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1.
ACS Appl Mater Interfaces ; 13(36): 43290-43300, 2021 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-34464079

RESUMO

We report the first successful combination of three distinct high-throughput techniques to deliver the accelerated design, synthesis, and property screening of a library of novel, bio-instructive, polymeric, comb-graft surfactants. These three-dimensional, surface-active materials were successfully used to control the surface properties of particles by forming a unimolecular deep layer on the surface of the particles via microfluidic processing. This strategy deliberately utilizes the surfactant to both create the stable particles and deliver a desired cell-instructive behavior. Therefore, these specifically designed, highly functional surfactants are critical to promoting a desired cell response. This library contained surfactants constructed from 20 molecularly distinct (meth)acrylic monomers, which had been pre-identified by HT screening to exhibit specific, varied, and desirable bacterial biofilm inhibitory responses. The surfactant's self-assembly properties in water were assessed by developing a novel, fully automated, HT method to determine the critical aggregation concentration. These values were used as the input data to a computational-based evaluation of the key molecular descriptors that dictated aggregation behavior. Thus, this combination of HT techniques facilitated the rapid design, generation, and evaluation of further novel, highly functional, cell-instructive surfaces by application of designed surfactants possessing complex molecular architectures.

2.
ACS Appl Mater Interfaces ; 13(33): 38969-38978, 2021 Aug 25.
Artigo em Inglês | MEDLINE | ID: mdl-34399054

RESUMO

Controlling the microstructure of materials by means of phase separation is a versatile tool for optimizing material properties. Phase separation has been exploited to fabricate intricate microstructures in many fields including cell biology, tissue engineering, optics, and electronics. The aim of this study was to use phase separation to tailor the spatial location of drugs and thereby generate release profiles of drug payload over periods ranging from 1 week to months by exploiting different mechanisms: polymer degradation, polymer diluent dissolution, and control of microstructure. To achieve this, we used drop-on-demand inkjet three-dimensional (3D) printing. We predicted the microstructure resulting from phase separation using high-throughput screening combined with a model based on the Flory-Huggins interaction parameter and were able to show that drug release from 3D-printed objects can be predicted from observations based on single drops of mixtures. We demonstrated for the first time that inkjet 3D printing yields controllable phase separation using picoliter droplets of blended photoreactive oligomers/monomers. This new understanding gives us hierarchical compositional control, from droplet to device, allowing release to be "dialled up" without manipulation of device geometry. We exemplify this approach by fabricating a biodegradable, long-term, multiactive drug delivery subdermal implant ("polyimplant") for combination therapy and personalized treatment of coronary heart disease. This is an important advance for implants that need to be delivered by cannula, where the shape is highly constrained and thus the usual geometrical freedoms associated with 3D printing cannot be easily exploited, which brings a hitherto unseen level of understanding to emergent material properties of 3D printing.


Assuntos
Anti-Hipertensivos/química , Doença das Coronárias/tratamento farmacológico , Portadores de Fármacos/química , Excipientes/química , Indóis/química , Polímeros/química , Anti-Hipertensivos/farmacologia , Dioxanos/química , Composição de Medicamentos , Liberação Controlada de Fármacos , Humanos , Indóis/farmacologia , Metacrilatos/química , Transição de Fase , Poliésteres/química , Impressão Tridimensional , Pirrolidinonas/química , Relação Estrutura-Atividade
3.
Molecules ; 26(11)2021 May 31.
Artigo em Inglês | MEDLINE | ID: mdl-34072733

RESUMO

Droplet microfluidics can produce highly tailored microparticles whilst retaining monodispersity. However, these systems often require lengthy optimisation, commonly based on a trial-and-error approach, particularly when using bio-instructive, polymeric surfactants. Here, micropipette manipulation methods were used to optimise the concentration of bespoke polymeric surfactants to produce biodegradable (poly(d,l-lactic acid) (PDLLA)) microparticles with unique, bio-instructive surface chemistries. The effect of these three-dimensional surfactants on the interfacial tension of the system was analysed. It was determined that to provide adequate stabilisation, a low level (0.1% (w/v)) of poly(vinyl acetate-co-alcohol) (PVA) was required. Optimisation of the PVA concentration was informed by micropipette manipulation. As a result, successful, monodisperse particles were produced that maintained the desired bio-instructive surface chemistry.


