Dr. Nicolas TAULIER
Theranostic nanosystems
Introduction
Medecine is moving towards a personalized therapy, that requires the development of adapted tools able to reduce the undesirable side effects of drugs while increasing their effectiveness.
In this context, I am studying new intravenously injectable theranostic agents. Their role is to allow an visualization of cancer tumors combined with a localized and controlled administration of drugs.
After injection, these theranostic agents are filtered by different organs: mainly the liver and the spleen for agents with a diameter larger than 200 nm, and by kidneys for agents smaller than 50 nm. If these organs are not those targeted by the theranostic agents, then they should possess a diameter D within the range 50 < D < 200 nm in order to freely circulate into the bloodstream and reach the targeted organ. Targeting will be carried out thanks to molecules disposed on the agent surface that will specifically bind a specific receptors of the targeted tissue.
Echography and magnetic resonance imaging (MRI) imaging methods are ideally suited to the use of contrast agents. Ultrasound has a real-time imaging capability, it is a cheap technology and is available in most hospitals. While MRI provides the best spatial resolution, but is expensive and of low availability. Commercial contrast agents available for both techniques are not suitable for theranostic applications. Indeed, commercial ultrasound contrast agents are micrometric bubbles (1 - 12 microns in diameter) that dissolve quickly in the vascular network, which represents a significant barrier to their use as quantitative markers or drug carriers. To the contrary, commercial MRI contrast agents are very small molecules, usually made of gadolinium, that leak easily through the wall of healthy vessels and get rapidly dispersed in all tissues.
It is possible to overcome the limitations of both imaging modalities using perfluorocarbon (PFC) nanodroplets as contrast agents. Indeed, these droplets can be detected by fluorine MRI (19F MRI). If however these nanodroplets represent inefficient ultrasound contrast agents it is possible to significantly improve their echogenicity by vaporising the droplet so that they become microbubbles. However, the use of perfluorocarbon nanodroplets as theranostic agent faces two major challenges: the production of stable droplets and encapsulation of drugs. These two difficulties are related to the fact that perfluorocarbons have little or no affinity for molecules that do not contain fluorine atoms.
My current research goals are to obtain nanoparticles that can be used efficiency as constrat agents (either for ultrasound, MRI or other imaging techniques) but also as drug carriers. In the latter case, I focus my work on a controlled and localized release of drugs that will be triggered by focused ultrasound wave. Whatever the targeted organ, a non-negligible amount of nanoparticles will not accumulate on the site to be treated. To fully reduce drug side effects, I also propose to use drugs which are themselves activated by ultrasound. In the absence of ultrasound, these drugs are therefore harmless.
Nanoparticles under study
We are studying nanoparticles composed of a perfluorocarbon liquid core encapsulated inside a shell. As shell materials, we used either:
- Polymers (in collaboration with Institut Galien),
- Fluorinated surfactants (in collaboration with Institut des Biomolécules Max Mousseron).
We are characterizing numerous properties of these nanoparticles when in suspension. Among these properties are
- Size distribution and mean size, using Coulter (qNano device) or DLS (ALV device) technique
- Density, using a densimeter (from Anton Paar)
- Compressibility, using ultrasound velocity measurements
- Rigidity, using AFM technique (Coll. with P. Guenoun)
We are also investigated the properties of fluorinated surfacants such as
- Critical micelle concentration
- Surface tension (air/water interface)
- Interfacial tension (perfluorocarbon/water interface)
These measurements help us to validate analytical and numerical models we are developing as well as to understand the relationship between the nanoparticles properties and their behavior.
Theranostic properties
We are evaluating the capacity of these nanoparticles to be good contrast agents as well as the use of ultrasound to deliver drug encapsulated inside these nanoparticles.
Modeling the interaction ultrasound-nanoparticles
We are developing simulations and analytical models in order to predict the behavior of these nanoparticles under an acoustic fields. In particular we wish to predict the following properties
- Backscattered signal,
- Vaporization of the perfluorocarbon core,
- Drug-release triggered by ultrasound
based on the physical and chemical knwoledge of the nanoparticle properties.
