Nicolas Tabary

Multilayered textile coating based on a β-cyclodextrin polyelectrolyte for the controlled release of drugs

The aim of this work was to develop the formation of multilayered coating incorporating a cyclodextrin polyelectrolyte onto a non-woven polyethylene terephthalate (PET) textile support in order to obtain reservoir and sustained release properties towards bioactive molecules. We optimized the multilayer assembly immobilization onto the PET surface according to the layer-by-layer (LbL) deposition process. After a pre-treatment of the textile support aiming to offer a sufficient ionic character to the surface, it was alternatively immersed into two polyelectrolytes aqueous solutions consisting of chitosan (CHT) as polycation on the one hand, and a β-cyclodextrin polymer (polyCTR-βCD) as polyanion on the other hand. In a second approach, a TBBA/polyCTR-βCD complex (4-tert-butylbenzoic acid, TBBA) was used in order to load the system with a drug model whose kinetics of release was assessed. Gravimetry, microscopy, OWLS, colorimetric titration, infrared and zetametry were used as characterization techniques. An effective deposition on the textile surface due to ionic interactions with alternation of up to 10 layers of each of both polyelectrolytes was clearly evidenced. However, we observed that layer formation occurred to a lesser extent when TBBA/polyCTR-βCD complex was applied instead of polyCTR-βCD alone. The release study showed that drug reservoir properties and release kinetics could be controlled by the number of layers in the system and that TBBA release was faster than the multilayered coating degradation.

Porous silicon-cyclodextrin based polymer composites for drug delivery applications

One of the main applications of porous silicon (PSi) in biomedicine is drug release, either as a single material or as a part of a composite. PSi composites are attractive candidates for drug delivery systems because they can display new chemical and physical characteristics, which are not exhibited by the individual constituents alone. Since cyclodextrin-based polymers have been proven efficient materials for drug delivery, in this work β-cyclodextrin-citric acid in-situ polymerization was used to functionalize two kinds of PSi (nanoporous and macroporous). The synthesized composites were characterized by microscopy techniques (SEM and AFM), physicochemical methods (ATR-FTIR, XPS, water contact angle, TGA and TBO titration) and a preliminary biological assay was performed. Both systems were tested as drug delivery platforms with two different model drugs, namely, ciprofloxacin (an antibiotic) and prednisolone (an anti-inflammatory), in two different media: pure water and PBS solution. Results show that both kinds of PSi/β-cyclodextrin-citric acid polymer composites, nano- and macro-, provide enhanced release control for drug delivery applications than non-functionalized PSi samples.

Methyl-β-cyclodextrin modified vascular prosthesis: Influence of the modification level on the drug delivery properties in different media

A textile polyester vascular graft was modified with methyl-β-cyclodextrin (MeβCD) to obtain a new implant capable of releasing antibiotics directly in situ at the site of operation over a prolonged period and thereby prevent post-operative infections. We investigated the influence of the curing parameters (time and temperature) that allow control of the degree of functionalization (DF) of the support by MeβCD. The inclusion of ciprofloxacin (CFX) in the MeβCD cavity was observed in solution by two-dimensional (1)H NMR spectroscopy. The amount of CFX loaded on the modified graft increased with DF. Depending on the release medium (water, phosphate-buffered saline, or human plasma) and the DF of the prostheses, different kinetic profiles of release of CFX were obtained. The sustained release of CFX in human plasma was shown by microbiological assays that indicated prolonged antimicrobial activity against Staphylococcus aureus and Escherichia coli. Viability tests demonstrated the non-toxicity of MeβCD to an epithelial cell line (HPMEC), although a decrease in endothelial cell number was observed on the functionalized prosthesis, probably due to the roughness of the coating and also to the nature of the MeβCD polymer present on the surface of the fibers.

Comparative study of vascular prostheses coated with polycyclodextrins for controlled ciprofloxacin release

A textile polyester vascular graft was modified with cyclodextrins to obtain a new implant capable of releasing antibiotics (here ciprofloxacin, CFX) over prolonged time periods and thereby reducing the risk of post-operative infections. In this study, we compared samples modified with native and modified cyclodextrins, presenting different cavity sizes (β or γ cyclodextrins) and different substituent groups (hydroxypropyl and methyl). Drug release was measured in water, phosphate buffer pH 7.4 and blood plasma. The inclusion of CFX in the cyclodextrins cavities was observed in solution by two-dimensional (1)H NMR spectroscopy and confirmed by (1)F NMR measurements. Grafts modification with all cyclodextrins induced an increase of their sorption capacity towards CFX whose extent depended on the nature of the cyclodextrin: a 4-fold and 10-fold increase was observed in the cases of hydroxypropyl cyclodextrins and methylated β-cyclodextrin, respectively. Depending on the type of release medium and nature of CD, different CFX release kinetics were obtained. The discussion highlighted not only the role of the host guest complexation, but also that of the electrostatic interactions that occur between the anionic crosslinks of the cyclodextrins polymers, and CFX that presents a zwitterionic character. The microbiological assessment confirmed sustained CFX release in human plasma and demonstrated antibacterial efficiency of CD modified prostheses against Staphylococcus aureus and Escherichia coli for at least 24 h (compared to 4 h in the case of virgin grafts).