Assuntos
Portadores de Fármacos , Copolímero de Ácido Poliláctico e Ácido Poliglicólico/química , Polímeros/química , Álcool de Polivinil/química , Tensoativos/química , Materiais Biocompatíveis/química , Biodegradação Ambiental , Composição de Medicamentos/métodos , Ácido Láctico/química , Microfluídica , Microscopia Eletrônica de Varredura , Tamanho da Partícula , Ácido Poliglicólico/química , Solventes , Propriedades de Superfície , Tensão Superficial
4.
Adv Sci (Weinh) ; 8(15): e2100249, 2021 08.
Artigo em Inglês | MEDLINE | ID: mdl-34050725

RESUMO

As the understanding of disease grows, so does the opportunity for personalization of therapies targeted to the needs of the individual. To bring about a step change in the personalization of medical devices it is shown that multi-material inkjet-based 3D printing can meet this demand by combining functional materials, voxelated manufacturing, and algorithmic design. In this paper composite structures designed with both controlled deformation and reduced biofilm formation are manufactured using two formulations that are deposited selectively and separately. The bacterial biofilm coverage of the resulting composites is reduced by up to 75% compared to commonly used silicone rubbers, without the need for incorporating bioactives. Meanwhile, the composites can be tuned to meet user defined mechanical performance with ±10% deviation. Device manufacture is coupled to finite element modelling and a genetic algorithm that takes the user-specified mechanical deformation and computes the distribution of materials needed to meet this under given load constraints through a generative design process. Manufactured products are assessed against the mechanical and bacterial cell-instructive specifications and illustrate how multifunctional personalization can be achieved using generative design driven multi-material inkjet based 3D printing.

5.
Adv Healthc Mater ; 10(6): e2001448, 2021 03.
Artigo em Inglês | MEDLINE | ID: mdl-33369242

RESUMO

Human pluripotent stem cells (hPSCs) can be expanded and differentiated in vitro into almost any adult tissue cell type, and thus have great potential as a source for cell therapies with biomedical application. In this study, a fully-defined polymer synthetic substrate is identified for hPSC culture in completely defined, xenogenic (xeno)-free conditions. This system can overcome the cost, scalability, and reproducibility limitations of current hPSC culture strategies, and facilitate large-scale production. A high-throughput, multi-generational polymer microarray platform approach is used to test over 600 unique polymers and rapidly assess hPSC-polymer interactions in combination with the fully defined xeno-free medium, Essential 8 (E8). This study identifies a novel nanoscale phase separated blend of poly(tricyclodecane-dimethanol diacrylate) and poly(butyl acrylate) (2:1 v/v), which supports long-term expansion of hPSCs and can be readily coated onto standard cultureware. Analysis of cell-polymer interface interactions through mass spectrometry and integrin blocking studies provides novel mechanistic insight into the role of the E8 proteins in promoting integrin-mediated hPSC attachment and maintaining hPSC signaling, including ability to undergo multi-lineage differentiation. This study therefore identifies a novel substrate for long-term serial passaging of hPSCs in serum-free, commercial chemically-defined E8, which provides a promising and economic hPSC expansion platform for clinical-scale application.


Assuntos
Técnicas de Cultura de Células , Células-Tronco Pluripotentes , Diferenciação Celular , Proliferação de Células , Humanos , Polímeros , Reprodutibilidade dos Testes
6.
Biomaterials ; 260: 120312, 2020 11.
Artigo em Inglês | MEDLINE | ID: mdl-32866726

RESUMO

Blood-contacting medical devices play an important role within healthcare and are required to be biocompatible, hemocompatible and resistant to microbial colonization. Here we describe a high throughput screen for copolymers with these specific properties. A series of weakly amphiphilic monomers are combinatorially polymerized with acrylate glycol monomers of varying chain lengths to create a library of 645 multi-functional candidate materials containing multiple chemical moieties that impart anti-biofilm, hemo- and immuno-compatible properties. These materials are screened in over 15,000 individual biological assays, targeting two bacterial species, one Gram negative (Pseudomonas aeruginosa) and one Gram positive (Staphylococcus aureus) commonly associated with central venous catheter infections, using 5 different measures of hemocompatibility and 6 measures of immunocompatibililty. Selected copolymers reduce platelet activation, platelet loss and leukocyte activation compared with the standard comparator PTFE as well as reducing bacterial biofilm formation in vitro by more than 82% compared with silicone. Poly(isobornyl acrylate-co-triethylene glycol methacrylate) (75:25) is identified as the optimal material across all these measures reducing P. aeruginosa biofilm formation by up to 86% in vivo in a murine foreign body infection model compared with uncoated silicone.