Related funding
- Projet AIDA (2014--2017) Appel d'offre Plan Cancer 2014-2019 (Porteur : F. COULOUVRAT), partenaires :
- Institut Jean le Rond d’Alembert, Paris (resp. F. COULOUVRAT)
- Institut des Nanoscience de Paris (INSP), Paris (resp. J.-L. THOMAS)
- Laboratoire d’Imagerie Biomédicale, Paris (resp. N. TAULIER)
- Project SonoTherag (2014-2017), Appel d’offre EuroNanoMed II (Porteur : C. CONTINO-PEPIN)
- Institut des Biomolécules Max Mousseron (IBMM), Avignon, France (resp. C. CONTINO-PEPIN)
- Laboratoire d’Imagerie Paramétrique, Paris, France (resp. N. TAULIER)
- Oslo University Hopistal, Oslo, Norway (resp. Q. PENG)
- Université de Genève, Genève, Suisse (resp. Rares SALOMIR)
- Intelligence In Medical Technologies (IMT), Paris, France (resp. P.-J. TOUBOUL)
- Project NABUCCO (2013-2014), Plan Cancer 2009-2013 (Porteur : F. COULOUVRAT), partenaires :
- Institut Jean le Rond d’Alembert, Paris (resp. F. COULOUVRAT)
- Institut des Nanoscience de Paris (INSP), Paris (resp. J.-L. THOMAS)
- Laboratoire d’Imagerie Paramétrique, Paris (resp. N. TAULIER)
- Laboratoire Interdisciplinaire sur l’Organisation Nanométrique et Supramoléculaire, CEA Saclay (resp. P. GUENOUN)
- Project nUCA (2012-2015), Appel d’offre NanoBiotechnologies [Investissements d’Avenir] (Porteur : N. TAULIER)
- Laboratoire d’Imagerie Paramétrique, Paris (resp. N. TAULIER)
- Institut des Biomolécules Max Mousseron (IBMM), Avignon (resp. C. CONTINO-PEPIN)
- Institut Galien, Châtenay-Malabry (resp. N. TSAPIS)
- Laboratoire de physique statistique de l’École Normale Supérieure, Paris (resp. W. URBACH)
- Project NACUNAT (2010-2013), Appel d’offre émergence UPMC 2010 (Porteur : N. TAULIER)
- Laboratoire d’Imagerie Paramétrique, Paris (resp. N. TAULIER)
- Institut Jean le Rond d’Alembert, Paris (resp. F. COULOUVRAT)
- Institut des Nanoscience de Paris (INSP), Paris (resp. J.-L. THOMAS)
Related publications
- Properties of theranostic nanoparticles determined in suspension by ultrasonic spectroscopy. K. Astafyeva,J.-L. Thomas, F. Coulouvrat, M. Guédra, O. Diou, L. Mousnier, N. Tsapis, W. Urbach, and N. Taulier. Phys. Chem. Chem. Phys. 17 (2015) 25483-25493 (doi:10.1039/C5CP04424C)
- Perfluorocarbon nanodroplets stabilized by fluorinated surfactants : characterization and potentiality as theranostic agent. K. Astafyeva, L. Somaglino, S. Desgranges, R. Berti, C. Patinote, D. Langevin, F. Lazeyras, R. Salomir, A. Polidorid, C. Contino-Pépin, W. Urbach, and N. Taulier. J. Mat. Chem. B 3 (2015) 2892-2907 (doi:10.1039/C4TB01578A)
- A model for ultrasound absorption and dispersion in dilute suspensions of nanometric contrast agents. F. Coulouvrat, J.-L. Thomas, K. Astafyeva, N. Taulier, J.-M. Conoir, W. Urbach. J. Acoust. Soc. Am. 132 (2012) 3748-3759. (doi:10.1121/1.4765639)
- Two-dimensional simulation of linear wave propagation in a suspension of polymeric microcapsules used as ultrasound contrast agents. G. Haïat, R. Berti, B. Galaz, N. Taulier, J.-J. Amman, and W. Urbach. J. Acoust. Soc. Am. 129 (2011) 1642-1652. (doi:10.1121/1.3543966)
- Experimental validation of a time domain simulation of high frequency ultrasonic propagation in a suspension of rigid particles. B. Galaz, G. Haïat, R. Berti, N. Taulier, J.-J. Amman, and W. Urbach. J. Acoust. Soc. Am. 127 (2010) 148-154 (doi:10.1121/1.3270399)
- Phospholipid decoration of microcapsules containing perfluorooctyl bromide used as ultrasound contrast agents. R. Diaz-Lopez, N. Tsapis, D. Libong, P. Chaminade, C. Connan, M.M. Chehimi, R. Berti, N. Taulier, W. Urbach, V. Nicolas, E. Fattal. Biomaterials 30 (2009) 1462-1472. (doi:10.1016/j.biomaterials.2008.11.032)
- Perfluorooctyl Bromide Polymeric Capsules as Dual Contrast Agents for Ultrasonography and Magnetic Resonance Imaging. E. Pisani, N. Tsapis, B. Galaz, M. Santin, R. Berti, N. Taulier, E. Kurtisovski, O. Lucidarme, M. Ourevitch, B.T. Doan, J.-C. Beloeil, B. Gillet, W. Urbach, S.L. Bridal, E. Fattal, Adv. Funct. Mat. 18 (2008) 2963-2971. (doi:10.1002/adfm.200800454)