Bioinspired Titanium Drug Eluting Platforms Based on a Poly-β-cyclodextrin–Chitosan Layer-by-Layer Self-Assembly Targeting Infections

In the field of implantable titanium-based biomaterials, infections and inflammations are the most common forms of postoperative complications. The controlled local delivery of therapeutics from implants through polyelectrolyte multilayers (PEMs) has recently emerged as a versatile technique that has shown great promise in the transformation of a classical medical implant into a drug delivery system. Herein, we report the design and the elaboration of new biodegradable multidrug-eluting titanium platforms based on a polyelectrolyte multilayer bioactive coating that target infections. These systems were built up in mild conditions according to the layer-by-layer (L-b-L) assembly and incorporate two biocompatible polysaccharides held together through electrostatic interactions. A synthetic, negatively charged β-cyclodextrin-based polymer (PCD), well-known for forming stable and reversible complexes with hydrophobic therapeutic agents, was exploited as a multidrug reservoir, and chitosan (CHT), a naturally occurring, positively charged polyelectrolyte, was used as a barrier for controlling the drug delivery rate. These polyelectrolyte multilayer films were strongly attached to the titanium surface through a bioinspired polydopamine (PDA) film acting as an adhesive first layer and promoting the robust anchorage of PEMs onto the biomaterials. Prior to the multilayer film deposition, the interactions between both oppositely charged polyelectrolytes, as well the multilayer growth, were monitored by employing surface plasmon resonance (SPR). Several PEMs integrating 5, 10, and 15 bilayers were engineered using the dip coating strategy, and the polyelectrolyte surface densities were estimated by colorimetric titrations and gravimetric analyses. The morphologies of these multilayer systems, as well as their naturally occurring degradation in a physiological medium, were investigated by scanning electron microscopy (SEM), and their thicknesses were measured by means of profilometry and ellipsometry studies. Finally, the ability of the coated titanium multilayer devices to act as a drug-eluting system and to treat infections was validated with gentamicin, a relevant water-soluble antibiotic commonly used in medicine due to its broad bactericidal spectrum.

A chlorhexidine-loaded biodegradable cellulosic device for periodontal pockets treatment

Absorbent points widely used in endodontic therapy were transformed into bioresorbable chlorhexidine delivery systems for the treatment of the periodontal pocket by preventing its recolonization by the subgingival microflora. These paper points (PPs) were first oxidized to promote their resorption, then grafted with β-cyclodextrin (CD) or maltodextrin (MD) in order to achieve sustained delivery of chlorhexidine. We investigated the oxidation step parameters through the time of reaction and the nitric and phosphoric acid ratios in the oxidizing mixture, and then the dextrin grafting step parameters through the time and temperature of reaction. A first selection of the appropriate functionalization parameters was undertaken in relation to the degradation profile kinetics of the oxidized (PPO) and oxidized-grafted samples (PPO-CD and PPO-MD). Samples were then loaded with chlorhexidine digluconate (digCHX), a widely used antiseptic agent in periodontal therapy. The release kinetics of digCHX from PPO-CD and PPO-MD samples were compared to PP, PPO and to PerioChip(®) (a commercial digCHX containing gelatine chip) in phosphate buffered saline (pH 7.4) by ultraviolet spectrophotometry. The cytocompatibility of the oxidized-grafted PP was demonstrated by cell proliferation assays. Finally, the disc diffusion test from digCHX loaded PPO-MD samples immersed in human plasma was developed on pre-inoculated agar plates with four common periodontal pathogenic strains: Fusobacterium nucleatum, Prevotella melaninogenica, Aggregatibacter actinomycetem comitans and Porphyromonas gingivalis. To conclude, the optimized oxidized-dextrin-grafted PPs responded to our initial specifications in terms of resorption and digCHX release rates and therefore could be adopted as a reliable complementary periodontal therapy.

Poly-(cyclo)dextrins as ethoxzolamide carriers in ophthalmic solutions and in contact lenses.

