Phenyl acrylate is a versatile monomer for the synthesis of acrylic diblock copolymer nano-objects via polymerization-induced self-assembly

Over the last decade or so, polymerization-induced self-assembly (PISA) has become widely recognized as a versatile technique for the rational synthesis of diblock copolymer nano-objects in the form of concentrated dispersions. However, there are relatively few examples of acrylic-based PISA formulations in the literature, partly because such copolymers typically possess relatively low glass transition temperatures (Tg) that preclude morphological characterization by transmission electron microscopy. To address this problem, we have selected phenyl acrylate (PhA) as a model monomer to generate the solvophobic block in three PISA formulations using reversible addition–fragmentation chain transfer (RAFT) polymerization. Thus, a poly(dimethyl acrylamide)-based chain transfer agent (CTA) is chain-extended using PhA via RAFT aqueous emulsion polymerization to produce a series of well-defined sterically-stabilized spheres whose mean diameter can be readily adjusted from 38 nm to 188 nm by varying the target degree of polymerization (DP). In contrast, RAFT alcoholic dispersion polymerization of PhA using a poly(acrylic acid) CTA leads to an evolution of copolymer morphology from spheres to worms to lamellae and finally vesicles as the target DP of the structure-directing PPhA block is increased. Similarly, RAFT dispersion polymerization of PhA in n-heptane also produces spheres, worms or vesicles depending on the target DP of the PPhA block. 1H NMR studies indicate that >98% PhA conversion is achieved in all cases, while GPC analysis indicates high blocking efficiencies. However, relatively broad molecular weight distributions are observed (Mw/Mn = 1.37 to 2.48), which suggests extensive chain transfer to polymer in such PISA syntheses, particularly in the case of the RAFT aqueous emulsion polymerization formulation. Nevertheless, the relatively high Tg of PPhA (50 °C) enables characterization of the various copolymer morphologies using conventional TEM

Characterisation of tumour blood flow using a 'tissue-isolated' preparation

Tumour blood flow was characterised in a 'tissue-isolated' rat tumour model, in which the vascular supply is derived from a single artery and vein. Tumours were perfused in situ and blood flow was calculated from simultaneous measurement of (1) venous outflow from the tumour and (2) uptake into the tumour of radiolabelled iodo-antipyrine (IAP). Comparison of results from the two measurements enabled assessment of the amount of blood 'shunted' through the tumours with minimal exchange between blood and tissue. Kinetics of IAP uptake were also used to determine the apparent volume of distribution (VDapp) for the tracer and the equilibrium tissue-blood partition coefficient (lambda). lambda was also measured by in vitro techniques and checks were made for binding and metabolism of IAP using high-pressure liquid chromatography. VDapp and lambda were used to calculate the perfused fraction (alpha) of the tumours. Tumour blood flow, as measured by IAP (TBFIAP), was 94.8 +/- 4.4% of the blood flow as measured by venous outflow, indicating only a small amount of non-exchanging flow. This level of shunting is lower than some previous estimates in which the percentage tumour entrapment of microspheres was used. The unperfused fraction ranged from 0 to 20% of the tumour volume in the majority of tumours. This could be due to tumour necrosis and/or acutely ischaemic tumour regions. For practical purposes, measurement of the total venous outflow of tumours is a reasonable measure of exchangeable tumour blood flow in this system and allows for on-line measurements. Tracer methods can be used to obtain additional information on the distribution of blood flow within tumours

Stimulus-responsive block copolymer nano-objects and hydrogels via dynamic covalent chemistry

Herein we demonstrate that dynamic covalent chemistry can be used to induce reversible morphological transitions in block copolymer nano-objects and hydrogels. Poly(glycerol monomethacrylate)–poly(2- hydroxypropyl methacrylate) (PGMA–PHPMA) diblock copolymer nano-objects (vesicles or worms) were prepared via polymerization-induced self-assembly. Addition of 4-carboxyphenylboronic acid (CPBA) leads to the formation of phenylboronate ester bonds with the 1,2-diol pendent groups on the hydrophilic PGMA stabilizer chains; such binding causes a subtle reduction in the packing parameter, which in turn induces either vesicle-to-worm or worm-to-sphere transitions. Moreover, CPBA binding is pH-dependent, so reversible transitions can be achieved by switching the solution pH, with relatively high copolymer concentrations leading to associated (de)gelation. This distinguishes these new physical hydrogels from the covalently cross-linked gels prepared using dynamic covalent chemistry reported in the literature

Synthesis of High Molecular Weight Poly(glycerol monomethacrylate) via RAFT Emulsion Polymerization of Isopropylideneglycerol Methacrylatefree

