Thesis

Nouveaux biomatériaux photosensibles pour des applications antimicrobiennes

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Abstract

Bien que la thérapie photodynamique a été découverte il y a plus d’un siècle par sa capacité à inactiver les microorganismes, elle a été développée principalement comme traitement thérapeutique anticancéreux. Récemment, avec le nombre croissant d'infections causées par des bactéries multirésistantes, la chimiothérapie photodynamique antimicrobienne (PACT) est considérée comme une approche antimicrobienne alternative prometteuse. La PACT est une stratégie thérapeutique non invasive, et a une action rapide. De plus, la PACT ne semble pas induire la mise en place de mécanismes de résistance par les bactéries, ce qui en fait une alternative attrayante, par exemple, aux traitements conventionnels des infections des plaies. Les photosensibilisateurs les plus utilisés dans le PACT sont les porphyrines et leurs dérivés. Cependant, ces composés souffrent d’une faible solubilité dans l'eau, d’auto-quenching et d’un manque de sélectivité contre les cellules bactériennes. Afin de pallier certains problèmes liés à l’utilisation des porphyrines en tant que photosensibilisateurs dans la PACT, nous nous sommes intéressés, au cours de ce travail, à deux stratégies pour l’optimisation de cette thérapie. La première consiste à coupler une porphyrine à deux dérivés de maltodextrines (maltohexaose ou maltotriose) utilisés récemment comme agent de ciblage bactérien pour l'imagerie médicale , afin d’améliorer la sélectivité de la porphyrine vis-à-vis les cellules bactériennes. L’évaluation biologique de ces conjugués a montré que l’association des porphyrines avec les maltooligosacharide augmente leur efficacité antibactérien Staphylococcus aureus et Staphylococcus epidermidis. La deuxième stratégie vise à incorporer des porphyrines dans des hydrogels à base de xylane. Pour cela, trois voies ont été explorées : dans une première approche, l’hydrogel a été synthétisé d’abord par réticulation de xylane avant de le chargé par une porphyrine cationique. Dans la deuxième, les porphyrines sont fixées d’abord par liaisons covalentes sur le xylane, puis les hydrogels ont été obtenus à partir de ces xylanes fonctionnalisés par un agent de réticulation. Dans la troisième méthode, l’hydrogel est obtenu directement par une réticulation directe du xylane par les porphyrines. Tous les hydrogels obtenus ont montré une bonne intégrité mécanique et un taux de gonflement élevé et une forte activité photoantibactérienne vis-à-vis des bactéries Gram positif et Gram négatif.

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Antibiotic resistance is one of the greatest challenges in the health system nowadays, representing a serious problem for public health. Initially, antibiotic-resistant strains were restricted to the hospital environment, but now they can be found everywhere. Globalization, excessive use of antibiotics in animal husbandry and aquaculture, use of multiple broad-spectrum agents, and lack of good antimicrobial stewardship can be listed as the factors most responsible for the spread of antibiotic resistance. The increase in the prevalence of antibiotic-resistant pathogens implies having fewer antimicrobial agents to treat infections. The estimate is that by 2050, there will be no effective antibiotic available, if no new drug is developed or discovered. This raises the need to search for alternative methods of controlling antibiotic-resistant pathogens. Considering this problem, the objective of this review is to outline the most frequent antibiotic-resistant bacteria and describe the advantageous and limitations of alternative methods that have been proposed to control them.
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Porphyrins are widely used in anticancer photodynamic therapy (PDT). However, low physiological solubility and lack of selectivity towards cancer cells are the main limitations of their clinical use. Nanoparticles are being intensively explored as photosensitizer carriers for PDT to overcome these limitations. The aims of this work are to synthesize core-shell hybrid nanoparticles formed by a silica core and xylan carrying a 5-(4-hydroxyphenyl)-10,15,20-triphenylporphyrin (TPPOH) shell, and evaluate their anticancer activity. To afford drug-controlled incorporation and enhance blood circulation, TPPOH was covalently linked to xylan. Different xylans with degrees of substitution in TPPOH ranging from 0.034 to 1.11, were obtained and characterized. Then, the xylan-TPPOH conjugate (PX) was used to coat the silica nanoparticles (PX SNPs). The obtained nano-objects were characterized and their therapeutic potential for photodynamic therapy evaluated against colorectal cancer cell lines. in vitro analysis showed that PX SNPs were 40-fold and 10-fold more effective against HCT116 cells and HT-29 cells respectively compared to free TPPOH.
