenced by the appearance of a blue color due to the conjugation of ene-yne sequences, exhibits a chromatic transition from the nonfluorescent blue color to a fluorescent red color when the NDs are heated or the pH of the suspension is basic. An estimate of the molecular weights reached by the polymerized PCDA in the shell, poly(PCDA), has been obtained using gel permeation chromatography and MALDI-TOF mass spectrometry. The poly(PCDA)/PFC NDs show good biocompatibility with fibroblast cells. ADV efficiency and acoustic properties before and after the transition were tested using a 1 MHz probe, revealing a resonance frequency between 1 and 2 MHz similar to other lipidic MBs. The surface of PCDA shelled NDs can be easily modified without influencing the stability and the acoustic performances of droplets. As a proof of concept we report on the conjugation of cyclic RGD and PEG chains of the particles to support targeting ability toward endothelial cells.

Point scintillator dosimetry in ultra-high dose rate electron "FLASH" radiation therapy: A first characterization.

FLASH radiation therapy is a novel technique combining ultra-high dose rates (UHDR) with very short treatment times to strongly decrease normal tissue toxicity while preserving the anti-tumoral effect. However, the radiobiological mechanisms and exact conditions for obtaining the FLASH-effect are still under investigation. There are strong indications that parameters defining the beam structure, such as dose per pulse, instantaneous dose rate and pulse repetition frequency (PRF) are of importance. UHDR irradiations therefore come with dosimetric challenges, including both dose assessment and temporal ones. In this work, a first characterization of 6 real-time point scintillating dosimeters with 5 phosphors (Al2O3:C,Mg; Y2O3:Eu; Al2O3:C; (C38H34P2)MnBr4 and (C38H34P2)MnCl4, was performed in an UHDR pulsed electron beam. The dose rate independence of the calibration was tested by calibrating the detector at conventional and UHDR. Dose rate dependence was observed, however, further investigation, including intermediate dose rates, is needed. Linearity of the response with dose was tested by varying the number of pulses and a linearity with R2> 0.9989 was observed up to at least 200 Gy. Dose per pulse linearity was investigated by variation of the pulse length and SSD. All point scintillators showed saturation effects up to some extent and the instantaneous dose rate dependence was confirmed. A PRF dependence was observed for the Al2O3:C,Mg and Al2O3:C- based point scintillators. This was expected as the luminescence decay time of these materials exceeds the inter-pulse time.

Ultrasound-assisted investigation of photon triggered vaporization of poly(vinylalcohol) phase-change nanodroplets: A preliminary concept study with dosimetry perspective.

PURPOSE: We investigate the vaporization of phase-change ultrasound contrast agents using photon radiation for dosimetry perspectives in radiotherapy. METHODS: We studied superheated perfluorobutane nanodroplets with a crosslinked poly(vinylalcohol) shell. The nanodroplets' physico-chemical properties, and their acoustic transition have been assessed firstly. Then, poly(vinylalcohol)-perfluorobutane nanodroplets were dispersed in poly(acrylamide) hydrogel phantoms and exposed to a photon beam. We addressed the effect of several parameters influencing the nanodroplets radiation sensitivity (energy/delivered dose/dose rate/temperature). The nanodroplets-vaporization post-photon exposure was evaluated using ultrasound imaging at a low mechanical index. RESULTS: Poly(vinylalcohol)-perfluorobutane nanodroplets show a good colloidal stability over four weeks and remain highly stable at temperatures up to 78 °C. Nanodroplets acoustically-triggered phase transition leads to microbubbles with diameters <10 µm and an activation threshold of mechanical index = 0.4, at 7.5 MHz. A small number of vaporization events occur post-photon exposure (6MV/15MV), at doses between 2 and 10 Gy, leading to ultrasound contrast increase up to 60% at RT. The nanodroplets become efficiently sensitive to photons when heated to a temperature of 65 °C (while remaining below the superheat limit temperature) during irradiation. CONCLUSIONS: Nanodroplets' core is linked to the degree of superheat in the metastable state and plays a critical role in determining nanodroplet' stability and sensitivity to ionizing radiation, requiring higher or lower linear energy transfer vaporization thresholds. While poly(vinylalcohol)-perfluorobutane nanodroplets could be slightly activated by photons at ambient conditions, a good balance between the degree of superheat and stability will aim at optimizing the design of nanodroplets to reach high sensitivity to photons at physiological conditions.