In this work we use RAFT crosslinking polymerisation coupled with a Chemspeed robotic synthesis p... more In this work we use RAFT crosslinking polymerisation coupled with a Chemspeed robotic synthesis platform to optimise conditions to produce PDMS-arm star polymers by an arm-first strategy. The high-throughput polymer product library demonstrated relatively low dispersity (Đ ≈ 1.5), high monomer conversion (>85%) and consistent size (20–40 nm). Varying the crosslinker resulted in differences in polymer product profiles as identified by size exclusion chromatography, with larger linkers between methacrylate handles causing reduced Mn and multimodal distribution compared to ethylene glycol dimethacrylate, regardless of starting arm composition or Mn . Thermogravimetric analysis revealed greater thermal stability for star polymers with increased PDMS content.
Free radical polymerization with reversible addition±fragmentation chain transfer (RAFT polymeriz... more Free radical polymerization with reversible addition±fragmentation chain transfer (RAFT polymerization) is discussed with a view to answering the following questions: (a) How living is RAFT polymerization? (b) What controls the activity of thiocarbonylthio compounds in RAFT polymerization? (c) How do rates of polymerization differ from those of conventional radical polymerization? (d) Can RAFT agents be used in emulsion polymerization? Retardation, observed when high concentrations of certain RAFT agents are used and in the early stages of emulsion polymerization, and how to overcome it by appropriate choice of reaction conditions, are considered in detail. Examples of the use of thiocarbonylthio RAFT agents in emulsion and miniemulsion polymerization are provided.
Macromolecular Chemistry and Physics, Jul 26, 2023
Reversible addition–fragmentation chain transfer polymerization (RAFT) is a popular method for th... more Reversible addition–fragmentation chain transfer polymerization (RAFT) is a popular method for the synthesis of well‐defined macromolecules, but its sensitivity to oxygen is a major limitation for many industrial applications. Recent research has focused on developing strategies to confer oxygen tolerance onto RAFT polymerization, eliminating the need for deoxygenation steps and allowing for simpler reaction conditions. This minireview highlights several promising approaches to achieve oxygen tolerance in RAFT polymerization, including enzyme‐mediated, alkylborane‐initiated, and photomediated methods. The potential applications of oxygen‐tolerant RAFT polymerization are also discussed, demonstrating the promise for significant advances in large‐scale industrial polymer synthesis.
4,4′-Azobis(4-cyanopentanoic acid) comprises two diastereoisomers that decompose at different rat... more 4,4′-Azobis(4-cyanopentanoic acid) comprises two diastereoisomers that decompose at different rates in aqueous media [racemic-ACPA: Ea = 132.2 kJ mol−1, A = 4.76 × 1015 s−1, 10 h t1/2 = 65 °C; meso-ACPA: Ea = 131.7 kJ mol−1, A = 2.98 × 1015 s−1,10 h t1/2 = 67 °C], but both decompose at a similar though faster rate in N,N-dimethylformamide [Ea = 134.0 kJ mol−1, A = 1.26 × 1016 s−1,10 h t1/2 = 63 °C]. The major product of decomposition in both aqueous and organic media is the ketenimine formed by C–N coupling of the radicals formed, which is irreversibly trapped as an amide in aqueous media.
Abstract A well-defined AB diblock copolymer of 2-vinyl-4,4-dimethylazlactone (VDA) and N,N-dimet... more Abstract A well-defined AB diblock copolymer of 2-vinyl-4,4-dimethylazlactone (VDA) and N,N-dimethylacrylamide (DMA) was generated by reversible addition-fragmentation chain transfer (RAFT) radical polymerization. The VDA-DMA diblock copolymer was reacted with 2-(methylthio)ethylamine (MTEA) and 3-(methylthio)propylamine (MTPA) to yield two novel thioether functional diblock copolymers whose structure was confirmed using 1H NMR and FTIR spectroscopy. Both diblock copolymers formed micelles (20–30 nm) in aqueous media as confirmed by dynamic light scattering (DLS) and transmission electron microscopy. The self-assembled micelles were loaded with Nile Red, a model hydrophobic drug to study their ROS-triggered release mechanism. On addition of hydrogen peroxide (H2O2), the most common ROS species, the hydrophobic thioether core of these micelles oxidized, and both diblock copolymers became more hydrophilic. This triggered their disassembly and subsequent cargo release as characterized by UV–visible spectroscopy. The Nile Red loaded micelles demonstrated similar in-vitro ROS-mediated release when exposed to endogenous oxidants in a model inflammation environment simulated by the presence of activated macrophages. The responsive nanomaterials developed in this article have promising potential as drug carriers in applications where ROS-triggered delivery of cargo is required such as in inflammatory conditions.
Triblock copolymers containing an ionophilic polymerized ionic liquid block, sandwiched between t... more Triblock copolymers containing an ionophilic polymerized ionic liquid block, sandwiched between two ionophobic polystyrene blocks, were investigated as solid polymer electrolytes (SPE) to simultaneously provide mechanically robust, free-standing membranes with high lithium conductivity and an optimized electrolyte composition. The conductivity reached 8 × 10–5 S cm–1 and 6.5 × 10–4 S cm–1 at 30 and 80 °C, respectively, with an anodic stability above 4.5 V. Highly stable Li metal symmetric cycling was demonstrated, with an overpotential of 130 mV for over 300 h at 50 °C at a current density of 0.5 mA cm–2/0.5 mAh cm–2. Attempts were also made to incorporate the SPE as the binder in an LMO cathode formulation. The best cell performance, however, was obtained when substituting the SPE in the LMO cathode formulation with a PMA solid-state gel electrolyte, resulting in a high-performance solid-state Li|polymer eletrolyte|LMO device with stable cycling at C/5, and an impressive capacity retention (i.e., 105 mAh g–1 after 150 cycles at 0.1 mA cm–2) with a Coulombic efficiency around 99.4%.
Radiant star nanoparticle (RSN) prodrugs were synthesized in a two-step process by first homopoly... more Radiant star nanoparticle (RSN) prodrugs were synthesized in a two-step process by first homopolymerizing RAFT transmers followed by copolymerization from the hyperbranched polymer core. Two trithiocarbonate-based transmers were synthesized containing either alkyl ester or acetal groups linking the polymerizable methacrylate group to the chain transfer agent (CTA). RAFT polymerization from the homopolymerized transmer cores yielded RSNs with linear polymer chains connected to hyperbranched cores. Hydrolysis studies conducted over a period of 30 days at 37 °C in acetate buffer showed that RSNs prepared from alkyl ester linked cores remained stable while acetal linked cores exhibited a progressive degradation into linear polymers over the same period. Macrophage targeting RSN prodrugs containing the antibiotic ciprofloxacin and receptor-targeting mannose residues were synthesized directly via RAFT polymerization of the prodrug and mannose monomers. Hydrolysis studies conducted in human serum showed that the RSNs released the covalently linked ciprofloxacin significantly faster than diblock copolymer micelles but moderately slower than soluble copolymers with comparable compositions. Flow cytometry showed substantially higher macrophage binding by the mannose-targeted RSNs while in vivo biocompatibility experiments showed no differences relative to phosphate buffer treated negative controls.
