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1.
Opt Lett ; 45(10): 2716-2719, 2020 May 15.
Artigo em Inglês | MEDLINE | ID: mdl-32412449

RESUMO

A robust method to selectively attach specific fluorophores onto the individual cores of a multicore fiber is reported in this Letter. The method is based on the use of ultrafast laser pulses to nanostructure the facet of the fiber core, followed by amine functionalization and sensor conjugation. This surface-machining protocol not only enables precise spatial selectivity, but it also facilitates high deposition densities of the sensor moieties. As a proof of concept, the successful deposition of three different fluorophores onto selected cores of a multicore fiber is demonstrated. The protocol was developed to include attachment of a fluorescence-based pH sensor using the ratiometric carboxynapthofluorescein.

2.
Chem Commun (Camb) ; 56(26): 3757-3760, 2020 Apr 04.
Artigo em Inglês | MEDLINE | ID: mdl-32125330

RESUMO

Here we report the synthesis of a novel methylene blue-polymyxin conjugate and demonstrate its light-mediated killing of Gram-negative bacteria on skin models of infection demonstrating a 108 decrease in bacterial colony-forming units.

3.
Mater Sci Eng C Mater Biol Appl ; 108: 110489, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-31923957

RESUMO

Three dimensional synthetic polymer scaffolds have remarkable chemical and mechanical tunability in addition to biocompatibility. However, the chemical and physical space is vast in view of the number of variables that can be altered e.g. chemical composition, porosity, pore size and mechanical properties to name but a few. Here, we report the development of an array of 3D polymer scaffolds, whereby the physical and chemical properties of the polymer substrates were controlled, characterized in parallel (e.g. micro-CT scanning of 24 samples) and biological properties screened. This approach allowed the screening of 48 different polymer scaffolds constructed in situ by means of freeze-casting and photo-polymerisation with the tunable composition and 3D architecture of the polymer scaffolds facilitating the identification of optimal 3D biomaterials. As a proof of concept, the array approach was used to identify 3D polymers that were capable of supporting cell growth while controlling their behaviour. Sitting alongside classical polymer microarray technology, this novel platform reduces the gap between the identification of a biomaterial in 2D and its subsequent 3D application.

4.
Adv Healthc Mater ; 9(4): e1901347, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31943855

RESUMO

Substrates for neuron culture and implantation are required to be both biocompatible and display surface compositions that support cell attachment, growth, differentiation, and neural activity. Laminin, a naturally occurring extracellular matrix protein is the most widely used substrate for neuron culture and fulfills some of these requirements, however, it is expensive, unstable (compared to synthetic materials), and prone to batch-to-batch variation. This study uses a high-throughput polymer screening approach to identify synthetic polymers that supports the in vitro culture of primary mouse cerebellar neurons. This allows the identification of materials that enable primary cell attachment with high viability even under "serum-free" conditions, with materials that support both primary cells and neural progenitor cell attachment with high levels of neuronal biomarker expression, while promoting progenitor cell maturation to neurons.

5.
Analyst ; 145(3): 975-982, 2020 Feb 03.
Artigo em Inglês | MEDLINE | ID: mdl-31829318

RESUMO

Proteases are ideal target biomarkers as they have been implicated in many disease states, including steps associated with cancer progression. Electrochemical peptide-based biosensors have attracted much interest in recent years. However, the significantly large size of the electrodes typically used in most of these platforms has led to performance limitations. These could be addressed by the enhancements offered by microelectrodes, such as rapid response times, improved mass transport, higher signal-to-noise and sensitivity, as well as more localised and less invasive measurements. We present the production and characterisation of a miniaturised electrochemical biosensor for the detection of trypsin, based on 25 µm diameter Pt microelectrodes (rather than the ubiquitous Au electrodes), benchmarked by establishing the equivalent Pt macroelectrode response in terms of quantitative response to the protease, the kinetics of cleavage and the effects of non-specific protein binding and temperature. Interestingly, although there was little difference between Au and Pt macroelectrode response, significant differences were observed between the responses of the Pt macroelectrode and microelectrode systems indicative of increased reproducibility in the microelectrode SAM structure and sensor performance between the electrodes, increased storage stability and a decrease in the cleavage rate at functionalised microelectrodes, which is mitigated by measurement at normal body temperature. Together, these results demonstrate the robustness and sensitivity of the miniaturised sensing platform and its ability to operate within the clinically-relevant concentration ranges of proteases in normal and disease states. These are critical features for its translation into implantable devices.

