Chitosan hydrogels incorporating colloids for sustained drug delivery.

In today's biomedical research, a huge effort is being made towards the development of efficient drug delivery systems, achieving sustainable and controlled delivery of drugs. Chitosan (CS) hydrogels are high water content materials with very relevant biological properties to that purpose. Their use for a local and delayed delivery has already been demonstrated for a wide variety of therapeutic agents. One relatively recent strategy to improve these CS-based systems consists in the insertion of colloids, embedding drugs, within their three-dimensional matrix. This provides a second barrier to the diffusion of drugs through the system, and allows to better control their release. The main objective of this review is to report the many existing complex systems composed of CS hydrogels embedding different types of colloids used as drug delivery devices to delay the release of drugs. The various biomedical applications of such final systems are also detailed in this review.

Chitosan hydrogels for sustained drug delivery.

Sustainable and controlled delivery of drugs is at the centre of a huge amount of undertaken researches. The ability of hydrogels, high water content materials, to achieve a local and delayed-delivery has already been demonstrated for a wide variety of therapeutic agents and various polymer natures. In particular, chitosan, a natural polymer, stands out as a first choice material for hydrogels elaboration in biomedical, cosmetic, and health related applications, owing to its interesting properties (as biocompatibility, biodegradability, antimicrobial capacity, and mucoadhesivity). Moreover, chitosan also allows drugs to go easier through biological barriers. The main objective of this review is to report the various uses of chitosan hydrogels as drug delivery devices to control and/or delay the release of drugs loaded into their three dimensional matrix. A wide spectrum of corresponding biomedical applications of these systems can be encountered in the literature, whatever the physicochemical nature of drugs (hydrophilic, hydrophobic, macromolecular), as detailed in this review.

Embedment of liposomes into chitosan physical hydrogel for the delayed release of antibiotics or anaesthetics, and its first ESEM characterization.

This work describes the characterization of an original liposomes/hydrogel assembly, and its application as a delayed-release system of antibiotics and anaesthetics. This system corresponds to drug-loaded liposomes entrapped within a chitosan (CS) physical hydrogel. To this end, a suspension of pre-formed 1,2-dipalmitoyl-sn-glycero-3-phosphocoline liposomes loaded with an antibiotic (rifampicin, RIF), an anaesthetic (lidocaine, LID), or a model fluorescent molecule (carboxyfluorescein, CF), was added to a CS solution. The CS gelation was subsequently carried out without any trace of chemical cross-linking agent or organic solvent in the final system. Liposomes within the resulting gelled CS matrix were characterized for the first time by environmental scanning electron microscopy. The release of drugs from the assembly was investigated by fluorescence or UV spectroscopy. The cumulative release profiles of RIF and LID (and also CF for comparison) were found to be lower from the "drug-in-liposomes-in-hydrogel" (DLH) assembly in comparison to "drug-in-hydrogel" (DH) system.

Citric acid-γ-cyclodextrin crosslinked oligomers as carriers for doxorubicin delivery.

Two citric acid crosslinked γ-cyclodextrin oligomers (pγ-CyD) with a MW of 21-33 kDa and 10-15 γ-CyD units per molecule were prepared by following green chemistry methods and were fully characterized. The non-covalent association of doxorubicin (DOX) with these macromolecules was investigated in neutral aqueous medium by means of circular dichroism (CD), UV-vis absorption and fluorescence. Global analysis of multiwavelength spectroscopic CD and fluorescence titration data, taking into account the DOX monomer-dimer equilibrium, evidenced the formation of 1 : 1 and 1 : 2 pγ-CyD unit-DOX complexes. The binding constants are 1-2 orders of magnitude higher than those obtained for γ-CyD and depend on the characteristics of the oligomer batch used. The concentration profiles of the species in solution evidence the progressive monomerization of DOX with increasing oligomer concentration. Confocal fluorescence imaging and spectral imaging showed a similar drug distribution within the MCF-7 cell line incubated with either DOX complexed to pγ-CyD or free DOX. In both cases DOX is taken up into the cell nucleus without any degradation.

Particle assemblies: toward new tools for regenerative medicine.