Journal of The Electrochemical Society, Jan 5, 2020
In this work, we present a polymerized ionic liquid block copolymer (PBCP) film where relevant pr... more In this work, we present a polymerized ionic liquid block copolymer (PBCP) film where relevant properties such as ionic conductivity and electrochemical parameters are tailored by using a ternary system comprised of poly(styrene-b-1-((2-acryloyloxy) ethyl)−3-butylimidazolium bis(tri-fluoromethanesulfonyl)imide), LiFSI salt and ethylene carbonate (EC) as a cosolvent. It was found that EC efficiently decreases the glass transition temperature of the ionic block, resulting in an improved ionic conductivity and efficient platting/stripping of lithium. By using an optimal ratio of EC/LiFSI at relatively high LiFSI amount, Li|Li symmetrical cells at 50°C show an overpotential as low as 70 mV at 0.1 mA.cm −2 along with a high lithium transport number of 0.56 (t Li +). All-solid-state full cells based on lithium iron phosphate cathode paired with a lithium metal anode reveal a rather stable cycling at both 50°C and 70°C. A negligible capacity fading is observed up to 30 cycles where a specific capacity as high as 161 mAh.g −1 is achieved with a coulombic efficiency of 99.9%. Thus, this work demonstrates an important pathway for tailoring the properties of solid state polymer electrolytes for emerging and specially designed block copolymer architectures comprising domains that give both excellent ionic conduction along with desirable mechanical properties.
Polymerization induced self-assembly (PISA) in acetic acid was employed to polymerize the hydroph... more Polymerization induced self-assembly (PISA) in acetic acid was employed to polymerize the hydrophilic sulfobetaine monomer 2-(N-3-sulfopropyl-N,N-dimethyl ammonium)ethyl methacrylate (DMAPS) and the hydrophobic monomer lauryl methacrylate (LMA). Polymerizations were conducted from a macro chain transfer agent (macro-CTA) consisting of 66% 2-hydroxyethyl methacrylate (HEMA) and 33% poly(ethylene glycol) methyl ether methacrylate FW ∼ 300 Da (O300). A degree of polymerization (DP) of 50 was targeted for the macro-CTA in order to yield diblock copolymers with significantly larger 2nd blocks. From the poly(HEMA-co-O300) macro-CTA, diblock copolymers of poly[(HEMA-co-O300)-b-(DMAPS)] and poly[(HEMA-co-O300)-b-(LMA)] were grown via PISA in acetic acid. In order to maintain colloidal stability, it was necessary to conduct PISA of DMAPS at 10 wt% monomer, while LMA polymerizations maintained stability at 20 wt% monomer. Mnvs. conversion plots for both DMAPS and LMA show linear increases in molecular weight over the course of the polymerizations. Analysis of the molecular weight distributions revealed a progressive narrowing throughout the polymerization from an initial bimodal state. Copolymers of DMAPS and LMA were also synthesized over a large range of comonomer feed ratios. These materials show composition-dependent sizes in buffered solutions between 11 nm for the copolymer containing 80% by mol DMAPS to 75 nm for the copolymer containing 40 mol% DMAPS. PISA in acetic acid was then used to prepare copolymers of DMAPS with a range of hydrophobic polymerizable prodrug monomers as well as a polymerizable peptide macromonomer. The resultant copolymers had narrow molecular weight distributions and were readily soluble in saline solutions.
Clinical studies have validated that antiretroviral (ARV) drugs can serve as an HIV pre-exposure ... more Clinical studies have validated that antiretroviral (ARV) drugs can serve as an HIV pre-exposure prophylactic (PrEP) strategy. Dosing adherence remains a crucial factor determining the final efficacy outcomes, and both long-acting implants and injectable depot systems are being developed to improve patient adherence. Here, we describe an injectable depot platform that exploits a new mechanism for both formation and controlled release. The depot is a polymeric prodrug synthesized from monomers that incorporate an ARV drug tenofovir alafenamide (TAF) with degradable linkers that can be designed to control release rates. The prodrug monomers are synthetically incorporated into homopolymer or block designs that exhibit high drug weight percent (wt%) and also are hydrophobized in these prodrug segments to drive depot formation upon injection. Drug release converts those monomers to more hydrophilic pendant groups via linker cleavage, and as this drug release proceeds, the polymer chains losing hydrophobicity are then disassociated from the depot and released over time to provide a depot dissolution mechanism. We show that long-acting TAF depots can be designed as block copolymers or as homopolymers. They can also be designed with different linkers, for example with faster or slower degrading p-hydroxybenzyloxycarbonyl (Benzyl) and ethyloxycarbonyl (Alkyl) linkers, respectively. Diblock designs of p(glycerol monomethacrylate)-b-p(Alkyl-TAF-methacrylate) and p(glycerol monomethacrylate)-b-p(Benzyl-TAF-methacrylate) were first characterized in a mouse subcutaneous injection model. The alkylcarbamate linker design (TAF 51 wt%) showed excellent sustained release profiles of the key metabolite tenofovir (TFV) in skin and plasma over a 50-day period. Next, the homopolymer design with a high TAF drug wt% of 73% was characterized in the same model. The homopolymer depots with p(Alkyl-TAFMA) exhibited sustained TFV and TAF release profiles in skin and blood over 60 days, and TFV-DP concentrations in peripheral blood mononuclear cells (PBMC) were found to be at least 10-fold higher than the clinically suggested minimally EC90 protective concentration of 24 fmol/106 cells. These are the first reports of sustained parent TAF dosing observed in mouse and TFV-DP in mouse PBMC. IVIS imaging of rhodamine labeled homopolymer depots showed that degradation and release of the depot coincided with the sustained TAF release. Finally, these polymers showed excellent stability in accelerated stability studies over a six-month time period, and exceptional solubility of over 700 mg/mL in the DMSO formulation solvent. The homopolymer designs have a drug reservoir potential of well over a year at mg/day dosing and may not require cold chain storage for global health and developed world long-acting drug delivery applications.
A goal in applying electrochemical methods to reversible addition−fragmentation chain transfer (R... more A goal in applying electrochemical methods to reversible addition−fragmentation chain transfer (RAFT) polymerization is to use electrochemical reduction to activate RAFT agents (SC(Z)S-R) to also act as initiators. The use of a mediator can limit side reactions that would otherwise inhibit polymerization. In this work, we present the use of anthraquinone (AQ) to mediate the electrochemical reduction of a trithiocarbonate RAFT agent, 4-cyano-4-(((dodecylthio)carbonothioyl)thio)pentanoic acid, and thereby initiate RAFT polymerization of methyl methacrylate (MMA). In a representative eRAFT reaction conducted in DMSO with a target degree of polymerization (DP) of 100, conversion reached 67% in 24 h at ambient temperature, with Đ = 1.19. The effect of reaction conditions on polymerization was studiedin general, the conversion rate was found to decrease as target DP increases. Dispersity increases as (i) target DP increases and (ii) mediator concentration increases. The livingness of AQ-mediated eRAFT polymerization was confirmed by eRAFT chain extension with MMA and by thermally initiated RAFT with styrene to form a block copolymer. AQ-mediated eRAFT was found to be unsuitable for polymerization of monosubstituted monomers (styrene, butyl acrylate, N,N-dimethylacrylamide, and N-vinylpyrrolidone). These results support the hypothesis that mediated electrochemical reduction of RAFT agents can yield an initiating species (R •), although polymerization is strongly dependent on diffusion and fragmentation kinetics.
3D bioprinting is a recent technique that can create complex cell seeded scaffolds and therefore ... more 3D bioprinting is a recent technique that can create complex cell seeded scaffolds and therefore holds great promise to revolutionize the biomedical sector by combining materials and structures that more closely mimic the 3D cell environment in tissues. The most commonly used biomaterials for printing are hydrogels, however, many of the hydrogels used still present issues of printability, stability, or poor cell-material interactions. We propose that bioinks with intrinsic self-assembling and shear thinning properties, such as xanthan gum, can be methacrylated (XGMA) and combined with a bio-functional material such as gelatin methacryloyl (GelMa) to create a stable, cell-interactive bioink with improved properties for 3D bioprinting. These biomaterials have reduced viscosity under high shear and recover their viscosity rapidly after the shear is removed, retaining their shape, which translates to easier extrusion whilst maintaining accurate fidelity after printing. This was confirme...