Article
Rapid emergence of multidrug resistant (MDR) “superbugs” poses a severe threat to global health. Notably, undeveloped diagnosis and concomitant treatment failure remain highly challenging. Herein, we report a sonotheranostic strategy to achieve bacteria-specific labeling and visualized sonodynamic therapy (SDT). Using maltohexaose-decorated cholesterol and bacteria-responsive lipid compositions, a smart nanoliposomes platform (MLP18) was developed for precise delivery of purpurin 18, a potent sonosensitizer proved in this study. Taking advantages of bacteria-specific maltodextrin transport pathway, the prepared MLP18 can specifically target to bacterial infection site and accurately distinguish the foci from sterile inflammation or cancer with highly selective fluorescence/photoacoustic signal on the bacteria-infected site of mice. Moreover, the bacteria-responsive feature of MLP18 activated an efficient release and internalization of high concentration sonosensitizer into bacterial cell, resulting in effective sonodynamic elimination of MDR bacteria. In situ MRI monitoring visualized such potent sonodynamic activity and indicated that MLP18-mediated SDT could successfully eradicate inflammation and abscess from mice with bacterial myositis. In view of the above advantages, the developed nanoliposomes may serve as a promising sonotheranostic platform against MDR bacteria in the areas of healthcare.
Article
Photodynamic therapy (PDT) has become an effective antibiosis method for overcoming antibiotic resistance. In this study, we developed a versatile bacterial membrane-binding chimeric peptide PpIX-[PEG8-(KLAKLAK)2]2 (denoted as PPK) by conjugating a photosensitizer protoporphyrin IX (PpIX) with the antimicrobial peptide (KLAKLAK)2 (KLA) for effective photodynamic inactivation of bacteria. The chimeric peptide PPK with positively charged property and α-helical conformation could rapidly bind to microbial cells through electrostatic interaction and membrane insertion. Moreover, PPK could disrupt bacterial membrane and further elicit lipid bilayer leakage to kill bacteria by toxic reactive oxygen species (ROS) generated by PpIX under 660 nm light. In vitro experiments demonstrated that cationic PPK possessed excellent antimicrobial activity against both Gram-positive bacteria Staphylococcus aureus (S. aureus) and Gram-negative bacteria Escherichia coli (E. coli). Afterward, PPK also exhibited perfect therapeutic effects on S. aureus-infected mice without any systemic side effect. This chimeric peptide PPK will find great potential for photodynamic antibiosis.
Article
C3‐(Trans‐arylethenyl)carbonylated chlorophyll derivatives possessing a bacteriochlorin or chlorin π‐system were synthesized by cross‐aldol (Claisen‐Schmidt) condensation of methyl pyrobacteriopheophorbide‐a or 3‐acetyl‐3‐devinyl‐pyropheophorbide‐a bearing the C3‐acetyl group with p‐(un)substituted benzaldehydes under basic conditions. The corresponding porphyrin‐type chlorophyll derivatives were prepared by the oxidation (17,18‐didehydrogenation) of the chlorin‐type. Their Qy absorption and fluorescence emission maxima in dichloromethane correlated well with Hammett substituent constants of the p‐substituents. Several electron‐withdrawing p‐substituents suppressed the emission due to photoinduced electron transfer quenching in a molecule. The substitution sensitivities for their maxima and fluorescence quantum yields decreased in the order of bacteriochlorin‐, chlorin‐, and porphyrin‐type derivatives. This article is protected by copyright. All rights reserved.
Article
In this work, we compare the antibacterial activity and hydroxyl radical generation of three different titanium dioxide nanostructures (immobilized titania nanoparticles, nanotubes and ultra-thin films) to find the optimum morphology and processing conditions that could enhance their antibacterial response when this kind of materials are used in catalyst fixed-bed reactors design. It was demonstrated that photocatalytic activity not only depends on direct contact of the catalyst with the pathogen, but also on the concentration of oxidizing species that can be generated in the nanostructured material itself. Based on our results of surface compositional analysis and the behavior of titania nanoparticles-based films, it is suggested that morphology of the titanium dioxide film’s surface is largely affected by the material affinity to the substrate underneath. After photoluminescence measurements and analysis, an electron transfer mechanism between the titanium dioxide nanoparticles and the spin-on glass matrix where they are embedded, was found to influence the photocatalytic activity of nanoparticle-based films. While it was observed a similar hydroxyl radical generation (determined by pNDA bleaching) in titania nanoparticle-based films and nanotubes in anatase phase, the antibacterial activity was higher in titania nanotubes. This phenomenon is explained by the fact that it has a relatively smooth surface that allows the bacteria to maintain greater contact in comparison with nanoparticle-based films.
