Vincent Ladmiral

Bioapplications of RAFT Polymerization

A living radical polymerization (LRP) is a free radical polymerization that aims at displaying living character, (i.e., does not terminate or transfer and is able to continue polymerization once the initial feed is exhausted by addition of more monomer). However, termination reactions are inherent to a radical process, and modern LRP techniques seek to minimize such reactions, therefore providing control over the molecular weight and the molecular weight distribution of a polymeric material. In addition, the better LRP techniques incorporate many of the desirable features of traditional free radical polymerization, such as compatibility with a wide range of monomers, tolerance of many functionalities, and facile reaction conditions. The control of molecular weight and molecular weight distribution has enabled access to complex architectures and site specific functionality that were previously impossible to achieve via traditional free radical polymerizations. These LRPs are classified in three different subgroups: (1) stable free-radical polymerization such as nitroxide mediated polymerization (NMP),1,2 (2) degenerative transfer polymerization, such as iodine transfer polymerization (ITP and RITP),3,4 single electron transfer-degenerative transfer living radical polymerization(SET-DTLRP),5,6reversibleaddition-fragmentation chain transfer (RAFT),7,8 and macromolecular design via the interchange of xanthates (MADIX)9,10 polymerization, and (3) metal mediated catalyzed polymerization, such as atom transfer radical polymerization (ATRP),11-14 single electron transfer-living radical polymerization (SET-LRP),15 and organotellurium mediated living radical polymrization16-19 Among the existing LRP techniques, RAFT and MADIX are probably the most versatile processes, as they are tolerant * E-mail: T.P.D., T.Davis@UNSW.edu.au; S.P., S.Perrier@ chem.usyd.edu.au. † Centre for Advanced Macromolecular Design (CAMD), School of Chemical Sciences & Engineering, UNSW. ‡ Centre for Advanced Macromolecular Design (CAMD), School of Biotechnology & Biomolecular Sciences, UNSW. § The University of Sydney. Chem. Rev. 2009, 109, 5402–5436 5402

Anionic polyelectrolyte-stabilized nanoparticles via RAFT aqueous dispersion polymerization.

We report the synthesis of anionic sterically stabilized diblock copolymer nanoparticles via polymerization-induced self-assembly using a RAFT aqueous dispersion polymerization formulation. The anionic steric stabilizer is a macromolecular chain-transfer agent (macro-CTA) based on poly(potassium 3-sulfopropyl methacrylate) (PKSPMA), and the hydrophobic core-forming block is based on poly(2-hydroxypropyl methacrylate) (PHPMA). The effect of varying synthesis parameters such as the salt concentration, solids content, relative block composition, and anionic charge density has been studied. In the absence of salt, self-assembly is problematic when using a PKSPMA stabilizer because of lateral repulsion between highly charged anionic chains. However, in the presence of added salt this problem can be overcome by reducing the charge density within the coronal stabilizer layer by either (i) statistically copolymerizing the KSPMA monomer with a nonionic comonomer (2-hydroxyethyl methacrylate, HEMA) or (ii) using a binary mixture of a PKSPMA macro-CTA and a poly(glycerol monomethacrylate) (PGMA) macro-CTA. These diblock copolymer nanoparticles were analyzed by (1)H NMR spectroscopy, gel permeation chromatography (GPC), dynamic light scattering (DLS), transmission electron microscopy (TEM), and aqueous electrophoresis. NMR studies suggest that the HPMA polymerization is complete within 2 h at 70 °C, and DMF GPC analysis confirms that the resulting diblock copolymers have relatively low polydispersities (M(w)/M(n) < 1.30). NMR also suggests a significant degree of hydration for the core-forming PHPMA chains. Depending on the specific reaction conditions, a series of spherical nanoparticles with mean diameters ranging from 50 to 200 nm with tunable anionic surface charge can be prepared. If a binary mixture of anionic and nonionic macro-CTAs is utilized, then it is also possible to access a vesicular morphology.

One-pot tandem living radical polymerisation–Huisgens cycloaddition process (“click”) catalysed by N-alkyl-2-pyridylmethanimine/Cu(I)Br complexes

Azide terminally functional poly(methyl methacrylate)s (Mn = 4000-6000, PDI = 1.21-1.28) have been prepared by living radical polymerization and successfully reacted with alkynes in a Huisgen cycloaddition (click) reaction in one pot using the same catalyst for both processes.