Assuntos
Antibacterianos , Infecções Estafilocócicas , Animais , Biofilmes , Camundongos , Pseudomonas aeruginosa , Staphylococcus aureus
7.
Sci Adv ; 6(23): eaba6574, 2020 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-32548270

RESUMO

Fungi have major, negative socioeconomic impacts, but control with bioactive agents is increasingly restricted, while resistance is growing. Here, we describe an alternative fungal control strategy via materials operating passively (i.e., no killing effect). We screened hundreds of (meth)acrylate polymers in high throughput, identifying several that reduce attachment of the human pathogen Candida albicans, the crop pathogen Botrytis cinerea, and other fungi. Specific polymer functional groups were associated with weak attachment. Low fungal colonization materials were not toxic, supporting their passive, anti-attachment utility. We developed a candidate monomer formulation for inkjet-based 3D printing. Printed voice prosthesis components showed up to 100% reduction in C. albicans biofilm versus commercial materials. Furthermore, spray-coated leaf surfaces resisted fungal infection, with no plant toxicity. This is the first high-throughput study of polymer chemistries resisting fungal attachment. These materials are ready for incorporation in products to counteract fungal deterioration of goods, food security, and health.

8.
Int J Pharm ; 578: 118805, 2020 Mar 30.
Artigo em Inglês | MEDLINE | ID: mdl-31715351

RESUMO

In this study, we investigate the viability of three-dimensional (3D) inkjet printing with UV curing to produce solid dosage forms containing a known poorly soluble drug, carvedilol. The formulation consists of 10 wt% carvedilol, Irgacure 2959, and a photocurable N-vinyl-2-pyrrolidone (NVP) and poly(ethylene glycol) diacrylate matrix, with the intention of forming an amorphous solid solution for release of carvedilol. Characterization of the printed tablets showed that the drug is an amorphous state and indicated hydrogen bonding interactions between the drug and cross-linked matrix. Several simple geometries (ring, mesh, cylinder, thin film) were printed, and the surface area to volume ratio of the prints was estimated. Over 80% carvedilol release was observed for all printed tablet geometries within ten hours. The release behaviour of carvedilol was fastest for the thin films, followed by the ring and mesh geometries, and slowest in the cylindrical forms. More rapid release was correlated to an increased surface area to volume ratio. This is the first study to implement 3D UV inkjet to make solid dispersion tablets suitable for poorly soluble drugs. Results also demonstrate that high drug-loaded tablets with a variety of release profiles can successfully be accessed with the same UV-curable inkjet formulation by varying the tablet geometry.


Assuntos
Antagonistas Adrenérgicos beta/química , Carvedilol/química , Polietilenoglicóis/química , Propano/análogos & derivados , Pirrolidinonas/química , Liberação Controlada de Fármacos , Tinta , Impressão Tridimensional , Propano/química , Solubilidade , Comprimidos , Tecnologia Farmacêutica , Raios Ultravioleta
9.
Adv Mater ; 31(49): e1903513, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31583791

RESUMO

Synthetic materials are an everyday component of modern healthcare yet often fail routinely as a consequence of medical-device-centered infections. The incidence rate for catheter-associated urinary tract infections is between 3% and 7% for each day of use, which means that infection is inevitable when resident for sufficient time. The O'Neill Review on antimicrobial resistance estimates that, left unchecked, ten million people will die annually from drug-resistant infections by 2050. Development of biomaterials resistant to bacterial colonization can play an important role in reducing device-associated infections. However, rational design of new biomaterials is hindered by the lack of quantitative structure-activity relationships (QSARs). Here, the development of a predictive QSAR is reported for bacterial biofilm formation on a range of polymers, using calculated molecular descriptors of monomer units to discover and exemplify novel, biofilm-resistant (meth-)acrylate-based polymers. These predictions are validated successfully by the synthesis of new monomers which are polymerized to create coatings found to be resistant to biofilm formation by six different bacterial pathogens: Pseudomonas aeruginosa, Proteus mirabilis, Enterococcus faecalis, Klebsiella pneumoniae, Escherichia coli, and Staphylococcus aureus.


