Elsevier

Carbohydrate Polymers

Volume 103, 15 March 2014, Pages 70-80
Carbohydrate Polymers

Characterisation and drug release performance of biodegradable chitosan–graphene oxide nanocomposites

https://doi.org/10.1016/j.carbpol.2013.12.012Get rights and content

Highlights

  • Graphene oxide (GO) improved the mechanical properties of chitosan.

  • GO also enhanced the drug delivery profiles of chitosan.

  • Chitosan–GO nanocomposites demonstrated pH-sensitive drug release.

  • These nanocomposites have high potential in transdermal drug delivery.

Abstract

Biodegradable chitosan–graphene oxide (GO) nanocomposites possess improved mechanical properties and drug delivery performance over chitosan and could prove to be a viable, controlled and pH-sensitive transdermal drug delivery system. Chitosan nanocomposites containing varying GO contents and drug loading ratios were investigated. The nanocomposite with 2 wt % GO provided the optimal combination of mechanical properties and drug-loading capacity. It offered a faster and a more substantial release of drug than chitosan as well as a slower biodegradation rate, owing to the abundant oxygenated functional groups, hydrophilicity and large specific surface area of GO sheets. The drug delivery profiles of the nanocomposite were dependent on the drug loading ratio, with 0.84:1 being the best ratio of drug to GO for a quick and high release of the loaded drug. The nanocomposite also demonstrated pH sensitivity of drug release, releasing 48% less drug in an acidic condition than in a neutral environment.

Introduction

Chitosan, the linear (1-4)-2-amino-2-deoxy-β-D-glucan, having a degree of acetylation close to 0.20, is currently isolated from marine chitin (Muzzarelli, 2012, Muzzarelli et al., 2012). It is both a biocompatible and biodegradable polymer, and has been noted for its haemostatic properties which assist in the formation of clots and thereby stop bleeding (Rao and Sharma, 1997, Kumar et al., 2004, Busilacchi et al., 2013). Chitosan has shown good potential for use in drug-eluding polymeric devices, having been used before as a diluent in polymer-coated oral tablets, which allow sustained delivery of various hydrophobic and hydrophilic drugs or site specific delivery to the colon without digestive degradation via pH sensitivity (Akbuǧa, 1993, Hou et al., 1985, Sawayanagi et al., 1982, Tozaki et al., 1997). Chitosan has been integrated with other drug delivery routes, most notably with gels (Knapczyk, 1993, Kristl et al., 1993), microspheres (Akbuǧa and Durmaz, 1994, Jameela and Jayakrishnan, 1995, Lorenzo-Lamosa et al., 1998), nanoparticles of chitosan (Bal et al., 2010, Bal et al., 2011) and films (Portero et al., 1998, Xie et al., 2005).

Graphene is an atomically thick sheet of sp2 carbon atoms and is the building block for other carbon structures like nanotubes, fullerenes and graphite (Geim & Novoselov, 2007). Graphene is a much sought after material as it was found to have the highest tensile strength (130 GPa) and Young's modulus (1 TPa) of any natural substance, a theoretical surface area of 2,630 m2 g−1, electron mobility of 10,000 cm2 v−1 s−1 and a thermal conductivity value of 4,000 W mK (Chen et al., 2012, Geim and Novoselov, 2007, Lee et al., 2008, Novoselov et al., 2004, Stoller et al., 2008). Previous work has combined graphene oxide (GO) nanosheets, created by the oxidation of graphene nanosheets, and chitosan together at low concentrations to create strong, biodegradable and biocompatible chitosan–GO nanocomposites (Han et al., 2011, Pan et al., 2011a, Pan et al., 2011b, Yang et al., 2010a, Yang et al., 2010b). However, these papers mainly focused on mechanical properties and there is a literature gap regarding the use of chitosan–GO nanocomposites for drug delivery and the effect that the integration of GO can have on biodegradation. As GO has ample phenol hydroxyl, epoxide and carboxylic functional groups to allow for better bonding to other molecules (Pan et al., 2011a, Pan et al., 2011b), a large surface area, excellent dispersibility within water and other aqueous mediums, low nanotoxicology (Wang et al., 2010, Zhang et al., 2011a, Zhang et al., 2011b) and is easy to manufacture (Liu et al., 2011a, Liu et al., 2011b), it is considered highly interesting in the biomedical field including drug delivery. When conjugated to GO, hydrophobic drugs have been shown to be dispersible in water solutions while maintaining their original potency (Liu et al., 2009, Sun et al., 2008a, Sun et al., 2008b, Zhang et al., 2010). An increase in gene therapeutic transport for graphene bonded drugs has also been noted (Bao et al., 2011).

