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Photomediated RAFT step-growth polymerization was performed with and without the presence of a photocatalyst using a trithiocarbonate-based CTA and a maleimide monomer.

Commercially available N-aromatic substituted bismaleimides were used in RAFT step-growth polymerization with a bifunctional RAFT agent, affording polymers having moderate to high molecular weights.

Reversible addition-Fragmentation Chain transfer (RAFT) step-growth polymerization is an emerging method that synergistically combines benefits of RAFT polymerization (functional group and user-friendly nature) and step-growth polymerization (versatility of the polymer...

Demonstrated is the successful A2 + B2 RAFT step-growth polymerization of bis-acrylamides. The synthesized poly(acrylamides) can be degraded by simply adding excess ethanolamine or PBu3.

RAFT step-growth polymerization was previously demonstrated with monomers that bear low rate of homopropagation to favor the chain transfer process; by contrast, acrylates are known to be fast homopropagating monomers, thereby posing serious challenges for RAFT step-growth. Here, we identified a chain transfer agent (CTA) that rapidly yields single unit monomer inserted (SUMI) CTA adducts with a model acrylate monomer. Using a bifunctional reagent of this CTA, we successfully demonstrated RAFT step-growth polymerization with diacrylates, yielding linear polymer backbones. Furthermore, we achieved inclusion of functionality (i.e., disulfide) into RAFT step-growth polymer via a disulfide incorporated bifunctional CTA. Grafting from this backbone resulted in molecular brush polymers with cleavable functionality in each repeat unit of the backbone, allowing selective degradation to afford well-defined unimolecular species of two polymeric side chains. Given the wide selection of commercially available diacrylates, RAFT step-growth polymerization of diacrylates will further enable facile synthesis of complex architectures with modular backbones.

We report the polymerisation-induced self-assembly of poly(lauryl methacrylate)-graft-poly(benzyl methacrylate) copolymers during reversible addition-fragmentation chain transfer (RAFT) grafting from polymerisation in a backbone-selective solvent. Electron microscopy images suggest the phase separation of grafts to result in a network of spherical particles, due to the ability of the branched architecture to freeze chain entanglements and to bridge core domains. Small-angle X-ray scattering data suggest the architecture promotes the formation of multicore micelles, the core morphology of which transitions from spheres to worms, vesicles, and inverted micelles with increasing volume fraction of the grafts. A time-resolved SAXS study is presented to illustrate the formation of the inverted phase during a polymerisation. The grafted architecture gives access to unusual morphologies and provides exciting new handles for controlling the polymer structure and material properties.

Research on controlling cationic polymerization through a degenerative chain-transfer (DCT) process has primarily focused on the family of vinyl ether monomers. To expand the monomer scope, a bette...

An orthogonal combination of cationic and radical RAFT polymerizations is used to synthesize bottlebrush polymers using two distinct RAFT agents. Selective consumption of the first RAFT agent is used to control the cationic RAFT polymerization of a vinyl ether monomer bearing a secondary dormant RAFT agent, which subsequently allows side‐chain polymers to be grafted from the pendant RAFT agent by a radical‐mediated RAFT polymerization of a different monomer, thus completing the synthesis of bottlebrush polymers. The high efficiency and selectivity of the cationic and radical RAFT polymerizations allow both polymerizations to be conducted in one‐pot tandem without intermediate purification.\ud \ud

Some of the main applications for synthetic polymers are found within the medical field (drug delivery, diagnostics, medical imaging). However, preparation of these macromolecules has been limited to those with access to chemistry facilities, potentially delaying biological evaluation. In this work, we aim to address this issue by utilising equipment typically found within a biological lab to establish a protocol for the preparation of well-defined macromolecules via RAFT polymerisation. By exploiting thermocycler technology, libraries of homopolymers, block- and statistical-copolymers were prepared in under 5 minutes per heating cycle using acrylamide monomers with ultrafast RAFT polymerisation. All the polymers prepared had excellent molar mass control and could be generated in under 15 min.