Assuntos
Antibacterianos/farmacologia , Materiais Biocompatíveis/farmacologia , Biofilmes/efeitos dos fármacos , Polímeros/farmacologia , Antibacterianos/química , Bactérias/efeitos dos fármacos , Infecções Bacterianas/prevenção & controle , Materiais Biocompatíveis/química , Incrustação Biológica/prevenção & controle , Humanos , Polímeros/química , Relação Estrutura-Atividade
10.
AAPS PharmSciTech ; 19(8): 3403-3413, 2018 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-30097806

RESUMO

An extrusion-based 3D printer was used to fabricate paracetamol tablets with different geometries (mesh, ring and solid) from a single paste-based formulation formed from standard pharmaceutical ingredients. The tablets demonstrate that tunable drug release profiles can be achieved from this single formulation even with high drug loading (> 80% w/w). The tablets were evaluated for drug release using a USP dissolution testing type I apparatus. The tablets showed well-defined release profiles (from immediate to sustained release) controlled by their different geometries. The dissolution results showed dependency of drug release on the surface area/volume (SA/V) ratio and the SA of the different tablets. The tablets with larger SA/V ratios and SA had faster drug release. The 3D printed tablets were also evaluated for physical and mechanical properties including tablet dimension, drug content, weight variation and breaking force and were within acceptable range as defined by the international standards stated in the US Pharmacopoeia. X-ray powder diffraction, differential scanning calorimetry and attenuated total reflectance Fourier transform infrared spectroscopy were used to identify the physical form of the active and to assess possible drug-excipient interactions. These data again showed that the tablets meet USP requirement. These results clearly demonstrate the potential of 3D printing to create unique pharmaceutical manufacturing, and potentially clinical, opportunities. The ability to use a single unmodified formulation to achieve defined release profiles could allow, for example, relatively straightforward personalization of medicines for individuals with different metabolism rates for certain drugs and hence could offer significant development and clinical opportunities.


Assuntos
Acetaminofen/química , Acetaminofen/farmacocinética , Liberação Controlada de Fármacos , Impressão Tridimensional , Tecnologia Farmacêutica/métodos , Varredura Diferencial de Calorimetria , Composição de Medicamentos/métodos , Excipientes/química , Espectroscopia de Infravermelho com Transformada de Fourier , Comprimidos/química , Difração de Raios X
11.
ACS Appl Mater Interfaces ; 10(8): 6841-6848, 2018 Feb 28.
Artigo em Inglês | MEDLINE | ID: mdl-29322768

RESUMO

A robust methodology is presented to identify novel biomaterials suitable for three-dimensional (3D) printing. Currently, the application of additive manufacturing is limited by the availability of functional inks, especially in the area of biomaterials; this is the first time when this method is used to tackle this problem, allowing hundreds of formulations to be readily assessed. Several functional properties, including the release of an antidepressive drug (paroxetine), cytotoxicity, and printability, are screened for 253 new ink formulations in a high-throughput format as well as mechanical properties. The selected candidates with the desirable properties are successfully scaled up using 3D printing into a range of object architectures. A full drug release study and degradability and tensile modulus experiments are presented on a simple architecture to validating the suitability of this methodology to identify printable inks for 3D printing devices with bespoke properties.


Assuntos
Impressão Tridimensional , Implantes Absorvíveis , Materiais Biocompatíveis , Tinta , Polímeros
12.
Int J Pharm ; 529(1-2): 523-530, 2017 Aug 30.
Artigo em Inglês | MEDLINE | ID: mdl-28673860

RESUMO

Additive manufacturing (AM) offers significant potential benefits in the field of drug delivery and pharmaceutical/medical device manufacture. Of AM processes, 3D inkjet printing enables precise deposition of a formulation, whilst offering the potential for significant scale up or scale out as a manufacturing platform. This work hypothesizes that suitable solvent based ink formulations can be developed that allow the production of solid dosage forms that meet the standards required for pharmaceutical tablets, whilst offering a platform for flexible and personalized manufacture. We demonstrate this using piezo-activated inkjetting to 3D print ropinirole hydrochloride. The tablets produced consist of a cross-linked poly(ethylene glycol diacrylate) (PEGDA) hydrogel matrix containing the drug, photoinitiated in a low oxygen environment using an aqueous solution of Irgacure 2959. At a Ropinirole HCl loading of 0.41mg, drug release from the tablet is shown to be Fickian. Raman and IR spectroscopy indicate a high degree of cross-linking and formation of an amorphous solid dispersion. This is the first publication of a UV inkjet 3D printed tablet. Consequently, this work opens the possibility for the translation of scalable, high precision and bespoke ink-jet based additive manufacturing to the pharmaceutical sector.