Efficient ophthalmic therapy requires the development of strategies that can provide sufficiently high drug levels in the ocular structures for a prolonged time. This work focuses on the suitability of poly-(cyclo)dextrins as carriers able to solubilize the carbonic anhydrase inhibitor (CAI) ethoxzolamide (ETOX), which is so far used for oral treatment of glaucoma. Topical ocular treatment should notably enhance the efficiency/safety profile of the drug. Natural α-, β- and γ-cyclodextrins and a maltodextrin were separately polymerized using citric acid as cross-linker agent under mild conditions. The resultant hydrophilic polymers exhibited larger capability to solubilize ETOX than the pristine (cyclo)dextrins. Moreover, they provided sustained drug diffusion in artificial lachrymal fluid. Interestingly the poly-(cyclo)dextrins solutions facilitate the loading of remarkably high doses of ETOX in poly(2-hydroxyethyl methacrylate)-based contact lenses. Exploiting ionic interactions between functional groups in the contact lenses and remnant free carboxylic acids in the citric acid linkers of poly-(cyclo)dextrins led to the retention of the drug-loaded poly-(cyclo)dextrins and, in turn, to sustained release for several weeks.

Effect of different carboxylic acids in cyclodextrin functionalization of cellulose nanocrystals for prolonged release of carvacrol.

Current investigations deal with new surface functionalization strategy of nanocrystalline cellulose-based substrates to impart active molecule release properties. In this study, cellulose nanocrystals (CNC) were surface-functionalized with β-cyclodextrin (β-CD) using succinic acid (SA) and fumaric acid (FA) as bridging agents. The main objective of this surface modification performed only in aqueous media was to obtain new active materials able to release antibacterial molecules over a prolonged period of time. The reactions were conducted by immersing the CNC film into a solution composed of β-CD, SA and FA, leading to CNC grafting. The materials were characterized by infrared spectroscopy (FT-IR), Quartz crystal microbalance-dissipation (QCM-D), AFM and phenolphthalein (PhP) was used to determine the efficiency of CNC grafting with β-CD. The results indicated that β-CD was successfully attached to the CNC backbone through the formation of ester bonds. Furthermore, carvacrol was entrapped by the attached β-CD and a prolonged release was confirmed. In particular, CNC grafted to β-CD in the presence of FA was selected as the best solution. The antibacterial activity and the controlled release were studied for this sample. Considerably longer bacterial activity against B. subtilis was observed for CNC grafted to β-CD compared to CNC and CNC-FA, confirming the promising impact of the present strategy.

Controlled release of chlorhexidine digluconate using β-cyclodextrin and microfibrillated cellulose

This study aims to develop a high-performance delivery system using microfibrillated cellulose (MFC)-coated papers as a controlled release system combined with the well-known drug delivery agent, β-cyclodextrin (βCD). Chlorhexidine digluconate (CHX), an antibacterial molecule, was mixed with a suspension of MFC or a βCD solution or mixed with both the substances, before coating onto a cellulosic substrate. The intermittent diffusion of CHX (i.e., diffusion interrupted by the renewal of the release medium periodically) was conducted in an aqueous medium, and the release mechanism of CHX was elucidated by field emission gun-scanning electron microscopy, SEM, NMR, and Fourier transform infrared analyses. According to the literature, both βCD and MFC are efficient controlled delivery systems. This study indicated that βCD releases CHX more gradually and over a longer period of time compared to MFC, which is mainly due to the ability of βCD to form an inclusion complex with CHX. Furthermore from the release study, a complementary action when the two compounds were combined was deduced. MFC mainly affected the burst effect, while βCD primarily controlled the amount of CHX released over time. In this paper, two different types of controlled release systems are proposed and compared. Depending on the final application, the use of βCD alone would release low amounts of active molecules over time (slow delivery), whereas the combination of β-cyclodextrin and MFC would be more suitable for the release of higher amounts of active molecules over time (rapid delivery).

Build-up of an antimicrobial multilayer coating on a textile support based on a methylene blue-poly(cyclodextrin) complex.

The aim of this work was to develop an antibacterial multilayer coating activated with methylene blue (MB) and based on chitosan (CHT) and cyclodextrin polyelectrolyte (polyCD) onto a non-woven polyethylene terephthalate (PET) textile support. The MB-free and MB-loaded systems were built-up by applying the dip-coating technique, alternating soak cycles of the PET textile preliminarily modified with carboxylate groups in CHT and in polyCD or polyCD/MB complex solutions. The layer-by-layer assembly build-up was followed by optical waveguide lightmode spectroscopy on the one hand and by gravimetry once it was applied on the textile substrate on the other hand. Two chitosan grades were used, low molecular weight (CHT-L) and medium molecular weight (CHT-M). The influence of the molar ratio CD/MB in the polyCD solutions was varied and finally the system underwent a post reticulation with genipin. Such parameters influences were investigated with regard to the loading capacity in MB of the systems, the release kinetics profiles of MB in pure water, phosphate buffer and MEM media, and the degradation of the self-assembled coating in the same media. Finally, biological and microbiological tests were performed to demonstrate the cytocompatibility of the systems and their ability to display a sustained antibacterial effect of the device through the MB prolonged release.