Regenerative medicine is a demanding field in terms of design and elaboration of materials able to meet the specifications that this application imposes. The regeneration of tissue is a multiscale issue, from the signaling molecule through cell expansion and finally tissue growth requiring a large variety of cues that should be delivered in place and time. Hence, the materials should be able to accommodate cells with respect to their phenotypes, to allow cell division to the right tissue, to maintain the integrity of the surrounding sane tissue, and eventually use their signaling machinery to serve the development of the appropriate neo-tissue. They should also present the ability to deliver growth factors and regulate tissue development, to be degraded into safe products, in order not to impede tissue development, and finally be easily implanted/injected into the patients. In this context, colloid-based materials represent a very promising family of products because one can take advantage of their high specific area, their capability to carry/deliver bio-active molecules, and their capacity of assembling (eventually in vivo) into materials featuring other mechanical, rheological, physicochemical properties. Other benefits of great interest would be their ease of production even via high through-put processes and their potential manufacturing from safe, biodegradable and biocompatible parent raw material. This review describes the state-of-the-art of processes leading to complex materials from the assembly of colloids meeting, at least partially, the above-described specifications for tissue engineering and regenerative medicine.

Slow Reorganization of Small Phosphatidylcholine Vesicles upon Adsorption of Amphiphilic Polymers.

Static or dynamic light scattering measurements were performed in parallel, on dilute mixtures of DPPC/DPPA vesicles (typical radius 60 nm) and hydrophobically modified polymers. This technique gave evidence of the slow kinetics involved in both the reorganization of an adsorbed polymer layer and the membrane breakage. Hours, or sometimes days, were required in order to follow the variation of both the hydrodynamic radius and the scattering intensity at intermediate stages. Images of the intermediate species were collected using freeze-fracture electron microscopy (FFEM). Comparison of different polymers (of varying molecular weight or structure) revealed the prime importance of hydrophobicity on the disruption of membranes. Although the presence of a few percent of pendant alkyl chains along the polymer backbone induced adsorption to membranes, only the association with the more hydrophobic ones (>25 mol% of pendant octyl groups) resulted in small mixed objects of micellar size (radius about 10 nm). The drop of the mean radius of intermediate structures formed upon the vesicle breakage was also sensitive to temperature. A tentative mechanism was proposed on the basis of kinetics and FFEM studies. Copyright 2001 Academic Press.

Electrostatically driven immobilization of peptides onto (Maleic anhydride-alt-methyl vinyl ether) copolymers in aqueous media.

The covalent immobilization of a model peptide onto the MAMVE copolymer, via the formation of amide bonds, occurred in moderate yields in aqueous conditions. The improvement of the grafting reaction was achieved by adding at the amino terminus of the model peptide a sequence (tag) of three positively charged amino acids, lysine or arginine, and by taking profit of electrostatic attractive interactions between the negatively charged copolymer and the tagged peptides. The arginine tag was more efficient than the lysine tag for enhancing the immobilization reaction, proving that the effect was due to an electrostic driving force. On the basis of these results, a tentative mechanism is discussed, and Scatchard plots pointed out two regimes of binding. With the first, at low polymer load (up to 50% of saturation for a lysine tag and 60-70% for an arginine tag), the binding occurred with a positive cooperative effect, the already bound peptide participating to the binding of others. A second one for higher coverages, for which the binding occurred with a negative cooperativity, and saturation was reached in the presence of a large excess of peptide.

Covalent immobilization of proteins onto (Maleic anhydride-alt-methyl vinyl ether) copolymers: enhanced immobilization of recombinant proteins.

Two genetically modified HIV-1 capsid p24 proteins, RH24 and RH24K, were covalently bound to maleic anhydride-alt-methyl vinyl ether (MAMVE) copolymer, under aqueous conditions. We demonstrated that the addition of a six lysine unit tag at the COOH-terminus of RH24K greatly improved the grafting reaction which could take place under many different experimental conditions. The course of the reaction was controlled by electrostatic attractive forces between the protein and the negatively charged polymer, as the chemical binding was more efficient at low ionic strength. The maximum loading capacity of the polymer depended on whether the protein bore the lysine tag (RH24K) or not (RH24). Twenty-four molecules of RH24 could be immobilized per polymer chain and 49 for RH24K. Such a difference could be explained by a difference of orientation of the protein on the polymer, side-on for RH24 and end-on for RH24K to account for the observed high packing density.