Reversible-addition fragmentation chain transfer (RAFT) polymerization has been widely explored since its discovery due to its structural precision, versatility, and efficiency. However, the lack of tunability of the polymer backbone limits some applications. Herein, we synergistically combine RAFT and step-growth polymerization mechanisms, by employing a highly selective insertion process of a single monomer with a RAFT agent, to achieve RAFT step-growth polymerization. A unique feature of the RAFT step-growth polymers is that each backbone repeat unit bears a pendant RAFT agent, which can subsequently graft side chains in a second polymerization step and afford molecular brush polymers. Enabled by cleavable backbone functionality, we demonstrate transformation of the resulting brushlike polymers into linear chains of uniform size upon a stimulus.

The use of organic arsenicals in polymer chemistry and biomaterials science is limited despite the distinctive and versatile chemistry of arsenic. The interchangeable oxidation states of arsenic and the subsequent changes in chemical properties make it a promising candidate for redox-responsive materials. Thus, reversible addition–fragmentation chain transfer (RAFT) polymerization has been employed for the first time to synthesize thermoresponsive organic arsenical containing block copolymers. The polymers undergo simultaneous self-assembly and cross-linking, via the organic arsenical pendant groups, under reductive conditions (to reduce As(V) to As(III)) in the presence of polythiol reagents as cross-linkers. The formation of As–S bonds stabilizes the nanoparticles formed (Dh = 19–29 nm) and enables the stability and responsivity to oxidative stress of the particles, in aqueous and model biological solutions, to be tuned as a function of the number of thiols in the cross-linker or the [SH]/[As] stoichiometric ratio. The parent block copolymers and nanoparticles are nontoxic in vitro, and the tunable responsivity of these nanoparticles and the (bio)chemical activity of organic arsenical reagents could be advantageous for targeted drug delivery and the other bio(nano)medical applications. To the best our knowledge, this is the first time that arsenic–thiolate (As–S) bonding has been employed for stimuli-responsive cross-linking of polymeric nanoparticles.\ud \ud

Here arsenohydrogels are introduced for the first time as functional, tuneable and responsive hydrogels. The distinctive redox reactivity of arsenic has been exploited to crosslink high molecular weight (Mw > 300 kDa) polymeric arsenical scaffolds (PDMAmx-co-AsAmy) via reductive coupling of As(V) to As(I) which proceeds with the formation of As–As in the form of As(I)n homocycles. Soft arsenohydrogels (G′ ∼ 400–1700 Pa) that failed in compression tests at low compression and loading are formed when the polymer weight fraction is 2.5 wt%. When the polymer weight fraction is increased to 10 wt% the mechanical properties (stiffness and relaxation) of the arsenohydrogels are significantly improved and correlate with the mole fraction of arsenic (AsAm, y) present in the copolymer scaffolds. Furthermore, increasing the mole fraction of AsAm, reduces the degree of swelling and increases the stability of the gels against hydrolysis and oxidation of the As–As crosslinks. The functionality of the polymeric arsenical scaffolds has also been exploited to load arsenohydrogels with a model organic arsenical drug. The rate and degree of release of the loaded organic arsenical under simulated oxidative stress (H2O2) is inversely proportional to the mole fraction of arsenic in the original polymer scaffold. Finally, the polymeric arsenical scaffolds and the resulting arsenohydrogels have been shown to be non-toxic to NIH/3T3 (mouse fibroblast) and PC3 (human prostate cancer) cell lines. The properties and versitility of the arsenohydrogels alludes to their potential as a functional platform for biomaterials.

