Biodegradation, biodistribution and toxicity of chitosan

https://doi.org/10.1016/j.addr.2009.09.004Get rights and content

Abstract

Chitosan is a natural polysaccharide that has attracted significant scientific interest during the last two decades. It is a potentially biologically compatible material that is chemically versatile (–NH2 groups and various Mw). These two basic properties have been used by drug delivery and tissue engineering scientists to create a plethora of formulations and scaffolds that show promise in healthcare. Despite the high number of published studies, chitosan is not approved by the FDA for any product in drug delivery, and as a consequence very few biotech companies are using this material. This review will aim to provide information on these biological properties that affect chitosan's safe use in drug delivery. The term “Chitosan” represents a large group of structurally different chemical entities that may show different biodistribution, biodegradation and toxicological profiles. Here we aim to review research in this area and critically discuss chitosan's potential to be used as a generally regarded as safe (GRAS) material.

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].

Section snippets

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

References (97)

  • R.G. Boot et al.

    Identification of a novel acidic mammalian chitinase distinct from chitotriosidase

    J. Biol. Chem.

    (2001)
  • D. Hartl et al.

    Acidic mammalian chitinase is secreted via an adam17/epidermal growth factor receptor-dependent pathway and stimulates chemokine production by pulmonary epithelial cells

    J. Biol. Chem.

    (2008)
  • M.J. Kuranda et al.

    A di-n-acetylchitobiase activity is involved in the lysosomal catabolism of asparagine-linked glycoproteins in rat liver

    J. Biol. Chem.

    (1986)
  • G.H. Renkema et al.

    Purification and characterization of human chitotriosidase, a novel member of the chitinase family of proteins

    J. Biol. Chem.

    (1995)
  • S. Senel et al.

    Potential applications of chitosan in veterinary medicine

    Adv. Drug Deliv. Rev.

    (2004)
  • H. Zhang et al.

    In vitro degradation of chitosan by bacterial enzymes from rat cecal and colonic contents

    Biomaterials

    (2002)
  • F.S. Kittur et al.

    Low molecular weight chitosans-preparation by depolymerization with Aspergillus niger pectinase, and characterization

    Carbohydr. Res.

    (2003)
  • F.S. Kittur et al.

    Chitooligosaccharides—preparation with the aid of pectinase isozyme from Aspergillus niger and their antibacterial activity

    Carbohydr. Res.

    (2005)
  • E.L. McConnell et al.

    An investigation into the digestion of chitosan (noncrosslinked and crosslinked) by human colonic bacteria

    J. Pharm. Sci.

    (2008)
  • R.J. Verheul et al.

    Influence of the degree of acetylation on the enzymatic degradation and in vitro biological properties of trimethylated chitosans

    Biomaterials

    (2009)
  • L. Ma et al.

    Collagen/chitosan porous scaffolds with improved biostability for skin tissue engineering

    Biomaterials

    (2003)
  • Y. Kato et al.

    Evaluation of n-succinyl-chitosan as a systemic long-circulating polymer

    Biomaterials

    (2000)
  • T. Banerjee et al.

    Labeling efficiency and biodistribution of technetium-99m labeled nanoparticles: interference by colloidal tin oxide particles

    Int. J. Pharm.

    (2005)
  • C. Zhang et al.

    Pharmacokinetics, biodistribution, efficacy and safety of n-octyl-o-sulfate chitosan micelles loaded with paclitaxel

    Biomaterials

    (2008)
  • A.K. Gupta et al.

    Synthesis and surface engineering of iron oxide nanoparticles for biomedical applications

    Biomaterials

    (2005)
  • C. Zhang et al.

    Biological evaluation of n-octyl-o-sulfate chitosan as a new nano-carrier of intravenous drugs

    Eur. J. Pharm. Sci.

    (2008)
  • S.Y. Chae et al.

    Influence of molecular weight on oral absorption of water soluble chitosans

    J. Control. Release

    (2005)
  • F. Zheng et al.

