Crosslinked ionic polysaccharides for stimuli-sensitive drug delivery

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Abstract

Polysaccharides are gaining increasing attention as components of stimuli-responsive drug delivery systems, particularly since they can be obtained in a well characterized and reproducible way from the natural sources. Ionic polysaccharides can be readily crosslinked to render hydrogel networks sensitive to a variety of internal and external variables, and thus suitable for switching drug release on–off through diverse mechanisms. Hybrids, composites and grafted polymers can reinforce the responsiveness and widen the range of stimuli to which polysaccharide-based systems can respond. This review analyzes the state of the art of crosslinked ionic polysaccharides as components of delivery systems that can regulate drug release as a function of changes in pH, ion nature and concentration, electric and magnetic field intensity, light wavelength, temperature, redox potential, and certain molecules (enzymes, illness markers, and so on). Examples of specific applications are provided. The information compiled demonstrates that crosslinked networks of ionic polysaccharides are suitable building blocks for developing advanced externally activated and feed-back modulated drug delivery systems.

Introduction

Materials from renewable sources are attracting a growing attention in a variety of fields as a way to achieve sustainable development [1]. Pharmaceutical technology is not an exception and natural-source excipients are recovering positions against the synthetic materials [2], [3]. The strong development of organic chemistry and polymer science let synthetic excipients to rapidly occupy an outstanding place in the list of available materials in the second half of XX century [4]. Precise control of molecular weight and number and distribution of functional groups and the versatility to create chains of diverse architecture, and thus performance, are the main advantages of the synthesis methods. However, contamination due to toxic solvents and starting components (e.g. monomers) and environment concerns related to the accumulation of non-biodegradable plastics in the soil and the sea have become relevant drawbacks [5]. Interestingly, the improvements in the purification and the characterization techniques implemented for the synthetic materials are strongly benefiting the standardization of natural products [6]. Moreover, the current state-of-art in biotechnology makes it even possible to genetically engineer the sequences of the components of biomacromolecules [7], [8]. All these advances are notably prompting the availability of optimized and well characterized natural excipients; the two features that had been previously restricted their applications in the pharmaceutical field [9], [10]. It should be noticed that insufficient knowledge about the composition and structure limits not only the functionality, but also may compromise the safety and can lead to notable regulatory troubles [11]. Perhaps one of the materials that are taking more benefit from these advances is the polysaccharide family. Polysaccharides can be obtained from several sources including seaweeds, plants, bacterias, fungi, insects, crustacea, animals and even humans, and can be structurally tuned through genetic engineering [12], [13], [14], [15], [16]. In some cases, the natural sources can be extensively cultivated to extract the polysaccharides. In other cases, the source is involved in the obtaining of other products and the discards can be used to take out the polysaccharide. In fact polysaccharide-containing materials represent a relevant part of the by-products of the fishery and the agriculture activity [17]. Thus, the search of pharmaceutical and biomedical applications for materials coming from discards may give an added value to the source and contribute to solve the problem of unexploited waste accumulation [18], [19]. Most polysaccharides are intrinsically biocompatible because the resemblance of their structure with many body components. This fact together with their processability using common pharmaceutical equipment justify their common use as binders, fillers, and thickeners in solid and liquid formulations and as components for site-specific oral delivery systems [20]. Furthermore, they are readily degradable in soil and water by common microorganisms.

From a chemical point of view, the polysaccharide term gathers together quite diverse large carbohydrates that can be composed of only one kind of repeating monosaccharide (named homopolysaccharides or homoglycans; e.g. starch, cellulose) or formed by two or more different monomeric units (heteropolysaccharides or heteroglycans; e.g. agar, alginate, carrageenan). Polysaccharides can be also classified as non-polyelectrolites and polyelectrolites, which in turn are divided in positively and negatively charged [21]. The conformation of the polysaccharides chains is notably dependent not only on the pH and ionic strength of the medium, particularly in the case of the polyelectrolytes, but also on the temperature and the concentration of certain molecules (such as lecitins) [22]. Such sensitive conformation can be exploited to trigger phase transitions of isolated and crosslinked chains by the action of chemical or physical stimuli. The stimulus can directly act on the polysaccharide (e.g. application of a source of heating that modifies the temperature, or of an electric field that alter charge distribution), but also through an intermediary that transduces the signal (e.g. light irradiation on gold nanoparticles or oscillatory magnetic field on superparamagnetic iron oxide particles that lead to a local rise of temperature) [23]. The variety of stimuli to which the polysaccharides can respond makes them particularly attractive as components of smart drug delivery systems (DDSs). Differently from non-responsive DDSs conceived to release the drug according to a preestablished pattern, smart or intelligent DDSs offer the possibility of specifically releasing the drug in the affected tissues or cells, and/or to adapt the release profiles to the evolution of the illness or to certain physiological events [24]. As an additional unique feature, some polysaccharides may endow nanocarriers with surface properties that regulate the interactions with the main components they will enter into contact during absorption and biodistribution, namely mucosa, blood, and target cells. Biomimicking the surface of eukaryotic cells, bacteria and viruses, polysaccharides can facilitate the recognition and binding to desirable surfaces, while scaping from opsonization and complement activation [25], [26]. Thus, integration of the polysaccharide features in nano/micro/macro-hydrogel networks is particularly attractive to obtain novel biocompatible, responsive and even targetable DDSs, suitable to be administered via almost any route [13]. Polysaccharide networks can be obtained through crosslinking assisted by interactions of diverse strength, from weak physical entanglements to irreversible covalent bonds, as comprehensively described elsewhere [27], [28], [29].