Cationic polymers have been widely employed as gene delivery vectors to help circumvent extracellular and intracellular delivery barriers. Among them, polyethylenimine (PEI) is the most commonly used despite its associated high cytotoxicity. PEI is typically obtained by uncontrolled ring opening polymerisation of aziridine, leading to either linear polymer architectures with only secondary amines, or branched architectures containing primary, secondary, and tertiary amines. In contrast, we describe the preparation of hyperbranched poly(ethylenimine-co-oxazoline) that contains only secondary amines, via a fast thiol–yne based one pot reaction. A small library of these compounds with varying PEI contents was then used to study the effect of polymer architecture on pDNA polyplex formation, cytotoxicity, and in vitro transfection studies with plasmid DNA. Hyperbranched poly(ethylenimine-co-oxazoline) was found to have reduced toxicity compared to the commercial standard 25 000 g mol−1 branched PEI (bPEI), with transfection efficiencies only slightly lower than its bPEI counterpart. Obtained results highlight the importance of the polymer architecture on the transfection efficiency of a gene delivery system, which was demonstrated by excluding other parameters such as molecular weight and charge density.

In this report we demonstrate methanol as an effective degenerative chain transfer agent to control the cationic polymerisation (initiated by triflic acid) of electron rich p-alkoxy-styrenes, such as p-methoxystyrene (p-MOS). Kinetic analysis revealed that an induction period occurs initially during which free cationic polymerisation occurs at low monomer conversion before proceeding through the pseudo first order rate, analogous to the RAFT mechanism. Ethanol and isopropanol also demonstrated excellent control (Đ > 1.30), however, with an apparent increase in experimental molecular weight. Furthermore, methanol controlled polymers were successfully chain extended upon sequential monomer addition, demonstrating the ‘livingness’ of the alcohol mediated cationic polymerisation.

Tumor hypoxia is considered as one of the major factors that limit the efficiency of photodynamic therapy (PDT), in which oxygen (O2) is needed to generate singlet oxygen (1O2) for cell destruction. Inspired by the excellent O2 carrying ability of perfluorocarbon molecules in artificial blood, we prepared a series of polymer micelles with a perfluorocarbon core to carry both photo-sensitizer and O2 to the tumor site, aiming to improve PDT efficiency. We found that the accelerated generation of 1O2 correlated with the increased perfluorocarbon amount in solution. In vitro cell study further showed that the new perfluorocarbon formulation not only improved the production of 1O2, leading to enhanced photodynamic therapy efficiency, but also significantly reduced cell toxicity when compared with the one without these perfluoro units. This work provides a new option for improving PDT efficiency with the new perfluorocarbon-incorporated nanoplatform.

The chemical reactivity of arsenic is diverse and distinctive depending upon its interchangeable oxidation states. Alkyl and aryl arsines (As(I)) exist as oligomers, composed of labile and redox responsive As–As bonds which have been exploited to form reactive and responsive materials. Here, the lability and reactivity of As(I)-functional polymeric nanoparticles, derived from thermoresponsive polymers P(PEGA20-b-[NIPAm80-n-co-AsAmn]) (P1, n = 4; P2, n = 11; P3, n = 15; P4, n = 18), is elaborated by in situ reaction with functional acetylenes, resulting in the formation of vinylene–arsine cross-linked polymeric arsenical nanoparticles (NPV–As). Spherical particles with sizes

Tumor hypoxia is considered as one of the major factors that limit the efficiency of photodynamic therapy (PDT), in which oxygen (O

Cationic and highly branched poly (trimethylphosphonium ethylacrylate-co-poly (ethylene glycol) acrylate) (p (TMPEA-co-PEGA)), and its ammonium equivalent, have been synthesised from post-polymerisation modification of a poly (bromo ethylacrylate-co-poly (ethylene glycol) acrylate) (p (BEA-co-PEGA)) precursor polymer produced using reversible addition fragmentation chain transfer (RAFT) polymerisation. The cationic polymers were evaluated for their ability to complex nucleic acids, their in vitro cytotoxicity and their GFP pDNA transfection efficiency. The results show RAFT copolymerisation of BEA and PEGA is a simple route to polyphosphoniums showing reduced cytotoxicities and higher transfection efficiencies than their polyammonium alternatives.

