Olivier Bertrand

Self-Assembling Doxorubicin−Tocopherol Succinate Prodrug as a New Drug Delivery System: Synthesis, Characterization, and in Vitro and in Vivo Anticancer Activity

Self-assembled prodrugs forming nanoaggregates are a promising approach to enhance the antitumor efficacy and to reduce the toxicity of anticancer drugs. To achieve this goal, doxorubicin was chemically conjugated to d-α-tocopherol succinate through an amide bond to form N-doxorubicin-α-d-tocopherol succinate (N-DOX-TOS). The prodrug self-assembled in water into 250 nm nanostructures when stabilized with d-α-tocopherol poly(ethylene glycol) 2000 succinate. Cryo-TEM analysis revealed the formation of nanoparticles with a highly ordered lamellar inner structure. NMR spectra of the N-DOX-TOS nanoparticles indicated that N-DOX-TOS is located in the core of the nanoparticles while PEG chains and part of the tocopherol are in the corona. High drug loading (34% w/w) and low in vitro drug release were achieved. In vitro biological assessment showed significant anticancer activity and temperature-dependent cellular uptake of N-DOX-TOS nanoparticles. In vivo, these nanoparticles showed a greater antitumor efficacy than free DOX. N-DOX-TOS nanoparticles might have the potential to improve DOX-based chemotherapy.

Photo-responsive polymers: synthesis and applications

In this review, we highlight the progress realized in recent years on light-responsive polymers. More precisely, we provide some guidelines towards the rational design of photo-responsive block copolymers and we present the different photo-responsive moieties that have been used so far. We also discuss the different types of irreversible and reversible responses encountered by photo-responsive polymers. Finally, we discuss the application of light responsive polymers in material science.

Photo-induced micellization of block copolymers bearing 4,5-dimethoxy-2-nitrobenzyl side groups

The synthesis of photocleavable poly(dimethoxynitrobenzyl acrylate)-block-polystyrene block copolymers is described. The UV irradiation of these block copolymers, dissolved in a good solvent for both blocks, selectively cleaves the dimethoxynitrobenzyl protecting groups, leading to carboxylic acid moieties. Since the resulting hydrophilic poly(acrylic acid) block is insoluble in the solvent used, self-assembly of the diblocks into micelles is observed. This light-induced micellization process is further used to trap dyes into the core of the micelles.

Tuning micellar morphology and rheological behaviour of metallo-supramolecular micellar gels

Well-defined polystyrene-block-poly(tert-butylacrylate) diblock copolymers end-functionalized by a terpyridine ligand (PS-b-PtBA-[) were synthesized by nitroxide mediated polymerization (NMP) in the presence of an initiator bearing a terpyridine moiety. These materials were then hierarchically organized over two levels of self-assembly to yield metallo-supramolecular micellar gels. The first level of self-assembly is the formation of micelles in the dilute regime. Spherical or cylindrical micelles were obtained depending on the block copolymer composition as well as the method of preparation. The second level of self-assembly was triggered upon addition of Ni(II) ions to the concentrated micellar solutions. Rotational rheometry was used to probe the impact of the micellar morphology and the presence of a co-solvent on the mechanical properties of the gel.

Synthesis of diblock copolymers bearing p-methoxyphenacyl side groups

This contribution reports on the synthesis of light-responsive diblock copolymers containing para-methoxyphenacyl photocleavable side groups. The synthetic strategy consists in the direct polymerization of p-methoxyphenacyl methacrylate by Atom Transfer Radical Polymerization. Several catalytic systems have been screened to synthesize poly(p-methoxyphenacyl methacrylate) in a controlled way. In a second step, diblock copolymers containing a poly(p-methoxyphenacyl methacrylate) block and a block composed of either polystyrene, poly(tert-butyl acrylate) or poly(methyl methacrylate) have been synthesized to evidence the possibility of preparing copolymers with monomers belonging to the three main categories. The cleavage of the p-methoxyphenacyl moieties in solution has been finally demonstrated.

Synthesis of polymer precursors of electroactive materials by SET-LRP

The synthesis of electroactive polymer precursors by single electron transfer-living radical polymerisation (SET-LRP) is demonstrated here. Standard SET-LRP conditions are employed for the controlled polymerisation of 2,2,6,6-tetramethylpiperidin-4-yl methacrylate (TMPM). The controlled behaviour of the polymerisation under these conditions is demonstrated by kinetic experiments. Moreover, the synthesis of functional block copolymers is investigated with 3-azidopropyl methacrylate (AzPMA). The TMPM containing (co)polymers are oxidised to produce electroactive poly(TEMPO methacrylate) (PTMA). The redox behaviour of the PTMA was furthermore evidenced by cyclic voltamperometry. These polymers are promising in the frame of organic radical batteries.