6.
Front Oncol ; 9: 882, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31572676

RESUMO

The optical molecular imaging of inflammation is an emerging strategy for interventional medicine and diagnostics. The host's inflammatory response and adaptation to acute and chronic diseases provides unique signatures that have the potential to guide interventions. Thus, there are emerging a suite of molecular imaging and sensing approaches for a variety of targets in this area. This review will focus on two key cellular orchestrators that dominate this area, neutrophils and macrophages, with recent developments in molecular probes and approaches discussed.

7.
Mater Sci Eng C Mater Biol Appl ; 105: 110150, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31546442

RESUMO

Finding methods that fight bacterial infection or contamination, while minimising our reliance on antibiotics is one of the most pressing needs of this century. Although the utilisation of UV-C light and strong oxidising agents, such as bleach, are still efficacious methods for eliminating bacterial surface contamination, both methods present severe health and/or environmental hazards. Materials with intrinsic photodynamic activity (i.e. a material's ability upon photoexcitation to convert molecular oxygen into reactive oxygen species such as singlet oxygen), which work with light within the visible photomagnetic spectrum could offer a significantly safer alternative. Here we present a new, bespoke molybdenum cluster (Bu4N)2[{Mo6I8}(CF3(CF2)6COO)6], which is both efficient in the generation of singlet oxygen upon photoirradiation and compatible with the fluoropolymer (F-32L) known for its good oxygen permeability. Thus, (Bu4N)2[{Mo6I8}(CF3(CF2)6COO)6]/F-32L mixtures have been solution-processed to give homogenous films of smooth and fibrous morphologies and which displayed high photoinduced antibacterial activity against four common pathogens under visible light irradiation. These materials thus have potential in applications ranging from antibacterial coatings to filtration membranes and air conditioners to prevent spread of bacterial infections.


Assuntos
Anti-Infecciosos/farmacologia , Luz , Molibdênio/química , Molibdênio/farmacologia , Polímeros/farmacologia , Anti-Infecciosos/síntese química , Bactérias/efeitos dos fármacos , Bactérias/crescimento & desenvolvimento , Bactérias/efeitos da radiação , Contagem de Colônia Microbiana , Flúor/química , Espectroscopia de Ressonância Magnética , Modelos Moleculares , Polímeros/síntese química , Espectrometria de Fluorescência
8.
Angew Chem Int Ed Engl ; 58(40): 14189-14192, 2019 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-31397963

RESUMO

A ruthenium-based mitochondrial-targeting photosensitiser that undergoes efficient cell uptake, enables the rapid catalytic conversion of PtIV prodrugs into their active PtII counterparts, and drives the generation of singlet oxygen was designed. This dual mode of action drives two orthogonal cancer-cell killing mechanisms with temporal and spatial control. The designed photosensitiser was shown to elicit cell death of a panel of cancer cell lines including those showing oxaliplatin-resistance.

9.
Clin Infect Dis ; 2019 Jul 25.
Artigo em Inglês | MEDLINE | ID: mdl-31343064

RESUMO

BACKGROUND: The Global Programme to Eliminate Lymphatic Filariasis (GPELF) was launched in 2000 with the goal of eliminating LF as a public health problem by 2020. Despite considerable progress, around 60% is remaining with the deadline looming a year away. Consequently, there is a continued need for investment in both the mass drug administration (MDA) and morbidity management programmes, which this paper aims to demonstrate by estimating the health and economic burden of LF prior to MDA programmes starting in GPELF areas. METHODS: A previously developed model was used to estimate the number of individuals infected and those with symptomatic disease, along with the attributable number of disability-adjusted life years (DALYs). The economic burden was calculated by quantifying the costs incurred by the healthcare system in managing clinical cases, the patients' out-of-pocket costs, and their productivity costs. RESULTS: Prior to the MDA programme approximately 129 million were infected with LF, of which 43 million had clinical disease, corresponding to a DALY burden of 5.25 million. The average annual economic burden per chronic case was US$115, majority of which resulted from productivity costs. The total economic burden of LF was estimated at US$5.8 billion annually. CONCLUSION: These results demonstrate the magnitude of the LF burden and highlight the continued need to support the GPELF. Patients with clinical disease bore the majority of the economic burden but will not benefit much from the current MDA programme aimed at reducing transmission. This assessment further highlights the need to scale up morbidity management programmes.