Insulin has been used to treat diabetes for almost 100 years; yet, current rapid-acting insulin f... more Insulin has been used to treat diabetes for almost 100 years; yet, current rapid-acting insulin formulations do not have sufficiently fast pharmacokinetics to maintain tight glycemic control at mealtimes. Dissociation of the insulin hexamer, the primary association state of insulin in rapid-acting formulations, is the rate-limiting step that leads to delayed onset and extended duration of action. A formulation of insulin monomers would more closely mimic endogenous postprandial insulin secretion, but monomeric insulin is unstable in solution using present formulation strategies and rapidly aggregates into amyloid fibrils. Here, we implement high-throughput–controlled radical polymerization techniques to generate a large library of acrylamide carrier/dopant copolymer (AC/DC) excipients designed to reduce insulin aggregation. Our top-performing AC/DC excipient candidate enabled the development of an ultrafast-absorbing insulin lispro (UFAL) formulation, which remains stable under stressed aging conditions for 25 ± 1 hours compared to 5 ± 2 hours for commercial fast-acting insulin lispro formulations (Humalog). In a porcine model of insulin-deficient diabetes, UFAL exhibited peak action at 9 ± 4 min, whereas commercial Humalog exhibited peak action at 25 ± 10 min. These ultrafast kinetics make UFAL a promising candidate for improving glucose control and reducing burden for patients with diabetes.
The molecular weight distribution (MWD) has a significant impact on the properties of polymeric m... more The molecular weight distribution (MWD) has a significant impact on the properties of polymeric materials; however, the characterization of polymer MWDs has been limited to statistical parameters such as the number average molecular weight (Mn) and dispersity (Đ). These parameters do not fully express the features of polymer MWDs, thus limiting the ability to rationally design complex polymeric materials with tailored MWDs. Herein, a platform for the design and synthesis of arbitrary polymer MWDs is developed and experimentally validated. The platform is based on the description of polymer MWDs as a mathematical function, rather than individual statistical parameters. As such, the complete shape of arbitrary polymer MWDs can be designed using developed software. The software requires only a calibration using model monomodal MWDs directly obtained from GPC to design theoretical MWD. Using this platform in conjunction with a flow-mediated polymerization approach, a range of arbitrarily shaped polymer MWDs were successfully designed and prepared. Finally, complex triblock copolymer mixtures with tailored compositions and overall MWD were fabricated via one-pass flow-mediated polymerization using this computer-guided approach.
Electrochemical activation of thiocarbonylthio reversible addition−fragmentation chain transfer (... more Electrochemical activation of thiocarbonylthio reversible addition−fragmentation chain transfer (RAFT) agents (S=C(Z)S-R) is explored as a potential method for initiating RAFT polymerization under mild conditions without producing initiator-derived byproducts. Herein we apply cyclic voltammetry to establish a predominant reduction mechanism, where electrochemical reduction is coupled to an irreversible first-order chemical reaction. Structure-dependent trends in cyclic voltammograms (CVs), and comparison to absorption spectra, clarify the role of R- and Z-groups in determining reduction processes. The major reduction peak moves to more cathodic potentials in the series dithiobenzoates > trithiocarbonates > heteroaromatic dithiocarbamates > xanthates ∼ N-alkyl-N-aryldithiocarbamates, due to the Z- group influence on thiocarbonyl bond reactivity. More active (electron-withdrawing, radical stabilizing) R-groups shift the reduction peak anodically, in part due to their influence on the rate of the coupled chemical reaction. Analysis of CVs across a range of scan rates revealed that kinetic control over the reduction mechanism is influenced by both the charge transfer rate and chemical reaction rate.
Electrospun ultrafine fibres prepared using a blend of poly(lactide-co-glycolide) (PLGA) and brom... more Electrospun ultrafine fibres prepared using a blend of poly(lactide-co-glycolide) (PLGA) and bromine terminated poly(ʟ-lactide) (PLA-Br), were surface modified using surface-initiated (SI) Cu(0) mediated polymerization. Copolymers based on N-acryloxysuccinimide (NAS) and a low fouling monomer (either N,N-dimethylacrylamide (DMA), N-(2-hydroxypropyl)acrylamide (HPA) or N-acryloylmorpholine (NAM)) were grafted from the fibre surface to impart surface functionality and to reduce non-specific protein adsorption. Inclusion of the functional NAS monomer facilitated the conjugation of a non-bioactive cyclic RAD peptide and a bioactive cyclic RGD peptide, the latter expected to facilitate cell adhesion through its affinity for the α v β 3 integrin receptor. A detailed analysis of the surface of the electrospun fibre scaffolds in non-grafted form compared to the surface functionalized state is presented. Characteristic amino acid peaks are observed for both conjugated RGD and RAD peptides. Cell culture experiments confirmed cell specific attachment mediated through the presence of the bioactive RGD peptide mainly at high surface density.
Electrospun ultrafine fibres prepared using a blend of poly(lactide-co-glycolide) (PLGA) and brom... more Electrospun ultrafine fibres prepared using a blend of poly(lactide-co-glycolide) (PLGA) and bromine terminated poly(ʟ-lactide) (PLA-Br), were surface modified using surface-initiated (SI) Cu(0) mediated polymerization. Copolymers based on N-acryloxysuccinimide (NAS) and a low fouling monomer (either N,N-dimethylacrylamide (DMA), N-(2-hydroxypropyl)acrylamide (HPA) or N-acryloylmorpholine (NAM)) were grafted from the fibre surface to impart surface functionality and to reduce non-specific protein adsorption. Inclusion of the functional NAS monomer facilitated the conjugation of a non-bioactive cyclic RAD peptide and a bioactive cyclic RGD peptide, the latter expected to facilitate cell adhesion through its affinity for the α v β 3 integrin receptor. A detailed analysis of the surface of the electrospun fibre scaffolds in non-grafted form compared to the surface functionalized state is presented. Characteristic amino acid peaks are observed for both conjugated RGD and RAD peptides. Cell culture experiments confirmed cell specific attachment mediated through the presence of the bioactive RGD peptide mainly at high surface density.
We report on two important advances in radical polymerization with reversible addition–fragmentat... more We report on two important advances in radical polymerization with reversible addition–fragmentation chain transfer (RAFT polymerization). (1) Electrochemically initiated emulsion RAFT (eRAFT) polymerization provides rapid polymerization of styrene at ambient temperature. The electrolytes and mediators required for eRAFT are located in the aqueous continuous phase separate from the low-molar-mass-dispersity macroRAFT agent mediator and product in the dispersed phase. Use of a poly(N,N-dimethylacrylamide)-block-poly(butyl acrylate) amphiphilic macroRAFT agent composition means that no added surfactant is required for colloidal stability. (2) Direct photoinitiated (visible light) RAFT polymerization provides an effective route to high-purity, low-molar-mass-dispersity, side chain liquid-crystalline polymers (specifically, poly(4-biphenyl acrylate)) at high monomer conversion. Photoinitiation gives a product free from low-molar-mass initiator-derived by-products and with minimal termination. The process is compared with thermal dialkyldiazene initiation in various solvents. Numerical simulation was found to be an important tool in discriminating between the processes and in selecting optimal polymerization conditions.