High molecular weight water-soluble polymers are widely used as flocculants or thickeners. However, synthesis of such polymers via solution polymerization invariably results in highly viscous fluids, which makes subsequent processing somewhat problematic. Alternatively, such polymers can be prepared as colloidal dispersions; in principle, this is advantageous because the particulate nature of the polymer chains ensures a much lower fluid viscosity. Herein we exemplify the latter approach by reporting the convenient one-pot synthesis of high molecular weight poly(glycerol monomethacrylate) (PGMA) via the reversible addition−fragmentation chain transfer (RAFT) aqueous emulsion polymerization of a water-immiscible protected monomer precursor, isopropylideneglycerol methacrylate (IPGMA) at 70 °C, using a water-soluble poly(glycerol monomethacrylate) (PGMA) chain transfer agent as a steric stabilizer. This formulation produces a low-viscosity aqueous dispersion of PGMA−PIPGMA diblock copolymer nanoparticles at 20% solids. Subsequent acid deprotection of the hydrophobic core-forming PIPGMA block leads to particle dissolution and affords a viscous aqueous solution comprising high molecular weight PGMA homopolymer chains with a relatively narrow molecular weight distribution. Moreover, it is shown that this latex precursor route offers an important advantage compared to the RAFT aqueous solution polymerization of glycerol monomethacrylate since it provides a significantly faster rate of polymerization (and hence higher monomer conversion) under comparable conditions

H2O2 Enables Convenient Removal of RAFT End-Groups from Block Copolymer Nano-Objects Prepared via Polymerization-Induced Self-Assembly in Water

RAFT-synthesized polymers are typically colored and malodorous due to the presence of the sulfur-based RAFT end-group(s). In principle, RAFT end-groups can be removed by treating molecularly dissolved copolymer chains with excess free radical initiators, amines, or oxidants. Herein we report a convenient method for the removal of RAFT end-groups from aqueous dispersions of diblock copolymer nano-objects using H2O2. This oxidant is relatively cheap, has minimal impact on the copolymer morphology, and produces benign side products that can be readily removed via dialysis. We investigate the efficiency of end-group removal for various diblock copolymer nano-objects prepared with either dithiobenzoate- or trithiocarbonate-based RAFT chain transfer agents. The advantage of using UV GPC rather than UV spectroscopy is demonstrated for assessing both the kinetics and extent of end-group removal

Oil-in-oil pickering emulsions stabilized by diblock copolymer nanoparticles

Hypothesis Diblock copolymer nanoparticles have been shown to be Pickering emulsifiers for both oil-in-water and water-in-oil emulsions. Recently, we reported the preparation of sterically-stabilized diblock copolymer spheres in a low-viscosity silicone oil (Macromolecules 53 (2020) 1785–1794). We hypothesized that such spheres could be used as a Pickering emulsifier for a range of oil-in-oil emulsions comprising droplets of a bio-sourced oil dispersed in silicone oil. Experiments Diblock copolymer spheres were prepared via reversible addition-fragmentation chain transfer (RAFT) dispersion polymerization of benzyl methacrylate in silicone oil and characterized by dynamic light scattering and transmission electron microscopy. These spheres were evaluated as Pickering emulsifiers for a series of oil-in-oil Pickering emulsions. The influence of both sphere size and core-forming block composition was investigated. Findings \ud Optimization of the nanoparticle size and core-forming block composition enabled stable bio-sourced oil-in-silicone emulsions to be obtained for nine out of the ten bio-sourced oils investigated. These emulsions were characterized in terms of their mean droplet size by optical microscopy

Giant Pickering droplets: effect of nanoparticle size and morphology on stability