Polymer coated GO nanosheets have also been used as therapeutic carriers as the coating can improve the biocompatibility of GO. Chitosan coated GO was used to load and deliver hydrophobic and aromatic drugs, proving to be both biocompatible and highly effective in cancer cell reduction (Rana et al., 2011). Gene therapies were also investigated, with GO coated with poly(ethyleneimine) increasing the transfection efficiency of plasmid DNA and short interfering RNA in comparison to free therapeutics (Feng et al., 2011, Zhang et al., 2011a, Zhang et al., 2011a). Despite these benefits, only a limited number of papers have been published that use GO to improve the drug release profiles of polymers. Hydrogels of poly(vinyl alcohol) and GO have been analysed as possible drug delivery devices, but the drug itself was not bonded to the GO (Bai et al., 2010, Liu et al., 2012a, Liu et al., 2012b). A nanocomposite film of poly (sebacic anhydride) and GO was also studied, but here again the GO was only utilized as the reinforcing filler (Gao et al., 2011).

This work aims to investigate the effects of GO on the drug release profiles of chitosan as well as its mechanical properties and biodegradation rate, and to achieve optimized chitosan–GO nanocomposites for potential applications in load-bearing drug delivery devices such as microneedle arrays for transdermal drug delivery. It will determine the concentration of GO that provides the optimum mechanical and drug delivery properties, while also investigating the effect that drug loading ratios have on the release rate of drugs. Fluorescein sodium (FL) was selected as the drug model, used to analyse the release rate improvement of therapeutics from nanocomposites, due to its dispersibility within aqueous mediums and distinct absorption peaks between 450 to 500 nm, as well as a molecular weight of 376 g mol−1, similar in size to several important drugs such as the cancer drug cisplatin, the non-steroidal anti-inflammatory indomethacin, the beta blocker propranolol hydrochloride and the vasodilator timolol maleate.

Section snippets

Materials

Chitosan powder (Mw = 100,000–300,000, Acros Organics, deacetylation degree ≥ 90% as determined by free amine groups) was used as purchased from Fisher Scientific. The following chemicals were reagent grade and used as purchased from Sigma Aldrich; acetic acid, sulphuric acid, hydrogen peroxide, potassium permanganate, sodium nitrate, fluorescein sodium, phosphate buffered saline (PBS), lysozyme and graphite powder (≤20 μm).

Preparation of GO

The method for making GO has been described before by others (Marcano et

Characterization of GO

GO, produced through exfoliation of graphite oxide created from a modified Hummers method, was characterized by FT-IR, XRD, AFM and LS to confirm the chemical bonds present, the interlayer spacing and the dimensions of the GO, respectively. Four main groups can be noted on the FT-IR spectra shown in Figure 1 (A): at 1043 cm−1 for C–O bonds; at 1628 cm−1 for C = C bonds; at 1727 cm−1 for C = O bonds and at 3400 cm−1 for O–H bonds from retained free water in the sample (K. Liu et al., 2011a, Liu et

Conclusions

Biodegradable chitosan nanocomposite films with 0.25 to 5 wt % GO were prepared by solution casting. The nanocomposite containing 2 wt % GO exhibited the best combination of mechanical properties and drug-loading capacity, with the Young's modulus raising from 1 to 1.3 GPa, ultimate tensile strength from 24 to 34 MPa, and elongation at break from 14.5% to 17.7% compared to the pristine chitosan. Improvements of the mechanical properties were attributable to the high stiffness, strength,

Acknowledgements

The authors would like to thank the University of Sheffield for a start-up fund and Yinjun Wang and Dawn Bussey for assistance with AFM imaging.

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