Composite coatings are considered a promising approach to tailor the biointerface between a (impl... more Composite coatings are considered a promising approach to tailor the biointerface between a (implantable) biomaterial and adhering/surrounding cells or tissue. In this context, composite coatings assembled using a polymer matrix with embedded drug deposits are particularly interesting due to the advanced control over cargo loading, retention and release. Herein, we compare the assembly of such films consisting of various types of liposomes as subunits within a polymer film of either polydopamine (PDA) or, for the first time, tannic acid (TA) as an alternative. It is found that TA is a suitable capping layer for liposome-coated substrates which allows for post-modification. The composite coatings are suitable for supporting hepatocyte adhesion depending on the terminating polymer layer. Furthermore, incorporation of cholesterol–dopamine (Ch-DA) conjugates into the zwitterionic liposomes increases the numbers of deposited subunits. Finally, cytotoxic paclitaxel is loaded into the liposomes and delivered to the adhering hepatocytes. The capability of reducing hepatocyte adhesion to the composite coating varied. Composite coatings consisting of negatively charged liposomes with Ch-DA and a PDA capping layer are found to be most efficient after 24 and 48 h. Taken together, this fundamental comparison of different composite coatings illustrates the excellent opportunities to engineer the biological response towards the application in mind.
Clinical studies have validated that antiretroviral (ARV) drugs can serve as an HIV pre-exposure ... more Clinical studies have validated that antiretroviral (ARV) drugs can serve as an HIV pre-exposure prophylactic (PrEP) strategy. Dosing adherence remains a crucial factor determining the final efficacy outcomes, and both long-acting implants and injectable depot systems are being developed to improve patient adherence. Here, we describe an injectable depot platform that exploits a new mechanism for both formation and controlled release. The depot is a polymeric prodrug synthesized from monomers that incorporate an ARV drug tenofovir alafenamide (TAF) with degradable linkers that can be designed to control release rates. The prodrug monomers are synthetically incorporated into homopolymer or block designs that exhibit high drug weight percent (wt%) and also are hydrophobized in these prodrug segments to drive depot formation upon injection. Drug release converts those monomers to more hydrophilic pendant groups via linker cleavage, and as this drug release proceeds, the polymer chains losing hydrophobicity are then disassociated from the depot and released over time to provide a depot dissolution mechanism. We show that long-acting TAF depots can be designed as block copolymers or as homopolymers. They can also be designed with different linkers, for example with faster or slower degrading p-hydroxybenzyloxycarbonyl (Benzyl) and ethyloxycarbonyl (Alkyl) linkers, respectively. Diblock designs of p(glycerol monomethacrylate)-b-p(Alkyl-TAF-methacrylate) and p(glycerol monomethacrylate)-b-p(Benzyl-TAF-methacrylate) were first characterized in a mouse subcutaneous injection model. The alkylcarbamate linker design (TAF 51 wt%) showed excellent sustained release profiles of the key metabolite tenofovir (TFV) in skin and plasma over a 50-day period. Next, the homopolymer design with a high TAF drug wt% of 73% was characterized in the same model. The homopolymer depots with p(Alkyl-TAFMA) exhibited sustained TFV and TAF release profiles in skin and blood over 60 days, and TFV-DP concentrations in peripheral blood mononuclear cells (PBMC) were found to be at least 10-fold higher than the clinically suggested minimally EC90 protective concentration of 24 fmol/106 cells. These are the first reports of sustained parent TAF dosing observed in mouse and TFV-DP in mouse PBMC. IVIS imaging of rhodamine labeled homopolymer depots showed that degradation and release of the depot coincided with the sustained TAF release. Finally, these polymers showed excellent stability in accelerated stability studies over a six-month time period, and exceptional solubility of over 700 mg/mL in the DMSO formulation solvent. The homopolymer designs have a drug reservoir potential of well over a year at mg/day dosing and may not require cold chain storage for global health and developed world long-acting drug delivery applications.
In this work we use RAFT crosslinking polymerisation coupled with a Chemspeed robotic synthesis p... more In this work we use RAFT crosslinking polymerisation coupled with a Chemspeed robotic synthesis platform to optimise conditions to produce PDMS-arm star polymers by an arm-first strategy. The high-throughput polymer product library demonstrated relatively low dispersity (Đ ≈ 1.5), high monomer conversion (>85%) and consistent size (20–40 nm). Varying the crosslinker resulted in differences in polymer product profiles as identified by size exclusion chromatography, with larger linkers between methacrylate handles causing reduced Mn and multimodal distribution compared to ethylene glycol dimethacrylate, regardless of starting arm composition or Mn . Thermogravimetric analysis revealed greater thermal stability for star polymers with increased PDMS content.
Free radical polymerization with reversible addition±fragmentation chain transfer (RAFT polymeriz... more Free radical polymerization with reversible addition±fragmentation chain transfer (RAFT polymerization) is discussed with a view to answering the following questions: (a) How living is RAFT polymerization? (b) What controls the activity of thiocarbonylthio compounds in RAFT polymerization? (c) How do rates of polymerization differ from those of conventional radical polymerization? (d) Can RAFT agents be used in emulsion polymerization? Retardation, observed when high concentrations of certain RAFT agents are used and in the early stages of emulsion polymerization, and how to overcome it by appropriate choice of reaction conditions, are considered in detail. Examples of the use of thiocarbonylthio RAFT agents in emulsion and miniemulsion polymerization are provided.
Macromolecular Chemistry and Physics, Jul 26, 2023
Reversible addition–fragmentation chain transfer polymerization (RAFT) is a popular method for th... more Reversible addition–fragmentation chain transfer polymerization (RAFT) is a popular method for the synthesis of well‐defined macromolecules, but its sensitivity to oxygen is a major limitation for many industrial applications. Recent research has focused on developing strategies to confer oxygen tolerance onto RAFT polymerization, eliminating the need for deoxygenation steps and allowing for simpler reaction conditions. This minireview highlights several promising approaches to achieve oxygen tolerance in RAFT polymerization, including enzyme‐mediated, alkylborane‐initiated, and photomediated methods. The potential applications of oxygen‐tolerant RAFT polymerization are also discussed, demonstrating the promise for significant advances in large‐scale industrial polymer synthesis.
4,4′-Azobis(4-cyanopentanoic acid) comprises two diastereoisomers that decompose at different rat... more 4,4′-Azobis(4-cyanopentanoic acid) comprises two diastereoisomers that decompose at different rates in aqueous media [racemic-ACPA: Ea = 132.2 kJ mol−1, A = 4.76 × 1015 s−1, 10 h t1/2 = 65 °C; meso-ACPA: Ea = 131.7 kJ mol−1, A = 2.98 × 1015 s−1,10 h t1/2 = 67 °C], but both decompose at a similar though faster rate in N,N-dimethylformamide [Ea = 134.0 kJ mol−1, A = 1.26 × 1016 s−1,10 h t1/2 = 63 °C]. The major product of decomposition in both aqueous and organic media is the ketenimine formed by C–N coupling of the radicals formed, which is irreversibly trapped as an amide in aqueous media.
Abstract A well-defined AB diblock copolymer of 2-vinyl-4,4-dimethylazlactone (VDA) and N,N-dimet... more Abstract A well-defined AB diblock copolymer of 2-vinyl-4,4-dimethylazlactone (VDA) and N,N-dimethylacrylamide (DMA) was generated by reversible addition-fragmentation chain transfer (RAFT) radical polymerization. The VDA-DMA diblock copolymer was reacted with 2-(methylthio)ethylamine (MTEA) and 3-(methylthio)propylamine (MTPA) to yield two novel thioether functional diblock copolymers whose structure was confirmed using 1H NMR and FTIR spectroscopy. Both diblock copolymers formed micelles (20–30 nm) in aqueous media as confirmed by dynamic light scattering (DLS) and transmission electron microscopy. The self-assembled micelles were loaded with Nile Red, a model hydrophobic drug to study their ROS-triggered release mechanism. On addition of hydrogen peroxide (H2O2), the most common ROS species, the hydrophobic thioether core of these micelles oxidized, and both diblock copolymers became more hydrophilic. This triggered their disassembly and subsequent cargo release as characterized by UV–visible spectroscopy. The Nile Red loaded micelles demonstrated similar in-vitro ROS-mediated release when exposed to endogenous oxidants in a model inflammation environment simulated by the presence of activated macrophages. The responsive nanomaterials developed in this article have promising potential as drug carriers in applications where ROS-triggered delivery of cargo is required such as in inflammatory conditions.