The interaction between a pair of millimeter-sized nanoparticle-stabilized n-dodecane droplets was analyzed by high-speed video camera. The droplets were grown in the presence of either poly(glycerol monomethacrylate)-poly(benzyl methacrylate) (PGMA-PBzMA) diblock copolymer spheres or poly(glycerol monomethacrylate)-poly(2-hydroxypropyl methacrylate)-poly(benzyl methacrylate) (PGMA-PHPMA-PBzMA) triblock copolymer worms prepared by polymerization-induced self-assembly (PISA). The effect of nanoparticle morphology on droplet coalescence was analyzed by comparing 22 nm spheres to highly anisotropic worms with a mean worm width of 26 nm and comparable particle contact angle. Both morphologies lowered the interfacial tension, providing direct evidence for nanoparticle adsorption at the oil-water interface. At 0.03 % w/v copolymer, at least 90 seconds was required to stabilize the n-dodecane droplets in the presence of the worms, whereas no ageing was required to produce stable droplets when using the spheres, suggesting faster diffusion of the latter to the surface of the droplets. The enhanced stability of the sphere-coated droplets is consistent with the higher capillary pressure in this system as the almost planar interfaces approach. However, the more strongly adsorbing worms ultimately also confer stability. At lower copolymer concentrations (≤ 0.01% w/v) worm adsorption promoted droplet stability, whereas the spheres were unable to stabilize droplets even after longer ageing times. The effect of mean sphere diameter on droplet stability was also assessed while maintaining an approximately constant particle contact angle. Small spheres of either 22 nm or 41 nm stabilized n-dodecane droplets, whereas larger spheres of either 60 or 91 nm were unable to prevent coalescence when the two droplets were brought into contact. These observations are consistent with the greater capillary pressure stabilizing the oil-water interfaces coated with the smaller spheres. Addition of an oil-soluble polymeric diisocyanate cross-linker to either the 60 nm or the 91 nm spheres produced highly stable colloidosomes, thus confirming adsorption of these nanoparticles

Synthesis of crystallizable poly(behenyl methacrylate)-based block and statistical copolymers and their performance as wax crystal modifiers

Two series of behenyl methacrylate-based diblock and statistical copolymers have been prepared by reversible addition–fragmentation chain transfer (RAFT) solution polymerization in n-dodecane and evaluated as additives for the crystal habit modification of a model wax (n-octacosane). DSC studies indicated that each statistical copolymer exhibited a significantly lower crystallization temperature (Tc) and melting temperature (Tm) for the semi-crystalline behenyl methacrylate component than the corresponding diblock copolymer of almost identical overall composition. Temperature-dependent turbidimetry studies were conducted for each copolymer using a series of solutions of 5.0% w/w n-octacosane dissolved in n-dodecane to determine Tcool, which is the temperature at which zero transmittance is first observed owing to wax crystallization. At a constant molar copolymer concentration of 0.26 mM, each of the eight copolymers produced a reduction in Tcool of approximately 3–5 °C. Scanning electron microscopy (SEM) studies confirmed that the presence of such copolymers led to a reduction in the overall size and/or a higher crystal aspect ratio. The diblock and statistical copolymers were similar in their performance as potential wax crystal modifiers. However, the statistical copolymers were easier to prepare and did not suffer from any homopolymer contamination. Moreover, optical microscopy and SEM studies revealed that needle-like crystals were formed instead of platelets when employing behenyl methacrylate-rich statistical copolymers

Kinetic modelling of dissolution dynamic nuclear polarisation 13C magnetic resonance spectroscopy data for analysis of pyruvate delivery and fate in tumours

Dissolution dynamic nuclear polarisation (dDNP) of 13C-labelled pyruvate in magnetic resonance spectroscopy/imaging (MRS/MRSI) has the potential for monitoring tumour progression and treatment response. Pyruvate delivery, its metabolism to lactate and efflux were investigated in rat P22 sarcomas following simultaneous intravenous administration of hyperpolarised 13C-labelled pyruvate (13C1-pyruvate) and urea (13C-urea), a nonmetabolised marker. A general mathematical model of pyruvate-lactate exchange, incorporating an arterial input function (AIF), enabled the losses of pyruvate and lactate from tumour to be estimated, in addition to the clearance rate of pyruvate signal from blood into tumour, Kip, and the forward and reverse fractional rate constants for pyruvate-lactate signal exchange, kpl and klp. An analogous model was developed for urea, enabling estimation of urea tumour losses and the blood clearance parameter, Kiu. A spectral fitting procedure to blood time-course data proved superior to assuming a gamma-variate form for the AIFs. Mean arterial blood pressure marginally correlated with clearance rates. Kiu equalled Kip, indicating equivalent permeability of the tumour vasculature to urea and pyruvate. Fractional loss rate constants due to effluxes of pyruvate, lactate and urea from tumour tissue into blood (kpo, klo and kuo, respectively) indicated that T1s and the average flip angle, θ, obtained from arterial blood were poor surrogates for these parameters in tumour tissue. A precursor-product model, using the tumour pyruvate signal time-course as the input for the corresponding lactate signal time-course, was modified to account for the observed delay between them. The corresponding fractional rate constant, kavail, most likely reflected heterogeneous tumour microcirculation. Loss parameters, estimated from this model with different TRs, provided a lower limit on the estimates of tumour T1 for lactate and urea. The results do not support use of hyperpolarised urea for providing information on the tumour microcirculation over and above what can be obtained from pyruvate alone. The results also highlight the need for rigorous processes controlling signal quantitation, if absolute estimations of biological parameters are required