Ksenia Astafyeva

A model for ultrasound absorption and dispersion in dilute suspensions of nanometric contrast agents

Ultrasound dispersion and absorption are examined in dilute suspensions of contrast agents of nanometric size, with a typical radius around 100 nm. These kinds of contrast agents are designed for targeted delivery of drugs for cancer treatment. Compared to standard contrast agents used for imaging, particles are of smaller size to pass through the endothelial barrier, their shell, made up of biocompatible polymer, is stiffer to undergo a longer lifetime, and they have a liquid core instead of a gaseous one. Ultrasound propagation in dilute suspension is modeled by combining two modes for particle oscillations. The first one is a dilatational mode assuming an incompressible shell with a rheological behavior of Kelvin-Voigt or Maxwell type. The second one is a translational mode induced by visco-inertial interaction with the ambient fluid. The relative importance of these two modes of interaction on both dispersion and absorption is quantified and analyzed for a model system and for two radii (75 and 150 nm) and the two rheological models. The influence of shell parameters (Young modulus, viscosity, and relative thickness) is finally discussed.

Influence of shell compressibility on the ultrasonic properties of polydispersed suspensions of nanometric encapsulated droplets

Liquid droplets of nanometric size encapsulated by a polymer shell are envisioned for targeted drug delivery in therapeutic applications. Unlike standard micrometric gas-filled contrast agents used for medical imaging, these particles present a thick shell and a weakly compressible core. Hence, their dynamical behavior may be out of the range of validity of the models available for the description of encapsulated bubbles. In the present paper, a model for the ultrasound dispersion and absorption in a suspension of nanodroplets is proposed, accounting for both dilatational and translational motions of the particle. The radial motion is modeled by a generalized Rayleigh-Plesset-like equation which takes into account the compressibility of the viscoelastic shell, as well as the one of the core. The effect of the polydispersity of particles in size and shell thickness is introduced in the coupled balance equations which govern the motion of the particles in the surrounding fluid. Both effects of shell compressibility and polydispersity are quantified through the dispersion and absorption curves obtained on a wide ultrasonic frequency range. Finally, some results for larger gas-filled particles are also provided, revealing the limit of the role of the shell compressibility.

PEGylated nanocapsules of perfluorooctyl bromide: Mechanism of formation, influence of polymer concentration on morphology and mechanical properties

PEGylated nanocapsules containing a liquid core of perfluorooctyl bromide (PFOB) were formulated by an emulsion-evaporation process to be further used as ultrasound contrast agents (UCAs). In an attempt to modulate their acoustic response, related to their shell thickness-to-radius ratio, the initial concentration of polymer was varied in the formulation. Indeed, thinner shells may lead to higher echogenicity. PEGylated nanocapsules morphology was studied by electron microscopy, Small Angle Neutron Scattering and (19)F NMR spectroscopy and related to their mechanical properties to allow a better understanding of their mechanism of formation. We show that the variation of polymer concentration in the formulation impacts the formation mechanism of nanocapsules, and consequently their morphology and mechanical properties. Using low concentration of Poly(ethylene glycol)-b-poly(dl-lactide-co-glycolide) (PLGA-b-PEG), it is impossible to reduce the shell thickness of the UCA, most probably due to dewetting of the polymer layer at the PFOB/water interface. This leads to the coexistence of thick shells along with free PFOB droplets. On the other hand, for high polymer concentration, PEGylated nanocapsules with thick shells were produced with high encapsulation efficiency.

Stability of C(12)E(j) Bilayers Probed with Adhesive Droplets.