Triblock copolymers containing an ionophilic polymerized ionic liquid block, sandwiched between t... more Triblock copolymers containing an ionophilic polymerized ionic liquid block, sandwiched between two ionophobic polystyrene blocks, were investigated as solid polymer electrolytes (SPE) to simultaneously provide mechanically robust, free-standing membranes with high lithium conductivity and an optimized electrolyte composition. The conductivity reached 8 × 10–5 S cm–1 and 6.5 × 10–4 S cm–1 at 30 and 80 °C, respectively, with an anodic stability above 4.5 V. Highly stable Li metal symmetric cycling was demonstrated, with an overpotential of 130 mV for over 300 h at 50 °C at a current density of 0.5 mA cm–2/0.5 mAh cm–2. Attempts were also made to incorporate the SPE as the binder in an LMO cathode formulation. The best cell performance, however, was obtained when substituting the SPE in the LMO cathode formulation with a PMA solid-state gel electrolyte, resulting in a high-performance solid-state Li|polymer eletrolyte|LMO device with stable cycling at C/5, and an impressive capacity retention (i.e., 105 mAh g–1 after 150 cycles at 0.1 mA cm–2) with a Coulombic efficiency around 99.4%.
Radiant star nanoparticle (RSN) prodrugs were synthesized in a two-step process by first homopoly... more Radiant star nanoparticle (RSN) prodrugs were synthesized in a two-step process by first homopolymerizing RAFT transmers followed by copolymerization from the hyperbranched polymer core. Two trithiocarbonate-based transmers were synthesized containing either alkyl ester or acetal groups linking the polymerizable methacrylate group to the chain transfer agent (CTA). RAFT polymerization from the homopolymerized transmer cores yielded RSNs with linear polymer chains connected to hyperbranched cores. Hydrolysis studies conducted over a period of 30 days at 37 °C in acetate buffer showed that RSNs prepared from alkyl ester linked cores remained stable while acetal linked cores exhibited a progressive degradation into linear polymers over the same period. Macrophage targeting RSN prodrugs containing the antibiotic ciprofloxacin and receptor-targeting mannose residues were synthesized directly via RAFT polymerization of the prodrug and mannose monomers. Hydrolysis studies conducted in human serum showed that the RSNs released the covalently linked ciprofloxacin significantly faster than diblock copolymer micelles but moderately slower than soluble copolymers with comparable compositions. Flow cytometry showed substantially higher macrophage binding by the mannose-targeted RSNs while in vivo biocompatibility experiments showed no differences relative to phosphate buffer treated negative controls.
Journal of The Electrochemical Society, Jan 5, 2020
In this work, we present a polymerized ionic liquid block copolymer (PBCP) film where relevant pr... more In this work, we present a polymerized ionic liquid block copolymer (PBCP) film where relevant properties such as ionic conductivity and electrochemical parameters are tailored by using a ternary system comprised of poly(styrene-b-1-((2-acryloyloxy) ethyl)−3-butylimidazolium bis(tri-fluoromethanesulfonyl)imide), LiFSI salt and ethylene carbonate (EC) as a cosolvent. It was found that EC efficiently decreases the glass transition temperature of the ionic block, resulting in an improved ionic conductivity and efficient platting/stripping of lithium. By using an optimal ratio of EC/LiFSI at relatively high LiFSI amount, Li|Li symmetrical cells at 50°C show an overpotential as low as 70 mV at 0.1 mA.cm −2 along with a high lithium transport number of 0.56 (t Li +). All-solid-state full cells based on lithium iron phosphate cathode paired with a lithium metal anode reveal a rather stable cycling at both 50°C and 70°C. A negligible capacity fading is observed up to 30 cycles where a specific capacity as high as 161 mAh.g −1 is achieved with a coulombic efficiency of 99.9%. Thus, this work demonstrates an important pathway for tailoring the properties of solid state polymer electrolytes for emerging and specially designed block copolymer architectures comprising domains that give both excellent ionic conduction along with desirable mechanical properties.
Polymerization induced self-assembly (PISA) in acetic acid was employed to polymerize the hydroph... more Polymerization induced self-assembly (PISA) in acetic acid was employed to polymerize the hydrophilic sulfobetaine monomer 2-(N-3-sulfopropyl-N,N-dimethyl ammonium)ethyl methacrylate (DMAPS) and the hydrophobic monomer lauryl methacrylate (LMA). Polymerizations were conducted from a macro chain transfer agent (macro-CTA) consisting of 66% 2-hydroxyethyl methacrylate (HEMA) and 33% poly(ethylene glycol) methyl ether methacrylate FW ∼ 300 Da (O300). A degree of polymerization (DP) of 50 was targeted for the macro-CTA in order to yield diblock copolymers with significantly larger 2nd blocks. From the poly(HEMA-co-O300) macro-CTA, diblock copolymers of poly[(HEMA-co-O300)-b-(DMAPS)] and poly[(HEMA-co-O300)-b-(LMA)] were grown via PISA in acetic acid. In order to maintain colloidal stability, it was necessary to conduct PISA of DMAPS at 10 wt% monomer, while LMA polymerizations maintained stability at 20 wt% monomer. Mnvs. conversion plots for both DMAPS and LMA show linear increases in molecular weight over the course of the polymerizations. Analysis of the molecular weight distributions revealed a progressive narrowing throughout the polymerization from an initial bimodal state. Copolymers of DMAPS and LMA were also synthesized over a large range of comonomer feed ratios. These materials show composition-dependent sizes in buffered solutions between 11 nm for the copolymer containing 80% by mol DMAPS to 75 nm for the copolymer containing 40 mol% DMAPS. PISA in acetic acid was then used to prepare copolymers of DMAPS with a range of hydrophobic polymerizable prodrug monomers as well as a polymerizable peptide macromonomer. The resultant copolymers had narrow molecular weight distributions and were readily soluble in saline solutions.
Clinical studies have validated that antiretroviral (ARV) drugs can serve as an HIV pre-exposure ... more Clinical studies have validated that antiretroviral (ARV) drugs can serve as an HIV pre-exposure prophylactic (PrEP) strategy. Dosing adherence remains a crucial factor determining the final efficacy outcomes, and both long-acting implants and injectable depot systems are being developed to improve patient adherence. Here, we describe an injectable depot platform that exploits a new mechanism for both formation and controlled release. The depot is a polymeric prodrug synthesized from monomers that incorporate an ARV drug tenofovir alafenamide (TAF) with degradable linkers that can be designed to control release rates. The prodrug monomers are synthetically incorporated into homopolymer or block designs that exhibit high drug weight percent (wt%) and also are hydrophobized in these prodrug segments to drive depot formation upon injection. Drug release converts those monomers to more hydrophilic pendant groups via linker cleavage, and as this drug release proceeds, the polymer chains losing hydrophobicity are then disassociated from the depot and released over time to provide a depot dissolution mechanism. We show that long-acting TAF depots can be designed as block copolymers or as homopolymers. They can also be designed with different linkers, for example with faster or slower degrading p-hydroxybenzyloxycarbonyl (Benzyl) and ethyloxycarbonyl (Alkyl) linkers, respectively. Diblock designs of p(glycerol monomethacrylate)-b-p(Alkyl-TAF-methacrylate) and p(glycerol monomethacrylate)-b-p(Benzyl-TAF-methacrylate) were first characterized in a mouse subcutaneous injection model. The alkylcarbamate linker design (TAF 51 wt%) showed excellent sustained release profiles of the key metabolite tenofovir (TFV) in skin and plasma over a 50-day period. Next, the homopolymer design with a high TAF drug wt% of 73% was characterized in the same model. The homopolymer depots with p(Alkyl-TAFMA) exhibited sustained TFV and TAF release profiles in skin and blood over 60 days, and TFV-DP concentrations in peripheral blood mononuclear cells (PBMC) were found to be at least 10-fold higher than the clinically suggested minimally EC90 protective concentration of 24 fmol/106 cells. These are the first reports of sustained parent TAF dosing observed in mouse and TFV-DP in mouse PBMC. IVIS imaging of rhodamine labeled homopolymer depots showed that degradation and release of the depot coincided with the sustained TAF release. Finally, these polymers showed excellent stability in accelerated stability studies over a six-month time period, and exceptional solubility of over 700 mg/mL in the DMSO formulation solvent. The homopolymer designs have a drug reservoir potential of well over a year at mg/day dosing and may not require cold chain storage for global health and developed world long-acting drug delivery applications.