Article
It is known that multiple cationic charges are required to produce broad-spectrum antimicrobial photosensitizers (PS) for photodynamic inactivation (aPDI) or photodynamic therapy of bacteria and fungi. In the present study...
Thesis
L’émergence de nouvelles souches bactériennes résistantes a signé la fin de l’« âge d’or » des antibiotiques. L’organisation mondiale de la santé a reconnu l’imminence des problèmes associés à ces nouvelles bactéries, qui engendrent de nouveau une mortalité en augmentation. Afin de palier à ce problème, de nouvelles alternatives aux antibiotiques sont envisagées par les chercheurs à travers le monde. La thérapie photodynamique antimicrobienne est l’une de ces alternatives. Elle a su se démarquer grâce à son incapacité à induire la résistance bactérienne. Alors que les résultats furent initialement très prometteurs contre les bactéries Gram positif, une moins bonne sensibilité fut rapidement observée de la part des bactéries Gram négatif. Afin d’augmenter le potentiel antibactérien de cette technique, diverses stratégies furent élaborées comme l’utilisation de photosensibilisateurs cationiques, l’ajout d’un agent de ciblage, ou la présence d’un agent de perméabilisation membranaire. L’un de ces agents est la polymyxine B, un peptide antimicrobien qui arbore une très bonne affinité avec les bactéries Gram négatif. Dans cette étude, nous avons voulu associer chimiquement différents photosensibilisateurs avec des dérivés de polymyxines B de façon covalente, par l’intermédiaire d’un bras « spacer » ou d’une plateforme. L’association de ces deux familles de molécules a permis d’élaborer de nouveaux composés qui ont démontré une activité photobactéricide accrue contre un large spectre de bactérie. De plus, ces composés ont montré une affinité augmentée pour les bactéries, ce qui permettra de réduire les effets secondaires sur les cellules humaines. Cette étude confirme l’importance d’utiliser des peptides antimicrobiens afin d’améliorer la thérapie photodynamique. Ces travaux seront approfondis afin de permettre la création de nouveaux traitements dermatologiques basées sur cette nouvelle thérapie et efficaces contre un large spectre de souche bactérienne
Article
Diagnosis and localization of bacterial infections remains a significant clinical challenge. Harnessing bacteria-specific metabolic pathways such as the maltodextrin transport mechanism may allow to specifically localize and image even small or hidden colonies. This requires that the intra-bacterial tracer accumulation provided by the transporter is matched by high serum stability of the tracer molecule. Herein we report radiolabeled maltodextrins of varying chain lengths and with free non-reducing/reducing ends and evaluate their behavior against the starch degrading enzymes in the blood that compromise their serum stability. We show successful SPECT/CT imaging in a footpad infection model in vivo using the newly developed model tracer [99mTc]MB1143, and compare the signal with [18F]FDG-PET as a non-bacterial specific marker for inflammation. Although the [99mTc]MB1143 imaging signal is highly specific it is low, most probably due to insufficient serum stability of the tracer. A series of stability tests with different 18F-labelled maltodextrins finally yielded clear structural guidelines regarding substitution patterns and chain lengths of maltodextrin-based tracers for nuclear imaging of bacterial infections.
Article
In order to highlight the potential of PACT in case of infections by antibiotic resistant-strains, a new antimicrobial peptide conjugate has been synthesized, consisting of a derivative of polymyxin B and a cationic porphyrin covalently attached together to a spacer. A polymyxin-derived moiety was subjected to a primary structural modification consisting in the replacement of 4 diaminobutyrate residues with lysine ones. This modification was done in order to strongly reduce bactericidal activity, with the aim to eliminate the potential rise of polymyxin-resistant strains. Despite this modification, this new conjugate displayed a strong photobactericidal activity against Gram-positive as well as Gram-negative bacteria. It was further shown that this conjugate was able to strongly stick to the cell walls of either kind of strains, thus helping to inactivate bacteria through the production of ROS under light irradiation.