10.
Sci Rep ; 9(1): 8422, 2019 Jun 10.
Artigo em Inglês | MEDLINE | ID: mdl-31182770

RESUMO

Rapid in situ detection of pathogens coupled with high resolution imaging in the distal human lung has the potential to provide new insights and diagnostic utility in patients in whom pneumonia is suspected. We have previously described an antimicrobial peptide (AMP) Ubiquicidin (fragment UBI29-41) labelled with an environmentally sensitive fluorophore that optically detected bacteria in vitro but not ex vivo. Here, we describe further chemical development of this compound and demonstrate that altering the secondary structure of the AMP to generate a tri-branched dendrimeric scaffold provides enhanced signal in vitro and ex vivo and consequently allows the rapid detection of pathogens in situ in an explanted human lung. This compound (NBD-UBIdend) demonstrates bacterial labelling specificity for a broad panel of pathogenic bacteria and Aspergillus fumigatus. NBD-UBIdend demonstrated high signal-to-noise fluorescence amplification upon target engagement, did not label host mammalian cells and was non-toxic and chemically robust within the inflamed biological environment. Intrapulmonary delivery of NBD-UBIdend, coupled with optical endomicroscopy demonstrated real-time, in situ detection of bacteria in explanted whole human Cystic Fibrosis lungs.

11.
Org Biomol Chem ; 17(22): 5533-5537, 2019 06 05.
Artigo em Inglês | MEDLINE | ID: mdl-31090781

RESUMO

Taking inspiration from the assembly of so-called peptoids (N-alkylglycine oligomers) we present a new synthetic methodology whereby N-heterocyclic carbene (NHC) based Pd ligands were assembled using a sub-monomer approach and loaded with Pd via solid-phase synthesis. This allowed the rapid generation a library of NHC-palladium catalysts that were readily functionalised to allow bioconjugation. These catalysts were able to rapidly activate a caged fluorophore and 'switch-on' an anticancer prodrug in 3D cell culture.


Assuntos
Materiais Biocompatíveis/síntese química , Compostos Heterocíclicos/síntese química , Metano/análogos & derivados , Paládio/química , Técnicas de Síntese em Fase Sólida , Materiais Biocompatíveis/química , Materiais Biocompatíveis/farmacologia , Catálise , Sobrevivência Celular/efeitos dos fármacos , Compostos Heterocíclicos/química , Compostos Heterocíclicos/farmacologia , Humanos , Ligantes , Células MCF-7 , Metano/síntese química , Metano/química , Metano/farmacologia , Estrutura Molecular
12.
Sci Rep ; 9(1): 7713, 2019 May 22.
Artigo em Inglês | MEDLINE | ID: mdl-31118459

RESUMO

Physiological sensing deep in tissue remains a clinical challenge. Here a flexible miniaturised sensing optrode providing a platform to perform minimally invasive in vivo in situ measurements is reported. Silica microspheres covalently coupled with a high density of ratiometrically configured fluorophores were deposited into etched pits on the distal end of a 150 µm diameter multicore optical fibre. With this platform, photonic measurements of pH and oxygen concentration with high precision in the distal alveolar space of the lung are reported. We demonstrated the phenomenon that high-density deposition of carboxyfluorescein covalently coupled to silica microspheres shows an inverse shift in fluorescence in response to varying pH. This platform delivered fast and accurate measurements (±0.02 pH units and ±0.6 mg/L of oxygen), near instantaneous response time and a flexible architecture for addition of multiple sensors.

13.
ACS Comb Sci ; 21(5): 417-424, 2019 05 13.
Artigo em Inglês | MEDLINE | ID: mdl-30973701

RESUMO

Polymer microarrays were utilized for the high-throughput screening and discovery of optimal polymeric substrates capable of trapping functional ratiometric fluorescence-based pH sensors. This led to the identification of poly(methyl methacrylate- co-2-(dimethylamino) ethyl acrylate) (PA101), which allowed, via dip coating, the attachment of fluorescent pH sensors onto the tips of optical fibers, resulting in robust, rapid, and reproducible sensing of physiological pHs.