The stability of model surfactant bilayers from the poly(ethylene glycol) mono-n-dodecyl ether (C12Ej) family was probed. The surfactant bilayers were formed by the adhesion of emulsion droplets. We generated C12Ej bilayers by forming water-in-oil (w/o) emulsions with saline water droplets, covered by the surfactant, in a silicone and octane oil mixture. Using microfluidics, we studied the stability of those bilayers. C12E1 allowed only short-lived bilayers whereas C12E2 bilayers were stable over a wide range of oil mixtures. At high C12E2 concentration, a two-phase region was displayed in the phase diagram: bilayers formed by the adhesion of two water droplets and Janus-like particles consisting of adhering aqueous and amphiphilic droplets. C12E8 and C12E25 did not mediate bilayer formation and caused phase inversion leading to o/w emulsion. With intermediate C12E4 and C12E5 surfactants, both w/o and o/w emulsions were unstable. We provided the titration of the C12E2 bilayer with C12E4 and C12E5 to study and predict their stability behavior.

Design and characterization of biocompatible perfluorocarbon nanodroplets for theragnostic application

We have developed stable emulsions (≥ 3 months) made of nanodroplets (nD) of perfluorocarbon (PFC) dispersed in water to serve as theragnostic agent. nD are stabilized by in house fluorinated surfactants, named FTAC, which chemical structure can be modified to tune their properties. We have characterized nD size distributions (mean diameters from 200 to 600 nm), density, adiabatic compressibility, interfacial tension. US properties of the emulsions have been investigated such as attenuation. Lastly, ultrasonic signals backscattered by nanoemulsions were studied and compared with water to extract signal to noise ratio (SNR), by emitting single negative pulses at ≈40 MHz. At similar mean/mode diameters, we showed a strong dependence in SNR values (i) with size distribution, altered by the nature of the surfactant or by a centrifugation/filtration process, (ii) with core nature, and (iii) with nD volume fraction. Besides, hydrophobic drugs such as a thalidomide derivative (with anti-angiogenic properties), have been encapsulated by addition of 10% of triacetin in the nD core. So as to study drug release from nD, a dedicated setup of US cavitation was designed. Cavitation was generated in controlled conditions using a 1 MHz focused transducer (US bursts: 12-22 MPa peak) in a thin wall container immersed in water which temperature and degassed level were kept constant. The generation of cavitation in nD solutions resulted in a strong and reproducible SNR decrease.

Characterization of nanometric ultrasound contrast agents with a liquid perfluorocarbon core

In this work, we propose a new type of nanometric ultrasound contrast agents (nUCA) with a liquid core and we model their acoustic propagation through their dilute solutions. These capsules have a shell made of a biocompatible polymer or fluorinated surfactants and a liquid perfluorocarbon core to undergo a high lifetime. The capsules are small enough (from 100 nm to 1 μm) to pass through the tumor endothelium, and they remain stable in vitro for several months. Ultrasound attenuation and speed of sound measurements through dilute suspensions of nUCA were carried out from 3 to 90 MHz at various temperatures and concentrations. The acoustic propagation was modeled by combining (i) a dilatational mode taking into account the radial oscillations of the capsules, and (ii) a translational mode of oscillations induced by viscoinertial interaction with the continuous phase. The model makes possible to fit with good accuracy the experiments using values compatible with literature data. Moreover, it reveals inform...

Ultrasonic propagation in suspensions of encapsulated compressible nanoparticles

Dispersion and absorption are examined for dilute suspensions of encapsulated droplets of nanometric size, with typical radii around 100 nm. This new generation of contrast agents is designed for targeted delivery of drugs. Compared to standard contrast agents used for imaging, particles are of smaller size to pass the endothelial barrier, their shell made up of biocompatible material is stiffer to undergo a longer time life and they have a liquid (PFC) instead of a gaseous core. Ultrasound propagation of these suspensions is modeled by combining (i) a dilatational mode of oscillation assuming a compressible shell with a visco-elastic behavior of Kelvin-Voigt or Maxwell type (relaxation), (ii) a translational mode of oscillation induced by visco-inertial interaction with the ambient fluid, and (iii) polydispersion in terms of radius and shell thickness. Influence of the various effects will be examined. Experimental measurements of the dispersion and absorption properties of nanodroplets solutions over th...