    Chitosan nanoparticle as gene therapy vector via gastrointestinal mucosa administration: results of an in vitro and in vivo study

    Life Sci.

    (2007)
  • T. Ishii et al.

    Mechanism of cell transfection with plasmid/chitosan complexes

    Biochim. Biophys. Acta

    (2001)
  • K.W. Leong et al.

    DNA-polycation nanospheres as non-viral gene delivery vehicles

    J. Control. Release

    (1998)
  • I.K. Park et al.

    Visualization of transfection of hepatocytes by galactosylated chitosan-graft-poly(ethylene glycol)/DNA complexes by confocal laser scanning microscopy

    Int. J. Pharm.

    (2003)
  • K.A. Janes et al.

    Chitosan nanoparticles as delivery systems for doxorubicin

    J. Control. Release

    (2001)
  • H.Y. Nam et al.

    Cellular uptake mechanism and intracellular fate of hydrophobically modified glycol chitosan nanoparticles

    J. Control. Release

    (2009)
  • V. Dodane et al.

    Pharmaceutical applications of chitosan

    Pharm. Sci. Technol. Today

    (1998)
  • M. Thanou et al.

    Oral drug absorption enhancement by chitosan and its derivatives

    Adv. Drug Delivery Rev.

    (2001)
  • B. Carreño-Gómez et al.

    Evaluation of the biological properties of soluble chitosan and chitosan microspheres

    Int. J. Pharm.

    (1997)
  • N.G. Schipper et al.

    Chitosans as absorption enhancers of poorly absorbable drugs. 3: influence of mucus on absorption enhancement

    Eur. J. Pharm. Sci.

    (1999)
  • M.M. Thanou et al.

    Effects of n-trimethyl chitosan chloride, a novel absorption enhancer, on caco-2 intestinal epithelia and the ciliary beat frequency of chicken embryo trachea

    Int. J. Pharm.

    (1999)
  • T. Kean et al.

    Trimethylated chitosans as non-viral gene delivery vectors: cytotoxicity and transfection efficiency

    J. Control. Release

    (2005)
  • M. Jumaa et al.

    A new lipid emulsion formulation with high antimicrobial efficacy using chitosan

    Eur. J. Pharm. Biopharm.

    (2002)
  • Z. Guo et al.

    Novel derivatives of chitosan and their antifungal activities in vitro

    Carbohydr. Res.

    (2006)
  • Y. Song et al.

    Conjugate of mitomycin c with n-succinyl-chitosan: in vitro drug release properties, toxicity and antitumor activity

    Int. J. Pharm.

    (1993)
  • K. Sonaje et al.

    In vivo evaluation of safety and efficacy of self-assembled nanoparticles for oral insulin delivery

    Biomaterials

    (2009)
  • J. Garcia-Alonso et al.

    Purification and properties of beta-n-acetylhexosaminidase a from pig brain

    Int. J. Biochem.

    (1990)
  • A. Sanon et al.

    N-acetyl-beta-d-hexosaminidase from Trichomonas vaginalis: substrate specificity and activity of inhibitors

    Biomed. Pharmacother.

    (2005)
  • A. Martinou et al.

    Expression, purification, and characterization of a cobalt-activated chitin deacetylase (cda2p) from Saccharomyces cerevisiae

    Protein Expr. Purif.

    (2002)
  • Y.Q. Ye et al.

    Enhanced cytotoxicity of core modified chitosan based polymeric micelles for doxorubicin delivery

    J. Pharm. Sci.

    (2009)
  • S. Mao et al.

    Synthesis, characterization and cytotoxicity of poly(ethylene glycol)-graft-trimethyl chitosan block copolymers

    Biomaterials

    (2005)
  • Cited by (1438)

    View all citing articles on Scopus

    This review is part of the Advanced Drug Delivery Reviews theme issue on “Chitosan-Based Formulations of Drugs, Imaging Agents and Biotherapeutics”.

    1

    Tel.: +1 216 368 6750.

    View full text