Loïc Pichavant

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.

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.

Reactivity of vinyl ethers and vinyl ribosides in UV-initiated free radical copolymerization with acceptor monomers.

The reactivity of various vinyl ethers and vinyloxy derivatives of ribose in the presence of diethyl fumarate or diethyl maleate was investigated for evaluating the potential of donor-acceptor-type copolymerization applied to unsaturated monomers derived from renewable feedstock. The photochemically induced polymerization of model monomer blends in the bulk state was monitored by infrared spectroscopy. The method allowed us to examine the influence of monomer pair structure on the kinetic profiles. The simultaneous consumption of both monomers was observed, supporting an alternating copolymerization mechanism. A lower reactivity of the blends containing maleates compared with fumarates was confirmed. The obtained kinetic data revealed a general correlation between the initial polymerization rate and the Hansen parameter δ(H) associated with the H-bonding aptitude of the donor monomer.

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.

Compared reactivity of allyl ribosides in UV-initiated free radical copolymerization with acceptor monomers.

The free radical copolymerization of allyl ribosides with diethyl fumarate and maleate was investigated for evaluating the potential of donor-acceptor type copolymerization applied to unsaturated monomers derived from renewable feedstock. The photochemically induced polymerization of model monomer blends was conducted in solution as well as in liquid films of bulk reactants. Infrared spectroscopy was used to monitor the consumption of the allylic donor monomer and of the butenedicarboxylate acceptor monomers. The method allowed examining the influence of the nature of the monomer pair and of their relative concentration on the kinetic profiles. Comparison with reference vinyl ether monomers confirmed the expected lower reactivity of the blends containing allylic derivatives. SEC and NMR analysis supported the occurrence of degradative chain transfer during the reactions involving allylic monomers. However, allyl derivatives of glycerol as well as O-allyl ribosides were shown to undergo polymerization with high conversion of both monomers when blended in appropriate molar ratios.

Histone Deacetylase Inhibitors Delivery using Nanoparticles with Intrinsic Passive Tumor Targeting Properties for Tumor Therapy

Fast clearance, metabolism and systemic toxicity are major limits for the clinical use of anti-cancer drugs. Histone deacetylase inhibitors (HDACi) present these defects despite displaying promising anti-tumor properties on tumor cells in vitro and in in vivo model of cancers. Specific delivery of anti-cancer drugs into the tumor should improve their clinical benefit by limiting systemic toxicity and by increasing the anti-tumor effect. In this work, we describe a simple and flexible polymeric nanoparticle platform highly targeting the tumor in vivo and triggering impressive tumor weight reduction when functionalized with HDACi. Our nanoparticles were produced by Ring-Opening Metathesis Polymerization of azido-polyethylene oxide-norbornene macromonomers and functionalized using click chemistry. Using an orthotopic model of peritoneal invasive cancer, a highly selective accumulation of the particles in the tumor was obtained. A combination of epigenetic drugs involving a pH-responsive histone deacetylase inhibitor (HDACi) polymer conjugated to these particles gave 80% reduction of tumor weight without toxicity whereas the free HDACi has no effect. Our work demonstrates that the use of a nanovector with theranostic properties leads to an optimized delivery of potent HDACi in tumor and then, to an improvement of their anti-tumor properties in vivo.

Chapter 14:Reactivity of allyl and vinyl pentosides in photo-initiated donor-acceptor copolymerization

The present chapter is an attempt to compile the developments in the chemistry of carbohydrate-based monomers featuring an ethylenic moiety suited for free radical polymerization, in terms of design, reactivity and properties of the resulting polymers. Particularly, the reactivity of vinyl and allyl ethers derived from selected sugars was examined in donor-acceptor copolymerization with butenedioates (diethyl fumarate, DEF, or diethyl maleate, DEM) used as acceptor co-monomers. The reactivity of selected pairs of monomers was studied from the viewpoints of polymerization rates and of copolymerization mechanism. Kinetic studies confirmed the higher reactivity of vinyl ethers with respect to allyl analogs, the latter leading to extensive transfer reactions evidenced by the lower molecular weight of the resulting polymers and by the nature of the end groups. Vinyloxy monomers yield regular alternating copolymers with high molecular weight when copolymerized in undiluted liquid blends. Allyloxy monomers polymerized in the presence of DEF typically undergo random copolymerization with DEF homopropagation, as well as the dominant occurrence of transfer reactions as end of growth mechanism. The influence of structural factors, of dilution and of stoichiometry on the reactivity was examined in details so as to optimize polymerization efficiency. Some examples of possible routes towards pentose-based networks illustrate the approach using allyloxy model derivatives, polymerization of hybrid donor-acceptor monomers as well as the copolymerization of a multifunctional xyloside bearing several electron-donor unsaturations together with an acceptor comonomer. Finally, the influence of monomer composition on the thermo-physical properties of the resulting networks was evaluated.