Assuntos
Fibras Ópticas , Polimetil Metacrilato/química , Complexos de Coordenação/química , Fluoresceínas/química , Corantes Fluorescentes/química , Ensaios de Triagem em Larga Escala , Análise em Microsséries , Paládio/química , Espectrometria de Fluorescência
14.
Nat Chem ; 11(6): 578-586, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-30988414

RESUMO

Polymerization reactions conducted inside cells must be compatible with the complex intracellular environment, which contains numerous molecules and functional groups that could potentially prevent or quench polymerization reactions. Here we report a strategy for directly synthesizing unnatural polymers in cells through free radical photopolymerization using a number of biocompatible acrylic and methacrylic monomers. This offers a platform to manipulate, track and control cellular behaviour by the in cellulo generation of macromolecules that have the ability to alter cellular motility, label cells by the generation of fluorescent polymers for long-term tracking studies, as well as generate a variety of nanostructures within cells. It is remarkable that free radical polymerization chemistry can take place within such complex cellular environments. This demonstration opens up a multitude of new possibilities for how chemists can modulate cellular function and behaviour and for understanding cellular behaviour in response to the generation of free radicals.


Assuntos
Radicais Livres/química , Polimerização/efeitos da radiação , Ácidos Polimetacrílicos/síntese química , Poliestirenos/síntese química , Acrilatos/química , Acrilatos/efeitos da radiação , Acrilatos/toxicidade , Citoesqueleto de Actina/efeitos dos fármacos , Compostos de Anilina/química , Compostos de Anilina/efeitos da radiação , Compostos de Anilina/toxicidade , Movimento Celular/efeitos dos fármacos , Fluorescência , Células HeLa , Humanos , Metacrilatos/química , Metacrilatos/efeitos da radiação , Metacrilatos/toxicidade , Propano/análogos & derivados , Propano/química , Propano/efeitos da radiação , Fase S/efeitos dos fármacos , Estirenos/química , Estirenos/efeitos da radiação , Estirenos/toxicidade , Raios Ultravioleta , Compostos de Vinila/química , Compostos de Vinila/efeitos da radiação , Compostos de Vinila/toxicidade
15.
Acta Biomater ; 90: 146-156, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-30910621

RESUMO

Cartilage degeneration or damage treatment is still a challenge, but, tissue engineering strategies, which combine cell therapy strategies, which combine cell therapy and scaffolds, and have emerged as a promising new approach. In this regard, polyurethanes and polyacrylates polymers have been shown to have clinical potential to treat osteochondral injuries. Here, we have used polymer microarrays technology to screen 380 different polyurethanes and polyacrylates polymers. The top polymers with potential to maintain chondrocyte viability were selected, with scale-up studies performed to evaluate their ability to support chondrocyte proliferation during long-term culture, while maintaining their characteristic phenotype. Among the selected polymers, poly (methylmethacrylate-co-methacrylic acid), showed the highest level of chondrogenic potential and was used to create a 3D hydrogel. Ultrastructural morphology, microstructure and mechanical testing of this novel hydrogel revealed robust characteristics to support chondrocyte growth. Furthermore, in vitro and in vivo biological assays demonstrated that chondrocytes cultured on the hydrogel had the capacity to produce extracellular matrix similar to hyaline cartilage, as shown by increased expression of collagen type II, aggrecan and Sox9, and the reduced expression of the fibrotic marker's collagen type I. In conclusion, hydrogels generated from poly (methylmethacrylate-co-methacrylic acid) created the appropriate niche for chondrocyte growth and phenotype maintenance and might be an optimal candidate for cartilage tissue-engineering applications. SIGNIFICANCE STATEMENT: Articular cartilage has limited self-repair ability due to its avascular nature, therefore tissue engineering strategies have emerged as a promising new approach. Synthetic polymers displaygreat potential and are widely used in the clinical setting. In our study, using the polymer microarray technique a novel type of synthetic polyacrylate was identified, that was converted into hydrogels for articular cartilage regeneration studies. The hydrogel based on poly (methylmethacrylate-co-methacrylic acid-co-PEG-diacrylate) had a controlable ultrastructural morphology, microstructure (porosity) and mechanical properties (stiffness) appropriate for cartilage engineering. Our hydrogel created the optimal niche for chondrocyte growth and phenotype maintenance for long-term culture, producing a hyaline-like cartilage extracellular matrix. We propose that this novel polyacrylate hydrogel could be an appropriate support to help in the treatment efficient cartilage regeneration.