RAFT dispersion polymerization in non-polar solvents: facile production of block copolymer spheres, worms and vesicles in n-alkanes

Well-defined poly(lauryl methacrylate-benzyl methacrylate) (PLMA-PBzMA) diblock copolymer nanoparticles are prepared in n-heptane at 90 °C via reversible addition–fragmentation chain transfer (RAFT) polymerization. Under these conditions, the PLMA macromolecular chain transfer agent (macro-CTA) is soluble in n-heptane, whereas the growing PBzMA block quickly becomes insoluble. Thus this dispersion polymerization formulation leads to polymerization-induced self-assembly (PISA). Using a relatively long PLMA macro-CTA with a mean degree of polymerization (DP) of 37 or higher leads to the formation of well-defined spherical nanoparticles of 41 to 139 nm diameter, depending on the DP targeted for the PBzMA block. In contrast, TEM studies confirm that using a relatively short PLMA macro-CTA (DP = 17) enables both worm-like and vesicular morphologies to be produced, in addition to the spherical phase. A detailed phase diagram has been elucidated for this more asymmetric diblock copolymer formulation, which ensures that each pure phase can be targeted reproducibly. 1H NMR spectroscopy confirmed that high BzMA monomer conversions (>97%) were achieved within 5 h, while GPC studies indicated that reasonably good blocking efficiencies and relatively low diblock copolymer polydispersities (Mw/Mn < 1.30) were obtained in most cases. Compared to prior literature reports, this all-methacrylic PISA formulation is particularly novel because: (i) it is the first time that higher order morphologies (e.g. worms and vesicles) have been accessed in non-polar solvents and (ii) such diblock copolymer nano-objects are expected to have potential boundary lubrication applications for engine oils.

Polymerization-Induced Self-Assembly of Galactose-Functionalized Biocompatible Diblock Copolymers for Intracellular Delivery

Recent advances in polymer science are enabling substantial progress in nanobiotechnology, particularly in the design of new tools for enhanced understanding of cell biology and for smart drug delivery formulations. Herein, a range of novel galactosylated diblock copolymer nano-objects is prepared directly in concentrated aqueous solution via reversible addition–fragmentation chain transfer polymerization using polymerization-induced self-assembly. The resulting nanospheres, worm-like micelles, or vesicles interact in vitro with galectins as judged by a turbidity assay. In addition, galactosylated vesicles are highly biocompatible and allow intracellular delivery of an encapsulated molecular cargo.

Zwitterionic poly(amino acid methacrylate) brushes.

A new cysteine-based methacrylic monomer (CysMA) was conveniently synthesized via selective thia-Michael addition of a commercially available methacrylate-acrylate precursor in aqueous solution without recourse to protecting group chemistry. Poly(cysteine methacrylate) (PCysMA) brushes were grown from the surface of silicon wafers by atom-transfer radical polymerization. Brush thicknesses of ca. 27 nm were achieved within 270 min at 20 °C. Each CysMA residue comprises a primary amine and a carboxylic acid. Surface zeta potential and atomic force microscopy (AFM) studies of the pH-responsive PCysMA brushes confirm that they are highly extended either below pH 2 or above pH 9.5, since they possess either cationic or anionic character, respectively. At intermediate pH, PCysMA brushes are zwitterionic. At physiological pH, they exhibit excellent resistance to biofouling and negligible cytotoxicity. PCysMA brushes undergo photodegradation: AFM topographical imaging indicates significant mass loss from the brush layer, while XPS studies confirm that exposure to UV radiation produces surface aldehyde sites that can be subsequently derivatized with amines. UV exposure using a photomask yielded sharp, well-defined micropatterned PCysMA brushes functionalized with aldehyde groups that enable conjugation to green fluorescent protein (GFP). Nanopatterned PCysMA brushes were obtained using interference lithography, and confocal microscopy again confirmed the selective conjugation of GFP. Finally, PCysMA undergoes complex base-catalyzed degradation in alkaline solution, leading to the elimination of several small molecules. However, good long-term chemical stability was observed when PCysMA brushes were immersed in aqueous solution at physiological pH.

Synthesis and characterization of poly(amino acid methacrylate)-stabilized diblock copolymer nano-objects

Amino acids constitute one of Natures most important building blocks. Their remarkably diverse properties (hydrophobic/hydrophilic character, charge density, chirality, reversible cross-linking etc.) dictate the structure and function of proteins. The synthesis of artificial peptides and proteins comprising main chain amino acids is of particular importance for nanomedicine. However, synthetic polymers bearing amino acid side-chains are more readily prepared and may offer desirable properties for various biomedical applications. Herein we describe an efficient route for the synthesis of poly(amino acid methacrylate)stabilized diblock copolymer nano-objects. First, either cysteine or glutathione is reacted with a commercially available methacrylate-acrylate adduct to produce the corresponding amino acid-based methacrylic monomer (CysMA or GSHMA). Well-defined water-soluble macromolecular chain transfer agents (PCysMA or PGSHMA macro-CTAs) are then prepared via RAFT polymerization, which are then chain-extended via aqueous RAFT dispersion polymerization of 2-hydroxypropyl methacrylate. In situ polymerization-induced self-assembly (PISA) occurs to produce sterically-stabilized diblock copolymer nano-objects. Although only spherical nanoparticles could be obtained when PGSHMA was used as the sole macro-CTA, either spheres, worms or vesicles can be prepared using either PCysMA macro-CTA alone or binary mixtures of poly(glycerol monomethacrylate) (PGMA) with either PCysMA or PGSHMA macro-CTAs. The worms formed soft free-standing thermo-responsive gels that undergo degelation on cooling as a result of a worm-to-sphere transition. Aqueous electrophoresis studies indicate that all three copolymer morphologies exhibit cationic character below pH 3.5 and anionic character above pH 3.5. This pH sensitivity corresponds to the known behavior of the poly(amino acid methacrylate) steric stabilizer chains.

