Valérie Héroguez

pH-controlled delivery of gentamicin sulfate from orthopedic devices preventing nosocomial infections

Since the beginning of the 1970s, controlled release technology has witnessed great advancement, and motivated numerous researchers in materials science. These systems overcome the drawbacks of traditional drug dosage form, and offer more effective and favorable methods to optimize drug delivery in optimum dose to specific sites or to prolong delivery duration. This paper deals with the synthesis of pH-controlled drug delivery systems for bone implant, allowing the local release of gentamicin sulfate (GS), an antibiotic commonly used to prevent infections during orthopedic surgeries. We present a biomaterial synthesis allowing the controlled release of GS at the site of surgical implantation (over an adjustable period of time). In our design, spherical nanoparticles (NPs) functionalized by the chosen antibiotic (Gentamicin sulfate, GS), are chemically anchored to the biomaterial surface. A cleavage reaction of the chemical bond between NPs and GS, effected by the contact of material with a solution presenting an acidic pH (in the case of infection, there is a decrease of the physiological medium pH), induces controlled release of the bioactive molecule in its native form. In this paper, we discuss the synthesis of a bioactive titanium based biomaterial in general, and the grafting of the NPs onto the titanium surfaces in particular. We have paid particular attention to the characterization of the drug surface density and the release kinetic of the active molecule as a function of the pH. In vitro bacterial growth inhibition tests after GS delivery at acidic pH (with Staphylococcus aureus) have also been carried out in order to prove the efficiency of such biomaterials.

Impact of RGD nanopatterns grafted onto titanium on osteoblastic cell adhesion.

This work reports on the synthesis of titanium bone implants functionalized with nanoparticles (NPs) containing Arg-Gly-Asp-Cys peptide (RGDC) and shows the adhesion behavior of cells seeded on these materials. RGDC peptides were first conjugated to a norbornenyl-poly(ethylene oxide) macromonomer (Nb-PEO). Then, functional NPs with a size of ∼300 nm and constituted of polynorbornene core surrounded by poly(ethylene oxide) shell were prepared by ring-opening metathesis polymerization in dispersed medium. The grafting density of these NPs on the titanium surface is up to 2 NPs·μm(-2) (80 pmol of RGDC per cm(-2) of NP surface). Cell adhesion was evaluated using preosteoblast cells (MC3T3-E1). Results of cells cultured for 24 h showed that materials grafted with NPs functionalized with RGDC peptides enhance specific cell adhesion and can create filopodia-like structures among NP sites by stressing the cells.

Nanoparticles Produced by Ring-Opening Metathesis Polymerization Using Norbornenyl-poly(ethylene oxide) as a Ligand-Free Generic Platform for Highly Selective In Vivo Tumor Targeting

We described a norbornenyl-poly(ethylene oxide) nanoparticles ligand-free generic platform, made fluorescent with straightforward preparation by ring-opening metathesis polymerization (ROMP). Our method allowed to easily obtain a drug delivery system (DDS) with facilitated functionalization by means of azide-alkyne click chemistry and with a high selectivity for the tumor in vivo, while cellular internalization is obtained without cell targeting strategy. We demonstrated that our nanoparticles are internalized by endocytosis and colocalized with acidic intracellular compartments in two models of aggressive tumoral cell lines with low prognostic and limited therapeutic treatments. Our nanoparticles could be of real interest to limit the toxicity and to increase the clinical benefit of drugs suffering rapid clearance and side effects and an alternative for cancers with poorly efficient therapeutic solutions by associating the drug delivery in the tumor tissue with an acid-sensitive release system.

Ring opening polymerisation of highly concentrated inverse emulsions to obtain microcellular foams

High internal phase emulsions (HIPEs) have been prepared and polymerised by ring-opening metathesis polymerisation using different monomers and initiators. The influence of the monomer structure and the experimental conditions on the stability of the HIPE and the morphology of the resulting materials has been studied.