16.
Biomed Opt Express ; 10(1): 181-195, 2019 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-30775092

RESUMO

We present a dual-color laser scanning endomicroscope capable of fluorescence lifetime endomicroscopy at one frame per second (FPS). The scanning system uses a coherent imaging fiber with 30,000 cores. High-speed lifetime imaging is achieved by distributing the signal over an array of 1024 parallel single-photon avalanche diode detectors (SPADs), minimizing detection dead-time maximizing the number of photons detected per excitation pulse without photon pile-up to achieve the high frame rate. This also enables dual color fluorescence imaging by temporally shifting the dual excitation lasers, with respect to each other, to separate the two spectrally distinct fluorescent decays in time. Combining the temporal encoding, to provide spectral separation, with lifetime measurements we show a one FPS, multi-channel endomicroscopy platform for clinical applications and diagnosis. We demonstrate the potential of the system by imaging SmartProbe labeled bacteria in ex vivo samples of human lung using lifetime to differentiate bacterial fluorescence from the strong background lung autofluorescence which was used to provide structural information.

17.
Chembiochem ; 20(7): 872-876, 2019 04 01.
Artigo em Inglês | MEDLINE | ID: mdl-30394615

RESUMO

Traditionally, prodrug activation has been limited to enzymatic triggers or gross physiological aberrations, such as pH, that offer low selectivity and control over dosage. In recent years, the field of prodrug activation chemistry has been transformed by the use of bioorthogonal reactions that can be carried out under biological conditions at sub-millimolar concentrations, with the tetrazine-mediated inverse electron demand Diels-Alder reaction amongst the most recognised. Their high reaction rates, chemoselectivity and excellent biocompatibility make tetrazines ideal small molecules for activating prodrugs. Recently the tetrazine moiety has been used as a prodrug for a pyridazine thus broadening the scope of prodrug systems. This article discusses the concept of using tetrazines as small-molecule activators for prodrugs, and provides an overview of tetrazine-based prodrug systems, with a particular focus on the recently reported prodrug-prodrug activation strategy.


Assuntos
Compostos Heterocíclicos com 1 Anel/química , Pró-Fármacos/química , Linhagem Celular Tumoral , Química Click , Reação de Cicloadição , Humanos , Piridazinas/síntese química
18.
Nanomaterials (Basel) ; 8(12)2018 Dec 10.
Artigo em Inglês | MEDLINE | ID: mdl-30544753

RESUMO

The evaluation of the role of physicochemical properties in the toxicity of nanoparticles is important for the understanding of toxicity mechanisms and for controlling the behavior of nanoparticles. The surface charge of nanoparticles is suggested as one of the key parameters which decide their biological impact. In this study, we synthesized fluorophore-conjugated polystyrene nanoparticles (F-PLNPs), with seven different types of surface functional groups that were all based on an identical core, to evaluate the role of surface charge in the cellular uptake of nanoparticles. Phagocytic differentiated THP-1 cells or non-phagocytic A549 cells were incubated with F-PLNP for 4 h, and their cellular uptake was quantified by fluorescence intensity and confocal microscopy. The amount of internalized F-PLNPs showed a good positive correlation with the zeta potential of F-PLNPs in both cell lines (Pearson's r = 0.7021 and 0.7852 for zeta potential vs. cellular uptake in THP-1 cells and nonphagocytic A549 cells, respectively). This result implies that surface charge is the major parameter determining cellular uptake efficiency, although other factors such as aggregation/agglomeration, protein corona formation, and compositional elements can also influence the cellular uptake partly or indirectly.

20.
Chem Sci ; 9(36): 7198-7203, 2018 Sep 28.
Artigo em Inglês | MEDLINE | ID: mdl-30288239

RESUMO

The selective and biocompatible activation of prodrugs within complex biological systems remains a key challenge in medical chemistry and chemical biology. Herein we report, for the first time, a dual prodrug activation strategy that fully satisfies the principle of bioorthogonality by the symbiotic formation of two active drugs. This dual and traceless prodrug activation strategy takes advantage of the INVDA chemistry of tetrazines (here a prodrug), generating a pyridazine-based miR21 inhibitor and the anti-cancer drug camptothecin and offers a new concept in prodrug activation.

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