Block copolymers containing an organic arsenical (AsAm) have been synthesised by aqueous SET-LRP. The block copolymers are pH and thermoresponsive, forming nanoparticles in aqueous solution. Under reductive conditions the particles are stabilised through the formation of As–As bonds and stability can be tuned as a function of the AsAm monomer feed.

Living systems are driven by molecular machines that are composed of folded polypeptide chains, which are assembled together to form multimeric complexes. Although replicating this type of system is a longstanding goal in polymer science, the complexity the structures impose is synthetically very challenging, and generating synthetic polymers to mimic the process of these assemblies appears to be a more appealing approach. To this end, we report a linear polymer programmable for stepwise folding and assembly to higher order structures. To achieve this, a diblock copolymer composed of 4-acryloylmorpholine and glycerol acrylate was synthesised with high precision via reversible addition fragmentation chain transfer polymerisation (Đ < 1.22). Both intramolecular folding and intermolecular assembly were driven by a pH responsive cross-linker, benzene-1,4-diboronic acid. The resulting intramolecular folded single chain nanoparticles were well defined (Đ < 1.16) and successfully assembled into a multimeric structure (Dh = 245 nm) at neutral pH with no chain entanglement. The assembled multimer was observed with a spherical morphology as confirmed by TEM and AFM. These structures were capable of unfolding and disassembling either at low pH or in the presence of sugar. This work offers a new perspective for the generation of adaptive smart materials.

Poly(styrene-co-maleic anhydride) copolymers (PSMA) with controlled number and distribution of maleic anhydride (MAnh) units were synthesized by reversible addition–fragmentation chain transfer polymerization using chain-transfer agents (CTA) suitable for industrial scale processes. Linear- and star-shaped alternating PSMA polymers were prepared in a single-step synthesis, while a one-pot sequential chain-extension strategy was utilized to prepare diblock, multiblock, and multisite copolymer architectures. A library of grafted PSMAs with controlled density and distribution of side chains was achieved by the subsequent grafting of long aliphatic alcohol chains (C22) to the MAnh units. The influence of structure, composition, and long alkyl chain addition on PSMAs behavior in solution was studied with triple-detection size exclusion chromatography, while their thermal properties were examined by thermogravimetric analysis and differential scanning calorimetry. Overall, the side chain density and distribution did not impact the polymer conformations in solution (random coil); however, an effect on the molecular size (Rh) and structure density (intrinsic viscosity) were observed. The materials density was shown to be dependent on polymer architectures as lower intrinsic viscosity was observed for the star copolymer. All the materials had similar degradation points (400 °C), while the rate of degradation showed a dependence on the MAnh content and polymeric architecture. Ultimately, the grafting of long aliphatic side chains (crystalline) onto the PSMA backbone, even at low density, was shown to drastically change the microphase ordering, as all the grafted copolymers became semicrystalline. The difference of the crystallization temperature between low density multisite materials (Tc ≈ 8 °C) and the high density alternating material (Tc ≈ 40 °C) highlights the major importance of controlling copolymer composition and structure to tune material properties.

The in situ one-pot synthesis of peptide–polymer bioconjugates is reported. Conjugation occurs efficiently without the need for purification of dithiophenol maleimide functionalized polymer as a disulfide bridging agent for the therapeutic oxytocin. Conjugation of polymers was demonstrated to be reversible and to significantly improve the solution stability of oxytocin.

