Michael R. Whittaker

Cu(0)-Mediated Living Radical Polymerization: A Versatile Tool for Materials Synthesis

Materials Synthesis Athina Anastasaki,†,‡ Vasiliki Nikolaou,† Gabit Nurumbetov,† Paul Wilson,†,‡ Kristian Kempe,†,‡ John F. Quinn,‡ Thomas P. Davis,†,‡ Michael R. Whittaker,†,‡ and David M. Haddleton*,†,‡ †Chemistry Department, University of Warwick, Library Road, CV4 7AL, Coventry, United Kingdom ‡ARC Centre of Excellence in Convergent Bio-Nano Science and Technology, Monash Institute of Pharmaceutical Sciences, Monash University (Parkville Campus), 399 Royal Parade, Parkville, Victoria 3152, Australia

Cellular Uptake of Densely Packed Polymer Coatings on Gold Nanoparticles

A variety of functional polymer chains prepared by RAFT were directly grafted onto 5, 10, and 20 nm gold nanoparticles (AuNPs). The polymer shell coating the AuNPs was densely packed because of the strong binding between the trithioester groups on the polymer chain-ends and gold. It was found that due to the densely packed nature of the shell the polymer chains were significantly stretched compared to their usual Gaussian coil conformation in water. This was even evident for polymer chains where ionic repulsion between neighboring chains should be significant. Therefore, with such high grafting densities the surface properties and size of the hybrid nanoparticles should be the only contributing factors in cellular uptake in epithelial Caco-2 cells. This study has provided valuable insight into the effects of charge and size of NPs for the application of NPs in the delivery of therapeutic agents across the intestine. Our results showed that the negatively charged AuNPs were taken up by the cells with greater efficiency than the neutral AuNPs, most probably due to binding with membrane proteins. The positively charged AuNPs as expected gave the greatest uptake efficiency. Interestingly, the uptake for PNIPAM-AuNPs (hydrophobic coating at 37 degrees C) increased from approximately 2% efficiency after a 30 min incubation to 8% after 2 h, and was much greater than the negative or neutral AuNPs. We believe that this was due to the interplay between the hydrophobic nature of the NPs and their increased size.

The importance of nanoparticle shape in cancer drug delivery

Introduction: Nanoparticles have been successfully used for cancer drug delivery since 1995. In the design of commercial nanoparticles, size and surface characteristics have been exploited to achieve efficacious delivery. However, the design of optimized drug delivery platforms for efficient delivery to disease sites with minimal off-target effects remains a major research goal. One crucial element of nanoparticle design influencing both pharmacokinetics and cell uptake is nanoparticle morphology (both size and shape). In this succinct review, the authors collate the recent literature to assess the current state of understanding of the influence of nanoparticle shape on the effectiveness of drug delivery with a special emphasis on cancer therapy. Areas covered: This review draws on studies that have focused on the role of nonspherical nanoparticles used for cancer drug delivery. In particular, the authors summarize the influence of nanoparticle shape on biocirculation, biodistribution, cellular uptake and overall drug efficacy. By comparing spherical and nonspherical nanoparticles, they establish some general design principles to serve as guidelines for developing the next generation of nanocarriers for drug delivery. Expert opinion: Pioneering studies on nanoparticles show that nonspherical shapes show great promise as cancer drug delivery vectors. Filamentous or worm-like micelles together with other rare morphologies such as needles or disks may become the norm for next-generation drug carriers, though at present, traditional spherical micelles remain the dominant shape of nanocarriers described in the literature due to synthesis and testing difficulties. The few reports that do exist describing nonspherical nanoparticles show a number of favorable properties that should encourage more efforts to develop facile and versatile nanoparticle synthesis methodologies with the flexibility to create different shapes, tunable sizes and adaptable surface chemistries. In addition, the authors note that there is a current lack of understanding into the factors governing (and optimizing) the inter-relationships of size, surface characteristics and shapes of many nanoparticles proposed for use in cancer therapy.

Photoinduced sequence-control via one pot living radical polymerization of acrylates

The ability to regulate the activation and deactivation steps via an external stimulus has always been a challenge in polymer chemistry. In an ideal photo-mediated system, whereby high monomer conversion and excellent end group fidelity can be maintained, precise control over the polymer composition and microstructure would be a significant breakthrough. Herein, we report, a versatile, simple and inexpensive method that allows for the synthesis of sequence-controlled multiblock copolymers in a one pot polymerization reaction at ambient temperature. In the absence of a conventional photoredox catalyst and dye-sensitisers, low concentrations of CuBr2 in synergy with Me6-Tren mediate acrylic block copolymerization under UV irradiation (λmax ≈ 360 nm). Four different acrylate monomers were alternated in various combinations within the polymer composition illustrating the potential of the technique. Narrow disperse undecablock copolymers were obtained (Đ < 1.2) with quantitative conversion achieved between the iterative monomer additions. The effect of the chain length was investigated allowing for higher molecular weight multiblock copolymers to be obtained. This approach offers a versatile and inexpensive platform for the preparation of high-order multiblock functional materials with additional applications arising from the precise spatiotemporal “on/off” control and resolution when desired.

