TEAM 3: POLYMER SELF-ASSEMBLY & LIFE SCIENCES
The LCPO Team 3 is headed by Sébastien Lecommandoux and involves Colin Bonduelle, Angela Mutschler, Bertrand Garbay, Jean-François Le Meins, Olivier Sandre, Christophe Schatz, Emmanuel Ibarboure, Amélie Vax-Weber, and Elisabeth Garanger.
Nature uses everyday controlled and directed self-assembly processes involving molecular and macromolecular building blocks for the organization of complex structures that possess specific functions. Our aim is to mimic such self-assembly rules, especially by using synthetic bio-inspired amphiphilic copolymers based on polypeptides, poly(amino acid)s, polysaccharides and their combinations.
We are interested in designing and synthesizing copolymers that can encode both self-assembly and bioactivity properties.
The understanding and characterization of multi-scale self-assembly of supramolecular structures that can interact with biological systems or mimic biological properties are of particular interest. We are especially captivated by the design of smart amphiphilic peptide-based polymers, by the control of their self-assembly properties and by their potential use as drug delivery and theranostic systems, bioreactors or artificial cell mimics.
Recent news: our paper in Angewandte Chemie International Edition, 53, 146 (2013) on compartmentalized polymersomes as synthetic cell mimics or plastic cells has been highlighted in Nature Chemistry 6, 5 (2014).
AMPHIPHILIC POLYPEPTIDE AND SACCHARIDE-BASED BLOCK COPOLYMERS
Regarding their outstanding self-assembly properties, amphiphilic block copolymers are near-ideal macromolecules to access complex and well-defined structures at the nano- and micro-scales. Inspired by natural self-assemblies (such as viruses, intracellular vesicles, nucleosomes, etc.) or aiming at specific biological applications, we design and synthesize amphiphilic block copolymers using peptides and saccharides as structural or functional segments.
–Polypeptides obtained by Ring-Opening Polymerization (ROP) of a-amino acid- N- carboxyanhydrides (NCA) are holding much of our attention regarding their biomimetism, biocompatibility, biodegradability and particular secondary structures.
– Macromolecular chimeras combining a structural and/or hydrophobic polymer segment (polypeptide, polyester, polycarbonate, etc.) and a natural biomacromolecule (oligo- or polysaccharide, peptide, protein) together conjugated by chemoselective ligation (“click-like chemistry”): featuring self-assembly and biological properties encoded at the molecular level, these chimeras shall ultimately lead to biofunctional self-assemblies.
– Recombinant polypeptides produced in E. coli bacteria: to reach the highest degrees of macromolecular precision simultaneously with large production scales, protein-engineering techniques are also used in our group to access protein-like polymers based on elastin motif.
Our group has a long-term experience in solution self-assembly processes of amphiphilic block copolymers. With a whole toolbox of formulation methods in hand, including solvent-displacement methods (“nanoprecipitation”), direct dissolution, emulsion-centrifugation, microfluidics or electroformation. We engage significant efforts to correlate macromolecular architectures, formulation routes and resulting morphologies.
We are also interested in studying the underlying mechanism of formation of nanostructures resulting from processes at thermodynamic equilibrium or from dynamic self-assembly. Advanced physico-chemical characterization methods are also extensively performed to best describe self-assembled structures at different scales, such as scattering techniques (light and neutron scattering – DLS, SLS, SANS) and microscopy (optical, fluorescence, TEM, AFM). Our portfolio of complex, well-defined, self-assembled structures includes:
– Polymersomes: containing a hydrophilic inner space separated from the outside environment by a double-layer membrane, these can be nanometer-sized or giant micrometer-sized vesicles.
– Compartmentalized vesicles such as Polymersomes-in-Polymersomes (PiPs) or Liposomes-in-Polymersomes (LiPs) as rough synthetic mimics of biological cells and their intracellular organelles.
– Hybrid polymer-lipid vesicles featuring a mixed membrane of biocompatible polymers (diblocks, grafts, terpolymers) and phospholipids, natural components of biological membranes.
– Dynamic core-shell micelles with variable surface densities of bioactive peptides.
– Virus-like particles made of an electrostatic core coated by a bilayer of amphiphilic block copolymer.
SELF-ASSEMBLY AND LIFE SCIENCES
Most of our research projects are turned towards life sciences, either with the goal of reproducing, mimicking and understanding natural and complex self-assembly mechanisms, or with the aim of addressing key issues of nanomedicine.
– Polymersomes as drug delivery systems: Polymer nano-assemblies present many advantages to solve the issues and achieve the promises of nanomedicine, such as typical drug loading content up to 10%, furtivity in the blood circulation, accumulation at the target organ or cells, and controlled drug delivery. Through collaborative projects with biologists, pharmacists, medical doctors and companies, we have developed a variety of polymersome systems to convey different therapeutic payloads such as chemotherapeutics (e.g. doxorubicin, paclitaxel) or biomolecules (siRNAs, peptides, proteins). The formulations are adapted to include simultaneously at least one bio-imaging modality (e.g. visible or near-infrared fluorescence, MRI contrast agents) and to graft specific surface ligands (e.g. small molecules, peptides, antibodies).
– Polymersomes for theranostics: Our team was pioneer in the development of magneto-chemotoxicity, which consists in the enhanced delivery of a chemotoxic drug by applying an external radiofrequency magnetic field (the permeability of the polymer coat/membrane being raised by heating of embedded magnetic nanoparticles in close vicinity). The use or iron oxide nanoparticles as magnetic hyperthermia inductors and as MRI contrast agents enables simultaneously the non-invasive monitoring of biodistribution and the therapeutic effect in vivo.
– Compartmentalized polymersomes as bioreactors: Simple enzymatic or photo-catalyzed reactions are currently studied in compartmented vesicles (PiPs, LiPs) as the first steps to reproduce the complex cell machinery (photosynthesis, protein synthesis…), with possible outcomes of this research in synthetic biology or autonomous implanted biosensors/bioactuators.
– Hybrid polymer-lipid vesicles: Because of the fine tuning of membrane properties in terms of permeability, viscosity, bending or stretching elasticity, as well as of the nano-structuring that can arise from polymer-lipid blends, i.e. phase-separation of the membrane into domains analogous to lipid rafts in cells, hybrid vesicles are currently under extensive study in our group.