Article
Salecan is a novel water soluble polysaccharide produced by a salt-tolerant strain Agrobacterium sp. ZX09. Poly(dimethylaminoethyl methacrylate) (PDMAEMA) is a pH, thermo, and ionic strength multi-sensitive polymer with anti-bacterial property. Here, we report a semi-interpenetrating polymer network (semi-IPN) hydrogel based on salecan and PDMAEMA. The obtained hydrogel is simultaneous sensitive to pH, ionic strength and temperature: the swelling ratio maximizes at pH 1.2 and shrinks at pH value greater than 3; besides, water content of the hydrogel decreases as the ionic strength increases; in terms of temperature, the hydrogel swells/deswells at temperatures below/above 40 °C. Cytotoxicity test shows the hydrogel is non-cytotoxic to COS-7 cells. Protein drug insulin was selected as model drug to test the in vitro release behavior of the hydrogel. Results show the release rate increases with the swelling ratio of the hydrogel. In addition, when the temperature is higher than the lower critical solution temperature (LCST) of PDMAEMA, the hydrogel shrinks to extrude more drug molecules. Moreover, the release rate and release amount were higher in acid condition (pH 1.2) than at pH 7.4. In summary, this polysaccharide hydrogel is a promising material for drug delivery.
Article
A novel compound, consisting of a cationic porphyrin covalently attached to a derivative of polymyxin B has been synthesized, which presents enhanced activity and targeting properties compared to usual cationic porphyrins recognized as efficient photosensitizers in photodynamic antimicrobial chemotherapy (PACT). A synthesis pathway was established to preserve the bactericidal activity of the peptide. Accordingly, the N-terminal amino acid (L-2,4-diaminobutyric acid) of polymyxin B (PMB) was switched for a cysteine residue. Then, the resulting derivative of PMB was covalently bound to 5-(4-aminophenyl)-10,15,20-tri(4-N-methylpyridyl)-21H,23H-porphyrin using a thiol-maleimide “click” coupling. The peptide-coupled photosensitizer has demonstrated an improved PACT efficiency compared to the cationic porphyrin alone. This enhancement has been observed against Staphylococcus aureus, Pseudomonas aeruginosa, and especially Escherichia coli. Flow cytometry analyses and confocal imaging microscopy demonstrated that the porphyrin-peptide conjugate selectively sticked to the cell walls of either Gram+ or Gram- bacteria, thus justifying the damages induced by singlet oxygen production.
Article
Benefiting from their inherent localized and controlled release properties, hydrogels are ideal delivery systems for therapeutic drugs or nanoparticles. In particular, the applications of hydrogels for the delivery and release of photo-responsive drugs or nanoparticles are receiving increasing attention. However, the effect of the hydrogel matrix on the fluorescence emission and singlet oxygen generation efficiency of the embedded photosensitizers (PSs) has not been clarified. Herein, meso-tetrakis (1-methylpyridinium-4-yl) porphyrin (TMPyP) as a water-soluble PS is encapsulated into an injectable hydrogel formed by glycol chitosan and dibenzaldehyde-terminated telechelic poly(ethylene glycol). Compared to free TMPyP, the TMPyP encapsulated in the hydrogel exhibits three distinct advantages: (1) More singlet oxygen was generated under the same laser irradiation condition; (2) Much longer tumor retention was observed due to the low fluidity of the hydrogel; (3) The fluorescence intensity of TMPyP was significantly enhanced in the hydrogel due to its decreased self-quenching effect. These excellent characteristics lead to remarkable anticancer efficacy and superior fluorescence emission property of the TMPyP-hydrogel system, promoting the development of imaging-guided photodynamic therapy.