RAFT synthesis of well-defined PVDF-b-PVAc block copolymers

RAFT polymerization of vinylidene fluoride (VDF), leading to relatively well defined poly(vinylidene fluoride) (PVDF), is negatively affected by chain inversion resulting in less easily reactivatable PVDFT-XA dormant chains (terminated with the tail end of an inversely added VDF unit; XA = xanthate moiety). Although slow reactivation of these chains by PVDF˙ radicals (in contrast to general belief) was recently demonstrated, slow radical exchange leads to progressive loss of chain growth control. This article deals with the possibility of synthesizing block copolymers from PVDF-XA macroCTAs by sequential addition. The investigations show that only PVDFH-XA (chains terminated with the head end of regularly added VDF) can be reactivated by PNVP˙ (poly(N-vinylpyrrolidone)) radicals and that PVDFT-XA chains are completely unreactive in the presence of PNVP˙, PB˙ (poly(butylacrylate)) or PDM˙ (poly(N,N′-dimethylacrylamide)). However, both PVDFH-XA and PVDFT-XA can be reactivated by PVAc˙ (poly(vinyl acetate)) radicals. The reactivation of the PVDFT-XA, albeit slower than that of the PVDFH-XA, is sufficiently fast to allow the synthesis of unprecedented well-defined PVDF-b-PVAc block copolymers with relatively high end-group fidelity. DFT calculations rationalize this behavior on the basis of faster radical exchange in the order PVDFH-XA/VAc > PVDFH-XA/NVP > PVDFT-XA/VAc ≫ PVDFT-XA/NVP. The success of the chain extension also relies on faster activation relative to homopropagation of the chain extending monomer, as well as fast addition of the released and to the monomer.

An amphiphilic poly(vinylidene fluoride)-b-poly(vinyl alcohol) block copolymer: synthesis and self-assembly in water

This study is the first report of the synthesis and self-assembly in water of an amphiphilic PVDF-b-PVA block copolymer. The block copolymer was prepared by sequential RAFT polymerization of VDF and VAc followed by saponification of the PVAc block and was characterized by 1H NMR and FTIR. The self-assembled nanoparticles were characterized by DLS and cryo-TEM.

Polymerization-induced self-assembly of PVAc-b-PVDF block copolymers via RAFT dispersion polymerization of vinylidene fluoride in dimethyl carbonate

Polymerization-induced self-assembly of PVAc-b-PVDF block copolymers (BCPs) in dimethyl carbonate (DMC) was performed and studied using vinylidene fluoride (VDF) RAFT dispersion polymerization protocols in DMC in the presence of PVAc macromolecular chain transfer agents (macro-CTAs). The polymerizations were conducted at 73 °C in DMC using three PVAc macro-CTAs of different molar masses and targeting various DPPVDF. The relatively high frequency of head-to-head (HH) additions in VAc polymerization and the much lower reactivity of the resulting PVAc chains terminated with a –CH(OAc)–CH2–SC(S)OCH2CH3 group (PVAcT–XA, where XA stands for the xanthate end-group) compared to their regularly terminated analogs (PVAcH–XA) leads to an accumulation of PVAcT–XA chains during polymerization. These PVAcT–XA reactivate slower than PVAcH–XA in the presence of PVDF˙ radicals. In addition, RAFT polymerization of VDF is prone to the same chain defect problem and to non-negligible transfer to DMC. In consequence, RAFT dispersion polymerization of VDF in the presence of PVAc macro-CTAs afforded PVAc-b-PVDF BCPs (contaminated with starting unreacted PVAc and PVDF homopolymers formed via transfer to DMC). These phenomena were studied using 1H and 19F NMR spectroscopy and size exclusion chromatography. Nevertheless, the VDF RAFT dispersion polymerization in DMC experiments resulted in self-assembled BCP morphologies in the form of crystalline (1–5 μm) ovoidal flakes. These flakes stack on top of each other and form star-like structures. The structures are thought to form by epitaxial growth of the PVDF crystals and interparticle interpenetration crystallization. Although they are formed under polymerization-induced self-assembly conditions, the morphologies of these BCP structures are governed by the crystallization of PVDF.