A goal in applying electrochemical methods to reversible addition−fragmentation chain transfer (R... more A goal in applying electrochemical methods to reversible addition−fragmentation chain transfer (RAFT) polymerization is to use electrochemical reduction to activate RAFT agents (SC(Z)S-R) to also act as initiators. The use of a mediator can limit side reactions that would otherwise inhibit polymerization. In this work, we present the use of anthraquinone (AQ) to mediate the electrochemical reduction of a trithiocarbonate RAFT agent, 4-cyano-4-(((dodecylthio)carbonothioyl)thio)pentanoic acid, and thereby initiate RAFT polymerization of methyl methacrylate (MMA). In a representative eRAFT reaction conducted in DMSO with a target degree of polymerization (DP) of 100, conversion reached 67% in 24 h at ambient temperature, with Đ = 1.19. The effect of reaction conditions on polymerization was studiedin general, the conversion rate was found to decrease as target DP increases. Dispersity increases as (i) target DP increases and (ii) mediator concentration increases. The livingness of AQ-mediated eRAFT polymerization was confirmed by eRAFT chain extension with MMA and by thermally initiated RAFT with styrene to form a block copolymer. AQ-mediated eRAFT was found to be unsuitable for polymerization of monosubstituted monomers (styrene, butyl acrylate, N,N-dimethylacrylamide, and N-vinylpyrrolidone). These results support the hypothesis that mediated electrochemical reduction of RAFT agents can yield an initiating species (R •), although polymerization is strongly dependent on diffusion and fragmentation kinetics.
3D bioprinting is a recent technique that can create complex cell seeded scaffolds and therefore ... more 3D bioprinting is a recent technique that can create complex cell seeded scaffolds and therefore holds great promise to revolutionize the biomedical sector by combining materials and structures that more closely mimic the 3D cell environment in tissues. The most commonly used biomaterials for printing are hydrogels, however, many of the hydrogels used still present issues of printability, stability, or poor cell-material interactions. We propose that bioinks with intrinsic self-assembling and shear thinning properties, such as xanthan gum, can be methacrylated (XGMA) and combined with a bio-functional material such as gelatin methacryloyl (GelMa) to create a stable, cell-interactive bioink with improved properties for 3D bioprinting. These biomaterials have reduced viscosity under high shear and recover their viscosity rapidly after the shear is removed, retaining their shape, which translates to easier extrusion whilst maintaining accurate fidelity after printing. This was confirme...
Insulin has been used to treat diabetes for almost 100 years; yet, current rapid-acting insulin f... more Insulin has been used to treat diabetes for almost 100 years; yet, current rapid-acting insulin formulations do not have sufficiently fast pharmacokinetics to maintain tight glycemic control at mealtimes. Dissociation of the insulin hexamer, the primary association state of insulin in rapid-acting formulations, is the rate-limiting step that leads to delayed onset and extended duration of action. A formulation of insulin monomers would more closely mimic endogenous postprandial insulin secretion, but monomeric insulin is unstable in solution using present formulation strategies and rapidly aggregates into amyloid fibrils. Here, we implement high-throughput–controlled radical polymerization techniques to generate a large library of acrylamide carrier/dopant copolymer (AC/DC) excipients designed to reduce insulin aggregation. Our top-performing AC/DC excipient candidate enabled the development of an ultrafast-absorbing insulin lispro (UFAL) formulation, which remains stable under stressed aging conditions for 25 ± 1 hours compared to 5 ± 2 hours for commercial fast-acting insulin lispro formulations (Humalog). In a porcine model of insulin-deficient diabetes, UFAL exhibited peak action at 9 ± 4 min, whereas commercial Humalog exhibited peak action at 25 ± 10 min. These ultrafast kinetics make UFAL a promising candidate for improving glucose control and reducing burden for patients with diabetes.
The molecular weight distribution (MWD) has a significant impact on the properties of polymeric m... more The molecular weight distribution (MWD) has a significant impact on the properties of polymeric materials; however, the characterization of polymer MWDs has been limited to statistical parameters such as the number average molecular weight (Mn) and dispersity (Đ). These parameters do not fully express the features of polymer MWDs, thus limiting the ability to rationally design complex polymeric materials with tailored MWDs. Herein, a platform for the design and synthesis of arbitrary polymer MWDs is developed and experimentally validated. The platform is based on the description of polymer MWDs as a mathematical function, rather than individual statistical parameters. As such, the complete shape of arbitrary polymer MWDs can be designed using developed software. The software requires only a calibration using model monomodal MWDs directly obtained from GPC to design theoretical MWD. Using this platform in conjunction with a flow-mediated polymerization approach, a range of arbitrarily shaped polymer MWDs were successfully designed and prepared. Finally, complex triblock copolymer mixtures with tailored compositions and overall MWD were fabricated via one-pass flow-mediated polymerization using this computer-guided approach.
Electrochemical activation of thiocarbonylthio reversible addition−fragmentation chain transfer (... more Electrochemical activation of thiocarbonylthio reversible addition−fragmentation chain transfer (RAFT) agents (S=C(Z)S-R) is explored as a potential method for initiating RAFT polymerization under mild conditions without producing initiator-derived byproducts. Herein we apply cyclic voltammetry to establish a predominant reduction mechanism, where electrochemical reduction is coupled to an irreversible first-order chemical reaction. Structure-dependent trends in cyclic voltammograms (CVs), and comparison to absorption spectra, clarify the role of R- and Z-groups in determining reduction processes. The major reduction peak moves to more cathodic potentials in the series dithiobenzoates > trithiocarbonates > heteroaromatic dithiocarbamates > xanthates ∼ N-alkyl-N-aryldithiocarbamates, due to the Z- group influence on thiocarbonyl bond reactivity. More active (electron-withdrawing, radical stabilizing) R-groups shift the reduction peak anodically, in part due to their influence on the rate of the coupled chemical reaction. Analysis of CVs across a range of scan rates revealed that kinetic control over the reduction mechanism is influenced by both the charge transfer rate and chemical reaction rate.
Electrospun ultrafine fibres prepared using a blend of poly(lactide-co-glycolide) (PLGA) and brom... more Electrospun ultrafine fibres prepared using a blend of poly(lactide-co-glycolide) (PLGA) and bromine terminated poly(ʟ-lactide) (PLA-Br), were surface modified using surface-initiated (SI) Cu(0) mediated polymerization. Copolymers based on N-acryloxysuccinimide (NAS) and a low fouling monomer (either N,N-dimethylacrylamide (DMA), N-(2-hydroxypropyl)acrylamide (HPA) or N-acryloylmorpholine (NAM)) were grafted from the fibre surface to impart surface functionality and to reduce non-specific protein adsorption. Inclusion of the functional NAS monomer facilitated the conjugation of a non-bioactive cyclic RAD peptide and a bioactive cyclic RGD peptide, the latter expected to facilitate cell adhesion through its affinity for the α v β 3 integrin receptor. A detailed analysis of the surface of the electrospun fibre scaffolds in non-grafted form compared to the surface functionalized state is presented. Characteristic amino acid peaks are observed for both conjugated RGD and RAD peptides. Cell culture experiments confirmed cell specific attachment mediated through the presence of the bioactive RGD peptide mainly at high surface density.