Chapter
Superparamagnetic iron oxide nanoparticles (SPIONs) have drawn attention because of their excellent superparamagnetic properties such as controllable size, large surface area-to-volume ratio, and nontoxicity. Surface functionalization of SPIONs with therapeutic molecules, including antimicrobial agents, has been successfully used in nanomedicine. Through application of an external magnetic field, antimicrobial-loaded SPIONs can be guided to the desired infection site allowing a direct and specific therapeutic effect with minimum side effects. The great advantage of SPIONs is their magnetic properties that allow direct delivery of matter into the pathogen zone without influencing the whole organism, which incites an increasing interest in the development of antimicrobial SPIONs. This approach is interesting because of emerging problems such as the increase of resistant bacterial strains, biofilm formation, and the possibility of treating and diagnosing parasitic diseases. In this context, this chapter presents and discusses what makes SPIONs so unique, showing recent progress, drawbacks, and challenges in the design of SPIONs as nanocarriers for antimicrobial agents. This chapter is intended to be a source of inspiration for new developments in this promising field.
Article
Hydrogel-based bioadhesives have emerged as alternatives for sutureless wound closure, since they can mimic the composition and physicochemical properties of the extracellular matrix. However, they are often associated with poor mechanical properties, low adhesion to native tissues, and lack antimicrobial properties. Herein, a new sprayable, elastic, and biocompatible composite hydrogel, with broad-spectrum antimicrobial activity, for the treatment of chronic wounds is reported. The composite hydrogels were engineered using two ECM-derived biopolymers, gelatin methacryloyl (GelMA) and methacryloyl-substituted recombinant human tropoelastin (MeTro). MeTro/GelMA composite hydrogel adhesives were formed via visible light-induced crosslinking. Additionally, the antimicrobial peptide Tet213 was conjugated to the hydrogels, instilling antimicrobial activity against Gram (+) and (−) bacteria. The physical properties (e.g. porosity, degradability, swellability, mechanical, and adhesive properties) of the engineered hydrogel can be fine-tuned by varying the ratio of MeTro/GelMA and the final polymer concentration. The hydrogels supported in vitro mammalian cellular growth in both two-dimensional and three dimensional cultures. The subcutaneous implantation of the hydrogels in rats confirmed their biocompatibility and biodegradation in vivo. The engineered MeTro/GelMA-Tet213 hydrogels can be used for sutureless wound closure strategies to prevent infection and promote healing of chronic wounds.
Article
The visible light-cured glycol chitosan (GC) hydrogel systems for the sustained release of growth factors (GFs) were prepared, and their efficacies in wound healing acceleration were investigated. Vascular endothelial growth factor (VEGF) and platelet-derived growth factor-BB (PDGF-BB) were selected as the dual GFs and commercially available Duoderm® was used as control. In order to increase intermolecular chain mobility, methoxy (polyethylene glycol) acetic acid (MPEG-COOH) was conjugated to GC through condensation reaction resulting in MPEG grafted GC (MPEG-g-GC). As a crosslinker, glycidyl methacrylate was covalently conjugated to the amine group of MPEG-g-GC (MPEG/GM-g-GC), and crosslinking of MPEG/GM-g-GC chains were made by visible light irradiation (MPEG-g-GC hydrogels). To enhance wound healing efficacy, specific amounts of GFs was incorporated into the crosslinking solutions at this photo-curing stage (VEGF/MPEG-g-GC, PDGF/MPEG-g-GC and VEGF/PDGF/MPEG-g-GC). The grafting of MPEG plasticized the samples yielding low viscoelastic properties, ranging from 56 Pa to 58 Pa. In vitro release test showed that GFs were rapidly released within 24 hours, and released in a sustained manner thereafter. In vivo studies showed that the GF-loaded samples further enhanced wound healing compared to control. Particularly, VEGF/PDGF/MPEG-g-GC, dual GFs releasing hydrogel, showed outstanding granulation effects among samples.
Article
Microbial adhesion, biofilm formation and associated microbial infection are common challenges faced by implanted biomaterials (e.g. hydrogels) in bioengineering applications. In this work, an injectable self-healing hydrogel with antimicrobial and antifouling properties was prepared through self-assembly of an ABA tri-block copolymer employing catechol functionalized polyethylene glycol (PEG) as A block and poly{[2-(methacryloyloxy)-ethyl] trimethyl ammonium iodide}(PMETA) as B block. This hydrogel exhibits excellent thermo-sensitivity, can effectively inhibit the growth of E. coli (>99.8% killing efficiency) and prevent cell attachment. It can also heal autonomously from repeated damage, through mussel-inspired catechol-mediated hydrogen bonding and aromatic interactions, exhibiting great potential in bioengineering applications.