Assuntos
Impressão Tridimensional , Comprimidos , Tecnologia Farmacêutica , Liberação Controlada de Fármacos , Hidrogel de Polietilenoglicol-Dimetacrilato/química , Indóis/química
13.
Phys Chem Chem Phys ; 19(31): 20412-20419, 2017 Aug 09.
Artigo em Inglês | MEDLINE | ID: mdl-28731101

RESUMO

Microwave annealing has emerged as an alternative to traditional thermal annealing approaches for optimising block copolymer self-assembly. A novel sample environment enabling small angle X-ray scattering to be performed in situ during microwave annealing is demonstrated, which has enabled, for the first time, the direct study of the effects of microwave annealing upon the self-assembly behavior of a model, commercial triblock copolymer system [polystyrene-block-poly(ethylene-co-butylene)-block-polystyrene]. Results show that the block copolymer is a poor microwave absorber, resulting in no change in the block copolymer morphology upon application of microwave energy. The block copolymer species may only indirectly interact with the microwave energy when a small molecule microwave-interactive species [diethylene glycol dibenzoate (DEGDB)] is incorporated directly into the polymer matrix. Then significant morphological development is observed at DEGDB loadings ≥6 wt%. Through spatial localisation of the microwave-interactive species, we demonstrate targeted annealing of specific regions of a multi-component system, opening routes for the development of "smart" manufacturing methodologies.

14.
Biomacromolecules ; 17(9): 2830-8, 2016 09 12.
Artigo em Inglês | MEDLINE | ID: mdl-27461341

RESUMO

Developing medical devices that resist bacterial attachment and subsequent biofilm formation is highly desirable. In this paper, we report the optimization of the molecular structure and thus material properties of a range of (meth)acrylate copolymers which contain monomers reported to deliver bacterial resistance to surfaces. This optimization allows such monomers to be employed within novel coatings to reduce bacterial attachment to silicone urinary catheters. We show that the flexibility of copolymers can be tuned to match that of the silicone catheter substrate, by copolymerizing these polymers with a lower Tg monomer such that it passes the flexing fatigue tests as coatings upon catheters, that the homopolymers failed. Furthermore, the Tg values of the copolymers are shown to be readily estimated by the Fox equation. The bacterial resistance performance of these copolymers were typically found to be better than the neat silicone or a commercial silver containing hydrogel surface, when the monomer feed contained only 25 v% of the "hit" monomer. The method of initiation (either photo or thermal) was shown not to affect the bacterial resistance of the copolymers. Optimized synthesis conditions to ensure that the correct copolymer composition and to prevent the onset of gelation are detailed.


Assuntos
Acrilatos/química , Antibacterianos/farmacologia , Bactérias/efeitos dos fármacos , Aderência Bacteriana/efeitos dos fármacos , Farmacorresistência Bacteriana , Polímeros/farmacologia , Hidrogel de Polietilenoglicol-Dimetacrilato/química , Substâncias Macromoleculares/química , Polimerização , Polímeros/química
15.
Macromol Rapid Commun ; 37(15): 1295-9, 2016 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-27315130

RESUMO

The use of dielectric property measurements to define specific trends in the molecular structures of poly(caprolactone) containing star polymers and/or the interbatch repeatability of the synthetic procedures used to generate them is demonstrated. The magnitude of the dielectric property value is shown to accurately reflect: (a) the number of functional groups within a series of materials with similar molecular size when no additional intermolecular order is present in the medium, (b) the polymer molecular size for a series of materials containing a fixed core material and so functional group number, and/or (c) the batch to batch repeatability of the synthesis method. The dielectric measurements are validated by comparison to spectroscopic/chromatographic data.


