Biodegradation, biodistribution and toxicity of chitosan☆
Introduction
Chitosan has found application in many areas of drug delivery and tissue engineering due to the broad range of compounds encompassed by this term. A naturally occurring polysaccharide, it shows promise for safe use in healthcare products. This review will concentrate on the biomedical aspects of this versatile material. Chitosan can be found in a variety of forms differing in size (average molecular weight; Mw) and degree of deacetylation (DD) and this diversity is exponentially increased by the numerous chemical modifications that have been investigated. In this review we use the abbreviations DD (degree of deacetylation) and Mw (average molecular weight) to cover the various chitosan types that have been used. Facile chemical modification is one of chitosan's great strengths, enabling its optimization to give appropriate biomaterials for therapeutic applications. The ‘tunable’ aspect of chitosan allows optimization of its biological profile.
Most commonly in drug delivery, chitosan is the carrier, or functional excipient (e.g. permeation enhancer) of the active compound being delivered. Therefore, chitosan uptake, distribution and, toxicity studies are very few. To allow biological tracking of chitosan, derivatives have been produced using fluorescence – FITC [1], 9-anthraldehyde [2] – and the radiolabels 125I [3], [4]99mTc [5], [6].
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Chitin and chitosan biodegredation
An important aspect in the use of polymers as drug delivery systems is their metabolic fate in the body or biodegradation. In the case of the systemic absorption of hydrophilic polymers such as chitosan, they should have a suitable Mw for renal clearance. If the administered polymer's size is larger than this, then the polymer should undergo degradation. Biodegradation (chemical or enzymatic) would provide fragments suitable for renal clearance. Chemical degradation in this case refers to acid
Chitosan biodistribution
One of the least studied aspects of chitosan is its biodistribution, especially using methods other than intravenous administration. This distribution is related to all aspects of the chitosan formulation from the molecular weight and degree of deacetylation to the nanoparticle size. In the case of a nanoparticulate formulation, the kinetics and biodistribution will initially be controlled by the size and charge of the nanoparticles and not by chitosan. However, after particle decomposition to
Chitosan's toxicity
Chitosan is widely regarded as being a non-toxic, biologically compatible polymer [59]. It is approved for dietary applications in Japan, Italy and Finland [60] and it has been approved by the FDA for use in wound dressings [61]. The modifications made to chitosan could make it more or less toxic and any residual reactants should be carefully removed. A summary of chitosan's reported LD50s and IC50s is shown in Table 2.
It is important to consider that the formulation of chitosan with a drug may
Chitosan: Potential as an FDA GRAS material
From the above mentioned studies it is clear that regulatory agencies encounter many difficulties in approving all existing chitosans as GRAS materials. At this time all chitosan GRAS applications are “At notifier's request, FDA ceased to evaluate the notice” [83]. However, GRAS status does not approve all uses of a substance except those “under the conditions of its intended use”. GRAS status primarily relates to food additives. Chitosan's chemical versatility and the variety of formulations
Concluding remarks
Native chitosan represents a vast resource with great medical potential. With 1157 articles related to chitosan indexed by PubMed in 2008, it is obvious that this is an active area which will yield many future therapeutic applications. Current studies show that, in general, chitosan is a relatively non-toxic, biocompatible material. However, care must be taken to ensure that it is pure, as protein, metal or other contaminants could potentially cause many deleterious effects both in derivative
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This review is part of the Advanced Drug Delivery Reviews theme issue on “Chitosan-Based Formulations of Drugs, Imaging Agents and Biotherapeutics”.
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