Multiblock copolymers (MBCPs) are an emerging class of materials that are becoming more accessible in recent years. However, to date there is still a lack of fundamental understanding of their physical properties. In particular, the glass transition temperature (Tg) which is known to be affected by the phase separation has not been well characterized experimentally. To this end, we report the first experimental study on the evolution of the Tgs and the corresponding phase separation of linear MBCPs with increasing number of blocks while keeping the overall degree of polymerization (DP) constant (DP = 200). Ethylene glycol methyl ether acrylate (EGMEA) and tert-butyl acrylate (tBA) were chosen as monomers for reversible addition-fragmentation chain transfer polymerization to synthesize MBCPs. We found the Tgs (as measured by differential scanning calorimetry) of EGMEA and tBA segments within the MCBPs to converge with increasing number of blocks and decreasing block length, correlating with the loss of the heterogeneity as observed from small-angle X-ray scattering (SAXS) analysis. The Tgs of the multiblock copolymers were also compared to the Tgs of the polymer blends of the corresponding homopolymers, and we found that Tgs of the polymer blends were similar to those of the respective homopolymers, as expected. SAXS experiments further demonstrated microphase separation of multiblock copolymers. This work demonstrates the enormous potential of multiblock architectures to tune the physical properties of synthetic polymers, by changing their glass transition temperature and their morphologies obtained from microphase separation, with domain sizes reaching under 10 nm.

Novel, well-defined organic arsenical homopolymers (Đ = 1.10-1.40) have been synthesised via RAFT polymerisation. Copolymerisation of the As-functional monomer with dimethylacrylamide yielded non-toxic polymer scaffolds (Đ ≈ 1.10) that could be manipulated in response to pH and undergo sequential reduction and substitution in the presence of thiols including cysteine and glutathione.

A range of glycopolymers composed of N-acetylgalactosamine were prepared via sequential Cu(I)-mediated polymerization and alkyne–azide click (CuAAC). The resulting polymers were shown, via multichannel surface plasmon resonance, to interact specifically with human macrophage galactose lectin (MGL; CD301) with high affinity (KD = 1.11 μM), but they did not bind to the mannose/fucose-selective human lectin dendritic-cell-specific intercellular adhesion molecule-3-grabbing nonintegrin (DC-SIGN; CD209). The effect of sugar ligand valency on the binding (so-called “glycoside cluster effect”) of poly(N-acetylgalactosamine) to MGL was investigated by varying first the polymer chain length (DP: 100, 64, 40, 23, 12) and then the architecture (4- and 8-arm star glycopolymers). The chain length did not have a significant effect on the binding to MGL (KD = 0.17–0.52 μM); however, when compared to a hepatic C-type lectin of a similar monosaccharide specificity, the asialoglycoprotein receptor (ASGPR), the binding affinity was more noticeably affected (KD = 0.37– 6.65 μM). These data suggest that known differences in the specific configuration/orientation of the carbohydrate recognition domains of MGL and ASGPR are responsible for the differences in binding observed between the different polymers of varied chain length and architecture. In the future, this model has the potential to be employed for the development of tissue-selective delivery systems.

Arsenic (As) exhibits diverse (bio)chemical reactivity and biological activity depending upon its oxidation state. However, this distinctive reactivity has been largely overlooked across many fields owing to concerns regarding the toxicity of arsenic. Recently, a clinical renaissance in the use of arsenicals, including organic arsenicals that are known to be less toxic than inorganic arsenicals, alludes to the possibility of broader acceptance and application in the field of polymer and biomaterials science. Here, current examples of polymeric/macromolecular arsenicals are reported to stimulate interest and highlight their potential as a novel platform for functional, responsive, and bioactive materials.

A microsurgical technique was used in performing anterior hepatic segmentectomy and pancreatoduodenectomy with reconstruction of the posterior hepatic artery in a 64-year-old man with widespread bile duct cancer from the intrapancreatic bile duct over the hepatic hilus. The anterior hepatic artery was obviously involved and the posterior hepatic artery just behind common hepatic duct was very close to the cancer. Microsurgical anastomosis between the remnant gastroduodenal artery and the posterior hepatic artery at the hepatic hilus made it possible to preserve the posterior segment of the liver and to perform a curative resection of the cancer. The patient had pyrexia because of suprahepatic abscess after the operation, but the abscess drained spontaneously. Postoperative arteriogram showed neither obstruction nor kinking of the reconstructed artery. He was discharged 2 months after surgery and has been enjoying a normal quality of life for 10 months since, with no signs of recurrence. It is suggested that a microsurgical technique is useful for performing an accurate anastomosis with good patency that allows not only a safe but also a highly curative operation for advanced bile duct cancer.