Electroactive polymer/carbon nanotube hybrid materials for energy storage synthesized via a “grafting to” approach

This paper describes the synthesis and characterization of a new hybrid material based on poly(2,2,6,6-tetramethylpiperidin-1-oxyl-4-yl methacrylate) (PTMA) for lithium battery applications. Our strategy relies on the anchoring of nitroxide-embedding polymer chains onto multi-walled carbon nanotubes (MWCNTs). The resulting hybrid material (MWCNT-g-PTMA) not only prevents the solubilization of the PTMA active material but also benefits from its structural design aspects. The MWCNT-g-PTMA structure confers high performances thanks to the precise distribution of the PTMA redox material with respect to the MWCNT conductive network, as confirmed by molecular modeling simulations of the polymer/MWCNT interface. Physicochemical characterizations are evidence of the success of MWCNT-g-PTMA synthesis with a polymer loading up to 30 wt%. Electrochemical analysis shows the potential of MWCNT-g-PTMA as a battery material, with a capacity reaching 85% of the theoretical value, a good cyclability (retention > 80% after 150 cycles) and excellent power performances (capacity at 60C exceeding 65% of the nominal value).

One-pot synthesis of electro-active polymer gels via Cu(0)-mediated radical polymerization and click chemistry

Recently, poly(2,2,6,6-tetramethylpiperidinyloxy-4-yl methacrylate) (PTMA) has attracted intensive attention for energy storage applications. Organic radical batteries built with this polymer display high power performance. However, the solubility of PTMA in commercial electrolytes shortens the lifespan and the overall performance of the battery. To circumvent this issue, we propose to immobilize PTMA in a three-dimensional network. Indeed, an electrolyte swollen network (gel) enables a good ionic diffusion and brings good mechanical properties to the cathodic material. Here we report on the synthesis of PTMA gels by a combination of Cu(0)-mediated reversible-deactivation radical polymerization and copper-catalyzed azide–alkyne cycloaddition (CuAAC). The structure of the accordingly obtained gels is characterized by NMR, SEC and FTIR and the mechanical properties of these materials are studied by rheology. Finally, their electrochemical performances are studied in the context of organic radical batteries.

Redox-controlled upper critical solution temperature behaviour of a nitroxide containing polymer in alcohol–water mixtures

Research on stimuli responsive polymers builds momentum as nature-inspired applications using man-made materials are increasingly sought. Here, we show for the first time the thermo-responsive upper critical solution temperature (UCST) behaviour of a nitroxide containing polymer based on (2,6,6,6-tetramethylpiperidin-1-yl)oxyl (TEMPO). It is demonstrated that poly(TEMPO methacrylate) (PTMA) exhibits a UCST-type cloud point temperature in alcohol–water mixtures that can be tuned by external electrical stimuli. To exemplify this, we studied the UCST behaviour of this polymer in alcohol–water mixtures. The reversible redox response of PTMA is used to tune the thermo-responsive behaviour of the solvated polymer. The effect of the oxidation extent in PTMA on UCST is demonstrated and a correlation between the chemical and electrochemical oxidation routes is presented.

Ring Opening Metathesis Polymerization of Cyclopentene Using a Ruthenium Catalyst Confined by a Branched Polymer Architecture

Multi-arm polystyrene stars functionalized with Grubbs-type catalysts in their cores were synthesized and used for the ring-opening metathesis polymerization (ROMP) of cyclopentene. The spatial confinement of the catalytic sites and the nanoscale phase separation between polystyrene and the growing polypentenamer chains lead to a dramatic inhibition of the ROMP termination and chain transfer steps. Consequently, cyclopentene polymerizations proceeded fast and with a high degree of conversion even in air. The Grubbs second generation catalyst was oxidatively inactivated under the same conditions. In contrast to conventional small-molecule catalysts, the ultimate degree of conversion of the cyclopentene monomer and the polydispersity of the product polypentenamer are not affected by the temperature. This indicates that spatial confinement of the catalyst results in a significant change in the activation parameters for the alkene metathesis ring-opening.