Synthesis of Functional Core, Star Polymers via RAFT Polymerization for Drug Delivery Applications

Poly(oligoethylene glycol) methyl ether acrylate was polymerized via reversible addition fragmentation transfer polymerization (RAFT), and then chain extended in the presence of both a cross-linker and vinyl benzaldehyde (VBA), yielding monodisperse star polymers. The presence of aldehyde groups in the core was exploited to attach doxorubicin. The drug loading was controlled by the amount of VBA incorporated (until 28 wt% in drug). The doxorubicin release was studied at pH = 5.5 and 7.4; conditions representative of endosomal and extra cellular environments. In vitro studies revealed that the doxorubicin-conjugated star polymers had a level of cytotoxicity comparable to that found for free doxorubicin. Confocal microscopy and flow cytometry studies confirmed efficient cell uptake of the star polymers.

Synthesis of multi-block copolymer stars using a simple iterative Cu(0)-mediated radical polymerization technique

In this communication, we describe a simple and highly efficient route to well-defined multi-block star copolymers based on copper(0)-mediated living radical polymerization. The technique involves a core first approach using a multi-functional initiator in connection with iterative copper(0)-mediated radical polymerization steps. Importantly, purification is not required between the successive chain extension steps as complete monomer conversion is reached before the addition of each consecutive monomer type.

Microgel stars viaReversible Addition Fragmentation Chain Transfer (RAFT) polymerisation — a facile route to macroporous membranes, honeycomb patterned thin films and inverse opal substrates

Arm first microgel polymers were successfully synthesised utilising Reversible Addition Fragmentation Chain Transfer (RAFT) polymerisation techniques. A functional prearm linear AB block copolymer intermediate, (polystyrene)-block-(polydivinylbenzene), was prepared via RAFT by simple one pot chain extension and arm coupling of a preprepared polystyrene macromer. The arms are coupled together via the residual unsaturation present in the polydivinylbenzene block by free radical means to form core-crosslinked microgels. It was found that the arm coupling process could be described by invoking a two-stage coupling system. The initial induction period consists of the formation of largely two-arm (on average) species. This is followed by a latter growth period, where true core-crosslinked microgels are formed consisting of polyarm clusters having 16 arms (on average) per cluster. These microgel materials were cast under specific conditions to form porous polymer films of varying quality. Image analysis of these films demonstrated the importance of the linear component : microgel component ratio in determining both a uniform pore size and the formation of a hexagonal close packed array of pores.

Optimizing the generation of narrow polydispersity ‘arm-first’ star polymers made using RAFT polymerization

In this article, the synthesis of well-defined, narrow polydispersity (PDI < 1.2) star polymersviaRAFT polymerisation is detailed. An ‘arm-first’ method is described using a crosslinked nanogel core. The synthetic conditions and variables were thoroughly investigated and optimised so that nearly quantitative arm incorporation was found to occur. The parameters studied included polymerization time, the arm molecular weight, and the nature of the solvent and cross-linker.

Magnetic nanoparticles with diblock glycopolymer shells give lectin concentration-dependent MRI signals and selective cell uptake

Multivalent glycopolymers exhibit a strong affinity for specific lectin proteins depending on their specific carbohydrate functionality. In this work, we report a facile one-pot synthesis of diblock PEG-glycopolymers using a combination of Cu(0) mediated living radical polymerization and click chemistry to attach three different carbohydrates, α-D-mannose, α-D-glucose and β-D-glucose, to iron oxide nanoparticle (IONP) surfaces. The resultant IONP@P(OEGA)-b-P(sugar) nanoparticles were then extensively characterized using a wide range of analytical techniques, including ATR-FTIR, XPS and TEM. Interestingly, α-D-mannose functionalized IONPs, (IONP@P(OEGA)-b-P(N3Man)), exhibited high r2 transverse relaxivity when measured in a 9.4 T MRI. A significant change in T2 relaxation was observed following binding to the lectin concanavalin A (Con A), with a response proportional to the lectin concentration. The results reported herein indicate that the specific binding of lectin to nanoparticle surfaces can be quantitatively detected using MRI, showing significant promise for future diagnostic applications. Additionally we found a significant improvement in cell uptake for IONPs functionalized with α-D-mannose, in a lung cancer cell line (A549).

Functional Iron Oxide Magnetic Nanoparticles with Hyperthermia‐Induced Drug Release Ability by Using a Combination of Orthogonal Click Reactions

Click and drug: A combination of orthogonal click reactions is employed for the preparation of functional iron oxide nanoparticles (IONPs) that show unprecedented hyperthermia-induced drug release through a magnetically stimulated retro-Diels-Alder (rDA) process. Magnetic stimulation induces sufficient local energy in close proximity to the cycloadduct to initiate the rDA process