Assuntos
Materiais Biocompatíveis/síntese química , Poliésteres/síntese química , Tensoativos/síntese química , Espectroscopia Dielétrica , Estrutura Molecular , Temperatura
16.
J Mech Behav Biomed Mater ; 59: 78-89, 2016 06.
Artigo em Inglês | MEDLINE | ID: mdl-26748261

RESUMO

Fully bioresorbable composites have been investigated in order to replace metal implant plates used for hard tissue repair. Retention of the composite mechanical properties within a physiological environment has been shown to be significantly affected due to loss of the integrity of the fibre/matrix interface. This study investigated phosphate based glass fibre (PGF) reinforced polycaprolactone (PCL) composites with 20%, 35% and 50% fibre volume fractions (Vf) manufactured via an in-situ polymerisation (ISP) process and a conventional laminate stacking (LS) followed by compression moulding. Reinforcing efficiency between the LS and ISP manufacturing process was compared, and the ISP composites revealed significant improvements in mechanical properties when compared to LS composites. The degradation profiles and mechanical properties were monitored in phosphate buffered saline (PBS) at 37°C for 28 days. ISP composites revealed significantly less media uptake and mass loss (p<0.001) throughout the degradation period. The initial flexural properties of ISP composites were substantially higher (p<0.0001) than those of the LS composites, which showed that the ISP manufacturing process provided a significantly enhanced reinforcement effect than the LS process. During the degradation study, statistically higher flexural property retention profiles were also seen for the ISP composites compared to LS composites. SEM micrographs of fracture surfaces for the LS composites revealed dry fibre bundles and poor fibre dispersion with polymer rich zones, which indicated poor interfacial bonding, distribution and adhesion. In contrast, evenly distributed fibres without dry fibre bundles or polymer rich zones, were clearly observed for the ISP composite samples, which showed that a superior fibre/matrix interface was achieved with highly improved adhesion.


Assuntos
Implantes Absorvíveis , Vidro/química , Fosfatos/química , Poliésteres/química , Teste de Materiais
17.
J Mater Chem B ; 4(44): 7119-7129, 2016 Nov 28.
Artigo em Inglês | MEDLINE | ID: mdl-32263649

RESUMO

Here we describe a methoxy poly(ethyleneglycol)-b-poly(ε-decalactone) (mPEG-b-PεDL) copolymer and investigate the potential of the copolymer as a vehicle for solubilisation and sustained release of indomethacin (IND). The indomethacin loading and release from mPEG-b-PεDL micelles (amorphous cores) was compared against methoxy poly(ethyleneglycol)-b-poly(ε-caprolactone)(mPEG-b-PCL) micelles (semicrystalline cores). The drug-polymer compatibility was determined through a theoretical approach to predict drug incorporation into hydrated micelles. Polymer micelles were prepared by solvent evaporation and characterised for size, morphology, indomethacin loading and release. All the formulations generated spherical micelles but significantly larger mPEG-b-PεDL micelles were observed compared to mPEG-b-PCL micelles. A higher compatibility of the drug was predicted for PCL cores based on Flory-Huggins interaction parameters (χsp) using the Hansen solubility parameter (HSP) approach, but higher measured drug loadings were found in micelles with PεDL cores compared to PCL cores. This we attribute to the higher amorphous content in the PεDL-rich regions which generated higher micellar core volumes. Drug release studies showed that the semicrystalline PCL core was able to release IND over a longer period (80% drug release in 110 h) compared to PεDL core micelles (80% drug release in 72 h).

18.
Biomacromolecules ; 17(1): 165-72, 2016 Jan 11.
Artigo em Inglês | MEDLINE | ID: mdl-26652915

RESUMO

The potential to replace shark-derived squalene in vaccine adjuvant applications with synthetic squalene/poly(isoprene) oligomers, synthesized by the controlled oligomerization of isoprene is demonstrated. Following on from our previous work regarding the synthesis of poly(isoprene) oligomers, we demonstrate the ability to tune the molecular weight of the synthetic poly(isoprene) material beyond that of natural squalene, while retaining a final backbone structure that contained a minimum of 75% of 1,4 addition product and an acceptable polydispersity. The synthesis was successfully scaled from the 2 g to the 40 g scale both in the bulk (i.e., solvent free) and with the aid of additional solvent by utilizing catalytic chain transfer polymerization (CCTP) as the control method, such that the target molecular weight, acceptable dispersity levels, and the desired level of 1,4 addition in the backbone structure and an acceptable yield (∼60%) are achieved. Moreover, the stability and in vitro bioactivity of nanoemulsion adjuvant formulations manufactured with the synthetic poly(isoprene) material are evaluated in comparison to emulsions made with shark-derived squalene. Emulsions containing the synthetic poly(isoprene) achieved smaller particle size and equivalent or enhanced bioactivity (stimulation of cytokine production in human whole blood) compared to corresponding shark squalene emulsions. However, as opposed to the shark squalene-based emulsions, the poly(isoprene) emulsions demonstrated reduced long-term size stability and induced hemolysis at high concentrations. Finally, we demonstrate that the synthetic oligomeric poly(isoprene) material could successfully be hydrogenated such that >95% of the double bonds were successfully removed to give a representative poly(isoprene)-derived squalane mimic.