The aim of this review is to provide an overview of the possibilities of using ionic polysaccharides as components of stimuli-responsive delivery systems, mainly for small drug molecules. The delivery of proteins is covered in another paper in this special issue of Advanced Drug Delivery Reviews. To avoid unnecessary repetitions with available literature, the review first offers a summarized outline of the main features of common ionic polysaccharides, and then analyzes in detail the responsiveness of crosslinked networks to a wide variety of environmental stimuli, including pH, temperature, ionic strength and electrical field, and its effect on drug delivery. The information has been organized as a function of the stimulus and not of the polysaccharide, with the purpose of providing functionality-based criteria for the selection of the most suitable polysaccharide for a given therapeutic purpose. In this sense, the analysis of the available information can be extrapolated to other polysaccharides or even to the design of new ones.

Section snippets

General features of ionic polysaccharides

Some polysaccharides, such as alginate, bear ionizable moieties in the native state or can be endowed with such moieties through subsequent processing, as in the case of chitosan obtained from deacetylation of chitin. Additionally, neutral and polyelectrolyte polysaccharides can be endowed with additional ionizable groups by means of substitution of some hydroxyl groups with ionic moieties or by grafting of polymerizable ionic monomers or preformed polymers. Moreover, the ionic groups can come

Chitosan

Chitosan networks show a typical pH-sensitive swelling, being swollen in acid medium and shrunk in neutral and alkaline medium. Thus, non-interacting drugs are released faster to media of acid pH [55]. The networks can be prepared as bulk monoliths, and also as micro- or nano-gels in one or two steps [33]. Chitosan films have been also obtained by crosslinking with different multivalent phosphates, namely pyrophosphate (Pyro) and tripolyphosphate (TPP) [56]. The films released faster riboflavin

Electrical field-responsive networks

In the last few years there has been an increased interest in DDSs sensitive to electrical fields for external regulation of drug release from transdermal or subcutaneously implanted systems [139], [140]. Changes in the polarity, the pH or the ionic strength of the gels are expected to occur during application of a certain current or voltage. These changes may lead to differences in the net osmotic pressure, which at the end is responsible for the drug release from the polymer matrices [141].

Light-responsive networks

A variety of approaches has been tested to develop topical DDSs sensitive to the solar range of UV–vis radiation, and also implantable devices sensitive to more penetrating near-infrared light radiation [150]. Polysaccharides can be endowed with light-sensitiveness by means of grafting of responsive moieties. For example, PEG-anthracene monomer was grafted along alginate or hyaluronic backbones to render hydrogels that, after crosslinking with adipic dihydrazide, change their properties

Temperature-responsive networks

Ionic polysaccharides show by themselves very limited temperature-sensitiveness. Exceptions to this general trend are gellan and xanthan gums, which undergo transitions between an ordered helix structure at low temperature to a disordered coil state at high temperature [153]. Such a transition is seen as a marked decrease in the apparent viscosity of the system, which is totally reversible without thermal hysteresis [50]. To reinforce this temperature-sensitiveness and to endow other ionic

Redox responsive networks

Responsiveness to oxidant and reducing agents has gained attention as a way to attain feed-back regulated release (e.g. triggered by radicals created during inflammatory processes) or very precise site-specific delivery (e.g. intracellular release in tumor tissues). For example, hyaluronic acid networks chemically crosslinked with EGDE have been shown to degrade in vitro by hydroxyl radicals produced by the reaction of H2O2 and FeSO4, and in vivo in response to inflammation [181]. Networks of

Magnetic responsive networks

The most common approach to endow a polymeric system with magnetic responsiveness is by means of the inclusion of magnetite (Fe3O4) nanoparticles. Combination of magnetite and ionic polysaccharides has been proved to render dually or multi-stimuli responsive DDSs [189], [190], [191]. For example, Fe3O4 superparamagnetic particles were coated with calcium-crosslinked chitosan and alginate in order to target the particles to specific sites of the gastrointestinal tract and to retain them there

Molecule responsive networks

The reversibility of Schiff base bonds, which are in intrinsic dynamic equilibrium with the aldehyde and the amine reactants, has been exploited to design chitosan networks coupled to dibenzaldehyde-functionalized poly(ethylene glycol) (dibenzaldehyde-PEG) chains that are able to respond to a variety of molecules [196]. The uncoupling and the recoupling are reversible enabling also the self-healing of the networks. For example, at acid pH, vitamin B6 derivates and aminoacids (lysine) cause the

Conclusion

Ionic polysaccharides offer the possibility to substitute, partially or even totally, synthetic polymers in the design of stimuli-responsive DDSs. Ionic polysaccharides are inherently endowed with pH- and ion-sensitiveness, which can be transmitted to physically and chemically crosslinked networks. Cationic polysaccharides are prone to swell in acid pH and to shrink at neutral/alkaline pH. Thus, networks showing swelling-controlled release deliver faster the drug at acid pH. The opposite effect

Acknowledgments

The authors acknowledge the financial support of MICINN (SAF2008-01679 and SAF2011-22771), FEDER, Xunta de Galicia (PGIDT07CSA002203PR and PGIDT10CSA203013PR), Spain, and Programa de Cooperación Transfronteriza España-Portugal (EU IBEROMARE). A.M. Puga and B. Blanco-Fernandez are grateful to the Ministerio de Economia y Competitividad and Ministerio de Educación, Cultura y Deporte of the Spanish Government for FPI (BES-2009-024735) and FPU (AP2009-3605) grants, respectively.

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