Electrospun ultrafine fibres prepared using a blend of poly(lactide-co-glycolide) (PLGA) and brom... more Electrospun ultrafine fibres prepared using a blend of poly(lactide-co-glycolide) (PLGA) and bromine terminated poly(ʟ-lactide) (PLA-Br), were surface modified using surface-initiated (SI) Cu(0) mediated polymerization. Copolymers based on N-acryloxysuccinimide (NAS) and a low fouling monomer (either N,N-dimethylacrylamide (DMA), N-(2-hydroxypropyl)acrylamide (HPA) or N-acryloylmorpholine (NAM)) were grafted from the fibre surface to impart surface functionality and to reduce non-specific protein adsorption. Inclusion of the functional NAS monomer facilitated the conjugation of a non-bioactive cyclic RAD peptide and a bioactive cyclic RGD peptide, the latter expected to facilitate cell adhesion through its affinity for the α v β 3 integrin receptor. A detailed analysis of the surface of the electrospun fibre scaffolds in non-grafted form compared to the surface functionalized state is presented. Characteristic amino acid peaks are observed for both conjugated RGD and RAD peptides. Cell culture experiments confirmed cell specific attachment mediated through the presence of the bioactive RGD peptide mainly at high surface density.
We report on two important advances in radical polymerization with reversible addition–fragmentat... more We report on two important advances in radical polymerization with reversible addition–fragmentation chain transfer (RAFT polymerization). (1) Electrochemically initiated emulsion RAFT (eRAFT) polymerization provides rapid polymerization of styrene at ambient temperature. The electrolytes and mediators required for eRAFT are located in the aqueous continuous phase separate from the low-molar-mass-dispersity macroRAFT agent mediator and product in the dispersed phase. Use of a poly(N,N-dimethylacrylamide)-block-poly(butyl acrylate) amphiphilic macroRAFT agent composition means that no added surfactant is required for colloidal stability. (2) Direct photoinitiated (visible light) RAFT polymerization provides an effective route to high-purity, low-molar-mass-dispersity, side chain liquid-crystalline polymers (specifically, poly(4-biphenyl acrylate)) at high monomer conversion. Photoinitiation gives a product free from low-molar-mass initiator-derived by-products and with minimal termination. The process is compared with thermal dialkyldiazene initiation in various solvents. Numerical simulation was found to be an important tool in discriminating between the processes and in selecting optimal polymerization conditions.
Composite coatings are considered a promising approach to tailor the biointerface between a (impl... more Composite coatings are considered a promising approach to tailor the biointerface between a (implantable) biomaterial and adhering/surrounding cells or tissue. In this context, composite coatings assembled using a polymer matrix with embedded drug deposits are particularly interesting due to the advanced control over cargo loading, retention and release. Herein, we compare the assembly of such films consisting of various types of liposomes as subunits within a polymer film of either polydopamine (PDA) or, for the first time, tannic acid (TA) as an alternative. It is found that TA is a suitable capping layer for liposome-coated substrates which allows for post-modification. The composite coatings are suitable for supporting hepatocyte adhesion depending on the terminating polymer layer. Furthermore, incorporation of cholesterol–dopamine (Ch-DA) conjugates into the zwitterionic liposomes increases the numbers of deposited subunits. Finally, cytotoxic paclitaxel is loaded into the liposomes and delivered to the adhering hepatocytes. The capability of reducing hepatocyte adhesion to the composite coating varied. Composite coatings consisting of negatively charged liposomes with Ch-DA and a PDA capping layer are found to be most efficient after 24 and 48 h. Taken together, this fundamental comparison of different composite coatings illustrates the excellent opportunities to engineer the biological response towards the application in mind.
Clinical studies have validated that antiretroviral (ARV) drugs can serve as an HIV pre-exposure ... more Clinical studies have validated that antiretroviral (ARV) drugs can serve as an HIV pre-exposure prophylactic (PrEP) strategy. Dosing adherence remains a crucial factor determining the final efficacy outcomes, and both long-acting implants and injectable depot systems are being developed to improve patient adherence. Here, we describe an injectable depot platform that exploits a new mechanism for both formation and controlled release. The depot is a polymeric prodrug synthesized from monomers that incorporate an ARV drug tenofovir alafenamide (TAF) with degradable linkers that can be designed to control release rates. The prodrug monomers are synthetically incorporated into homopolymer or block designs that exhibit high drug weight percent (wt%) and also are hydrophobized in these prodrug segments to drive depot formation upon injection. Drug release converts those monomers to more hydrophilic pendant groups via linker cleavage, and as this drug release proceeds, the polymer chains losing hydrophobicity are then disassociated from the depot and released over time to provide a depot dissolution mechanism. We show that long-acting TAF depots can be designed as block copolymers or as homopolymers. They can also be designed with different linkers, for example with faster or slower degrading p-hydroxybenzyloxycarbonyl (Benzyl) and ethyloxycarbonyl (Alkyl) linkers, respectively. Diblock designs of p(glycerol monomethacrylate)-b-p(Alkyl-TAF-methacrylate) and p(glycerol monomethacrylate)-b-p(Benzyl-TAF-methacrylate) were first characterized in a mouse subcutaneous injection model. The alkylcarbamate linker design (TAF 51 wt%) showed excellent sustained release profiles of the key metabolite tenofovir (TFV) in skin and plasma over a 50-day period. Next, the homopolymer design with a high TAF drug wt% of 73% was characterized in the same model. The homopolymer depots with p(Alkyl-TAFMA) exhibited sustained TFV and TAF release profiles in skin and blood over 60 days, and TFV-DP concentrations in peripheral blood mononuclear cells (PBMC) were found to be at least 10-fold higher than the clinically suggested minimally EC90 protective concentration of 24 fmol/106 cells. These are the first reports of sustained parent TAF dosing observed in mouse and TFV-DP in mouse PBMC. IVIS imaging of rhodamine labeled homopolymer depots showed that degradation and release of the depot coincided with the sustained TAF release. Finally, these polymers showed excellent stability in accelerated stability studies over a six-month time period, and exceptional solubility of over 700 mg/mL in the DMSO formulation solvent. The homopolymer designs have a drug reservoir potential of well over a year at mg/day dosing and may not require cold chain storage for global health and developed world long-acting drug delivery applications.
In this paper we explore RAFT (reversible addition-fragmentation chain transfer) single unit mono... more In this paper we explore RAFT (reversible addition-fragmentation chain transfer) single unit monomer insertion (SUMI) into dithiobenzoates. Styrene and N-isopropylacrylamide (NIPAm) were successfully inserted into 2-cyanopropan-2-yl dithiobenzoate. Attempted SUMI of methyl methacylate (MMA) provided an oligomeric insertion product due to the low transfer constant of the dithiobenzoate in MMA polymerization. A very low yield with maleic anhydride (MAH) reflects the low reactivity of MAH towards 2-cyanopropan-2-yl radicals. We also examined insertion of MAH, styrene and NIPAm into the styrene SUMI product. Insertion of MAH was rapid and efficient. SUMI with styrene and NIPAm was slower, which is attributed both to the low monomer concentrations used and the poor leaving group ability of the propagating species. The reaction with NIPAm is additionally complicated by initiator-derived by-products.