Assuntos
Adjuvantes Imunológicos/química , Butadienos/química , Hemiterpenos/química , Pentanos/química , Esqualeno/análogos & derivados , Esqualeno/química , Vacinas/química , Química Farmacêutica/métodos , Estabilidade de Medicamentos , Emulsões/química , Tamanho da Partícula , Polimerização
19.
Molecules ; 20(11): 20131-45, 2015 Nov 09.
Artigo em Inglês | MEDLINE | ID: mdl-26569198

RESUMO

Macromolecules that possess three-dimensional, branched molecular structures are of great interest because they exhibit significantly differentiated application performance compared to conventional linear (straight chain) polymers. This paper reports the synthesis of 3- and 4-arm star branched polymers via ring opening polymerisation (ROP) utilising multi-functional hydroxyl initiators and Sn(Oct)2 as precatalyst. The structures produced include mono-functional hydrophobic and multi-functional amphiphilic core corona stars. The characteristics of the synthetic process were shown to be principally dependent upon the physical/dielectric properties of the initiators used. ROP's using initiators that were more available to become directly involved with the Sn(Oct)2 in the "in-situ" formation of the true catalytic species were observed to require shorter reaction times. Use of microwave heating (MWH) in homopolymer star synthesis reduced reaction times compared to conventional heating (CH) equivalents, this was attributed to an increased rate of "in-situ" catalyst formation. However, in amphiphilic core corona star formation, the MWH polymerisations exhibited slower propagation rates than CH equivalents. This was attributed to macro-structuring within the reaction medium, which reduced the potential for reaction. It was concluded that CH experiments were less affected by this macro-structuring because it was disrupted by the thermal currents/gradients caused by the conductive/convective heating mechanisms. These gradients are much reduced/absent with MWH because it selectively heats specific species simultaneously throughout the entire volume of the reaction medium. These partitioning problems were overcome by introducing additional quantities of the species that had been determined to selectively heat.


Assuntos
Poliésteres/química , Polímeros/química , Técnicas de Química Sintética , Interações Hidrofóbicas e Hidrofílicas , Estrutura Molecular , Polimerização , Polímeros/síntese química , Temperatura
20.
Dalton Trans ; 42(1): 127-36, 2013 Jan 07.
Artigo em Inglês | MEDLINE | ID: mdl-23085824

RESUMO

The successful application of catalytic chain transfer polymerisation (CCTP) by adopting an 'in situ' catalyst preparation methodology in several polymerisation media is described. More specifically, this study is focused on reporting the development of 'in situ' CCTP within a CO(2) expanded phase polymerisation process, which achieved high yields of polymer whilst minimising both VOC footprint and CO(2) compression costs. The 'in situ' method is shown to be effective in controlling polymerisations conducted in both conventional solvents and bulk under inert atmosphere, delivering molecular weight reductions and a Cs value of appropriate similar magnitude to those achieved by the benchmark, commercially sourced CoPhBF catalyst. The 'in situ' effect has been achieved with equal efficiency when both using catalysts with different axial ligands and where the complex is required to undergo a facile ligand dissociation in order to create the required catalyst necessary to achieve CCTP control. Furthermore, both catalysts are shown to effectively control polymerisations in a CO(2) expanded phase process, in which a small amount of compressed CO(2) is introduced to reduce the viscosity of the reaction mixture, allowing for easy heat transfer and good catalyst diffusion during reaction. In this way, yield limitations imposed to avoid the Trommsdorff effect required in bulk processing and the need for post precipitation have been successfully overcome. Both of these factors further improve the sustainability of such a polymerisation process. However, the 'in situ', high pressure expanded phase environment was observed to retard the ligand dissociation required for catalyst activation.

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