Vancomycin Functionalized Nanoparticles for Bactericidal Biomaterial Surfaces

In this paper, we describe a simple and powerful way to synthesize antibacterial biomaterials with applications as implants in orthopedic surgery. Such implants are obtained by covalently grafting onto the Ti90A16 V4 alloy surface with vancomycin-functionalized nanoparticles. Nanoparticles were produced by ring-opening metathesis polymerization of α-norbornenyl-ω-vancomycin poly(ethylene oxide) macromonomers. Vancomycin is an interesting candidate because of its use in the field of implant associated infection as it is a glycopeptide which acts on bacterial walls. As a consequence, vancomycin does not need to be released for it to be active. In the first part of this paper, the synthesis and the complete characterization of these materials are described. In a second part, the in vitro antibacterial behavior is analyzed and discussed.

Outstanding Stability of Poorly-protected Pickering Emulsions

Pickering emulsions are surfactant-free emulsions, stabilized solely by colloidal particles. Most of these emulsions exhibit exceptionally high stability and bulk elasticity. In order to investigate the effect of interfacial particle interactions and structure on the emulsions properties, we synthesized particles (silica, core-shell latexes, neighborite cubes) whose interactions can be tuned by a composition variable (pH, ionic strength…) leading to stimulus-responsive materials. The systems could switch from kinetically stable to unstable on demand. Surprisingly, some kinetically stable emulsions were obtained at very low interfacial particle coverage. We demonstrate the generality of this phenomenology using different types of particles and we discuss the origin of the stabilization in the poorly-covered regime.

Vorinostat–Polymer Conjugate Nanoparticles for Acid-Responsive Delivery and Passive Tumor Targeting

In vivo histone deacetylase (HDAC) inhibition by vorinostat under clinically acceptable dosing is limited by its poor pharmacokinetics properties. A new type of nontoxic pH-responsive delivery system has been synthesized by ring-opening metathesis polymerization, allowing for the selective distribution of vorinostat in mesothelioma tumors in vivo and subsequent histone reacetylation. The delivery system is synthesized by generic click chemistry, possesses native stealth properties for passive tumor targeting, and does not need additional chemistry for cellular internalization. Although vorinostat alone at 50 mg/kg in mice showed no effect, our new delivery system with 2 mg/kg vorinostat promoted histone reacetylation in tumors without side effects, demonstrating that our strategy improves the activity of this HDAC inihibitor in vivo.

Polymers with novel topologies by ring-opening metathesis polymerization of macromonomers

This paper reviews the possibilities of engineering novel macromolecular topologies via alivingo ring-opening metathesis polymerization (ROMP) of miscellaneous macromonomers. It is shown that multibranched polystyrene poly(ethylene oxide) and polybutadiene poly-macromonomers of varying compactness and branch number can be prepared by ROMP of corresponding macromonomers, provided the macromonomers carry an end-standing norbornene unsaturation. Janus-type ar-chitectures are also accessible by this technique: such entirely novel topologies can be obtained by sequential ROMP of two different macromonomers whereas their statistical copolymerization affords heteroarmed macro-molecules. Advantage has also been taken of the versatility of this technique to prepare compact polymeric architectures that behave like unimicellar systems: structures whose inner part and outer layer are chemically different can be derived through homopoly-merization of macromonomers that are themselves block copolymers.

Synthesis of α‐ and ω‐norbornenyl‐polybutadiene macromonomers and their ring‐opening metathesis polymerization

Norbornene-ended polybutadiene (PBu) macromonomers have been prepared via two different routes: a-norbornenyl-polybutadiene was derived from a norbornene-containing carbanionic initiator, whereas ω-norbornenyl samples were obtained through deactivation of living polybutadienyl anions by a norbornene-based deactivator. Out of four alkylidene complexes tried, the molybdenum alkylidene complex that contains two alkoxide ligands was found to be the most suitable initiator for the ring-opening metathesis polymerization of these macromonomers.

Kinetic study of the polymerization of chloro ethyl vinyl ether initiated by the system hydrogen iodide/iodine

SummaryA kinetic study of the cationic polymerization of chloroethyl vinyl ether initiated by the system hydrogen iodide — iodine has been performed in order to understand some particular characteristics of the system. As previously reported by Higashimura the polymerization shows a living character at low temperature in toluene. A polymerization process with a first order in iodine and 0.3 order with respect to monomer, has been observed. These results are consistent with the existence of reversible elementary processes involving iodine and monomer.