This paper focuses on one of the next directions in the evolution of reversible addition-fragment... more This paper focuses on one of the next directions in the evolution of reversible addition-fragmentation (RAFT) polymerization, namely, progress towards the synthesis of discrete or uniform, sequence-defined (co)polymers. Following a brief review of RAFT-single unit monomer insertion (RAFT-SUMI), we describe recent developments in the field. We point to difficulties in achieving consecutive RAFT-SUMI and report two strategies for overcoming the issue of initiator-derived by-products. We show that the selection of RAFT agent is critical in selective RAFT-SUMI of N,N-dimethylacrylamide (DMAm) into a trithiocarbonate in aqueous solution. Finally we recount on the use of photoRAFT- or PET-RAFT-SUMI in the high yield synthesis of discrete oligomers comprising two or more consecutive SUMI steps.
This chapter summarizes the basics of undertaking a reversible addition–fragmentation chain trans... more This chapter summarizes the basics of undertaking a reversible addition–fragmentation chain transfer (RAFT) polymerization for a common set of monomer classes including styrenics, acrylates, methacrylates, acrylamides, methacrylamides, vinyl esters, and vinyl amides. It highlights the role of RAFT agent selection and reaction conditions. It is aimed at newcomers, including undergraduate and postgraduate students, industry researchers, as well as nonexperts in polymerization who are interested in exploring the potential of RAFT polymerization. For readers with limited access to journals, this chapter provides many examples of basic RAFT polymerizations from the academic literature.
This paper will discuss aspects of (co)polymerization of acrylates with reversible addition-fragm... more This paper will discuss aspects of (co)polymerization of acrylates with reversible addition-fragmentation chain transfer (RAFT). An explanation for bimodal molecular weight distributions observed when making high molecular weight acrylic polymers with narrow molecular weight distributions (Mw/Mn≤1.1) at high conversion involves copolymerization of the macromonomer formed by backbiting-β-scission. Evidence for this mechanism is provided. RAFT copolymerization is illustrated by the synthesis of novel copolymer intercalants/ exfoliants/dispersants for unmodified layered silicates (sodium montmorillonite) in polypropylene (PP) nanocomposites. Block and gradient copolymers were prepared based on a long chain acrylate (e.g. octadecyl acrylate, ODA) and various polar comonomers (e.g. acrylic acid, dimethylaminoethyl acrylate, maleic anhydride, methacrylic acid, N-vinyl pyrrolidone).
This review focuses on the approaches to the synthesis of functional polymers for optoelectronic ... more This review focuses on the approaches to the synthesis of functional polymers for optoelectronic applications that make use of radical polymerization with reversible addition–fragmentation chain transfer (RAFT) polymerization. Optoelectronic applications include hole/electron transport in photovoltaics (OPVs), light emitting diodes (OLEDs and PLEDs), thin-film transistors (TFTs), sensors, light-harvesting and related applications. In this context we consider metallopolymers (polymers that incorporate a metal or possess metal ligating functionality as a pendant group to the backbone, as an end-group or as a connecting group), organic semiconductors (polymers with an organic semiconductor moiety either as a block or as a pendant group), and various surfaces, nanoparticles and quantum dots that are formed by RAFT polymerization or where a RAFT-synthesized polymer forms an integral part of the process or structure.
Polymer coatings are of central importance for many biomedical applications. In the past few year... more Polymer coatings are of central importance for many biomedical applications. In the past few years, poly(dopamine) (PDA) has attracted considerable interest for various types of biomedical applications. This feature article outlines the basic chemistry and material science regarding PDA and discusses its successful application from coatings for interfacing with cells, to drug delivery and biosensing. Although many questions remain open, the primary aim of this feature article is to illustrate the advent of PDA on its way to become a popular polymer for bioengineering purposes.
Cholesterol is a molecule with many tasks in nature but also a long history in science. This feat... more Cholesterol is a molecule with many tasks in nature but also a long history in science. This feature article highlights the contribution of this small compound to bionanotechnology. We discuss relevant chemical aspects in this context followed by an overview of its self-assembly capabilities both as a free molecule and when conjugated to a polymer. Further, cholesterol in the context of liposomes is reviewed and its impact ranging from biosensing to drug delivery is outlined. Cholesterol is and will be an indispensable player in bionanotechnology, contributing to the progress of this potent field of research.
La presente invention concerne des compositions de microstructures nanocomposites a activite ther... more La presente invention concerne des compositions de microstructures nanocomposites a activite therapeutique ameliorees, comprenant des compositions de nanoparticules et des preparations de nanoparticules. Les modes de realisation preferes de l'invention incluent des compositions de nanoparticules qui comprennent des nanoparticules d'un agent a activite therapeutique, dispersees au sein d'une matrice porteuse. La presente invention concerne egalement une methode de synthese desdites compositions et preparations qui implique une synthese par voie mecano-chimique a l'etat solide. En outre, la presente invention concerne des produits therapeutiques obtenus a l'aide desdites compositions, ainsi que des methodes de traitement employant lesdites compositions.
This work describes a controlled radical polymerization process using the RAFT approach (Reversib... more This work describes a controlled radical polymerization process using the RAFT approach (Reversible Addition-Fragmentation Chain Transfer) under continuous flow conditions. A series of different monomers, including acrylates, acrylamides, styrene and vinyl acetate were polymerized inside a continuous flow steel tubing reactor. High conversions between 80 and 100 % were achieved at temperatures typically between 70 and 110 °C and in comparatively short reaction times of the order of 2 h. For these polymerisations, a series of different RAFT agents, including trithiocarbonates, dithiobenzoates and dithiocarbamates as well as different solvents and radical initiators were used. The synthesised polymers, exhibited low dispersities, typically between 1.15–1.20, and average molecular weights similar to those prepared in a conventional batch process. The herein presented continuous approach provides a facile alternative scale-up route to conventional batch polymerization, and using the maximum reactor capacity of this continuous flow system, a total of up to 1 kg of RAFT polymer per day could be produced. Due to the living character of the RAFT approach, the polymeric product can be polymerized further in a second continuous reactor, using sequential processing flow technology. In this second stage, a monomer with different chemical or physical properties can be introduced in order to synthesise a second polymer block. Generally, sequential flow processing for the synthesis of block copolymers eliminates the need for isolation of the intermediates and therefore reduces handling time of reagents and solvents, which makes it a significant improvement on the safety of the chemical process.
iii Abstract The synthesis of amine end-functionalised polymers by controlled free radical techni... more iii Abstract The synthesis of amine end-functionalised polymers by controlled free radical techniques has been investigated with a focus on methods that provide primary amino end-functionalised polystyrene. The aim of these investigations was to provide precursors to block and graft polyolefins and polyesters by interchain coupling reactions.
Reactive extrusion has been used to convert post-consumer recycled HDPE from milk bottles, into a... more Reactive extrusion has been used to convert post-consumer recycled HDPE from milk bottles, into a grade which can be injection moulded into large products such as crates and mobile garbage bins. The modified materials have been successfully injection moulded at a level of 100% modified recycled HDPE, without blending with other materials, using conventional equipment and tooling. Physical properties approach that of virgin materials but still require further improvement to meet all performance criteria.
Reactive extrusion has been used to convert post-consumer recycled HDPE from milk bottles, into a... more Reactive extrusion has been used to convert post-consumer recycled HDPE from milk bottles, into a grade which can be injection moulded into large products such as crates and mobile garbage bins. The modified materials have been successfully injection moulded at a level of 100% modified recycled HDPE, without blending with other materials, using conventional equipment and tooling. Physical properties approach that of virgin materials but still require further improvement to meet all performance criteria.
Silica spheres of various sizes and mesoporosity were coated with poly(dopamine) (PDA) shells wit... more Silica spheres of various sizes and mesoporosity were coated with poly(dopamine) (PDA) shells with controllable wall thickness. The silica cores of the hybrid particles were then removed by treatment with HF, leaving behind PDA microcapsules.
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Papers by Almar Postma