門脈枝塞栓術 (以下, PE) の効果と肝再生, 胆汁うっ滞下でのPEの効果につき検討した.家兎を用い, 部分肝切除, PE, 胆管結紮切離 (以下, BL), PE兼BLの各モデルを作成して検討した.肥大葉の3H-thymidine摂取率 (in vitro) はPE施行後は第1～7日に軽度上昇 (第7日: 229.1±72.0%) したが, 胆汁うっ滞による障害はなかった (205.4±52.5%).胆汁うっ滞下PE後の塞栓葉の萎縮は強く, 第14日非塞栓葉重量 (2.18±0.06%;対体重比) は胆汁非うっ滞下PE後 (1.14±0.04%) より高値だった.門脈枝塞栓および胆汁うっ滞のある部のin vitroでのDNA合成能は第5日に上昇 (356.2±68.2%) し, この部での再生のpotentialは高まっていると思われたが, bromodeoxy-uridine標識率 (in vivo) では再生は認めなかった.以上より部分胆管閉塞下でもPEの効果が期待でき, 塞栓巣の胆道ドレナージは非塞栓葉の再生の点からは, むしろ行わないほうが効果的である可能性が示唆された.

An attempt was made to optimize the rectal delivery of morphine, using cyclodextrins as an absorption enhancer and polysaccharides as a swelling hydrogel in Witepsol H-15 hollow-type suppositories, and this was tested in rabbits. alpha- and beta-cyclodextrins enhanced the rate and extent of bioavailability, the former being more effective; gamma-cyclodextrin decreased the absorption of morphine. The in-vitro membrane permeation studies using excised rectal sacs revealed that alpha-cyclodextrin enhanced the permeation of morphine through the rectal membranes. In contrast, viscous polysaccharides such as xanthan gum retarded the plasma morphine levels after the rectal administration, reflecting in-vitro slow release characteristics. A combination of alpha-cyclodextrin and xanthan gum produced sustained plasma profiles of morphine along with an increased rectal bioavailability (more than 4 times). From the observation of the distribution behavior of suppositories in rabbit rectum and colon after the rectal administration, xanthan gum was found to prevent the upward spread of the drug. Gross and microscopic observations suggested that this preparation was less irritating to the rectal mucosa.

Rabitts were used in these experiments. The spike potentials of the duodenum and choledocho-duodenal junction, the pressure in the common bile duct and the discharge of bile into the duodenum were recorded simultaneously in vivo.In the duodenum and the choledocho-duodenal junction, the rate of the rhythmic burst of spike potentials was 12-16 cycles/min.Similar results were obtained in both regions by the administrations of acetylcholine, prostigmine, bethanechol chloride, pilocarpine, atropine, adrenaline, morphine, cholecystokinin, secretin and amyl-nitrite. Thus, the action of the choledocho-duodenal junction is not independent of that of the duodenum.The pressure in the common bile duct rises simultaneously with the appearance of the spike potentials of the choledocho-duodenal junction.The discharge of bile into the duodenum was prevented by the muscle contraction of the choledocho-duodenal junction, when the bursts of spike potentials appeared. Bile was discharged into the duodenum by relaxation of the choledochoduodenal junction. When the pressure in the common bile duct was kept constant at about 80mm H2O, the discharge of bile into the duodenum was increased by the administration of C. C. K. during the resting intervals of the remarkable bursts of spike potentials.