Elsevier

Journal of Molecular Liquids

Volume 256, 15 April 2018, Pages 90-99
Journal of Molecular Liquids

Fabrication and characterization of triple-responsive composite hydrogel for targeted and controlled drug delivery system

https://doi.org/10.1016/j.molliq.2018.02.026Get rights and content

Highlights

  • Triple-responsive composite hydrogel was prepared.

  • In vitro drug release studies were investigated.

  • Fe3O4 was incorporated into bacterial cellulose and gelatin hydrogel.

Abstract

In this study, to prepare a new magnetic composite hydrogel (Mag-H) based on gelatin/bacterial cellulose (BC), we synthesized gelatin-coated magnetic nanoparticles and then incorporated into the gelatin/BC matrices, followed by chemical crosslinking with glutaraldehyde. The physicochemical properties of Mag-H were evaluated by Fourier transform infrared spectroscopy (FTIR), X-ray diffractometry (XRD), thermogravimetric analysis (TGA), vibrating sample magnetometer (VSM), texture analyzer, swelling test, and in vitro drug release behavior using methylene blue (MB) as a model drug. The FTIR spectra showed that glutaraldehyde crosslinked with gelatin. To improve the thermal and mechanical properties of gelatin hydrogel (Gel-H), the BC and magnetic nanoparticles were incorporated into the gelatin network. Due to the superparamagnetism of magnetic nanoparticles, Mag-H possessed a powerful magnetic property for achieving a magnetic targeting. Mag-H had a maximum swelling ratio of 1085 ± 12% in phosphate buffer saline (pH 1.2) at 37 °C, meanwhile its maximum drug release of 80.77 ± 0.33% was observed at the same condition with an external magnetic field application. Interestingly, Mag-H showed temperature-, pH-, and magnetic field-responsive properties, which would be a promising candidate for targeted and controlled drug delivery system.

Introduction

The smart hydrogels are of great interest in biomedical and pharmaceutical applications due to changing their swelling behaviors or network structures in response to specific stimuli, either exogenous (temperature, magnetic field, light, or electric pulses) or endogenous stimuli (pH or enzyme concentration) [1,2]. These hydrogels have been developed as responsive drug delivery systems that can deliver a drug in spatial-, temporal-, and dosage-controlled manners with the application of stimuli. It is well known that there are many factors affecting an efficient drug delivery in human body due to variations in gastrointestinal physiological or pathological conditions such as pH or temperature. The smart hydrogels are needed to respond to multiple stimuli by using polymers with multiple responsive properties. One of multi-responsive hydrogels is gelatin-based hydrogel because of its temperature- and pH-stimuli response [3,4]. With charming features of gelatin including biocompatibility, biodegradability, low immunogenicity, and low cytotoxicity, the gelatin's safety has been already proven for use in biomedical applications [5]. Bacterial cellulose (BC) is widely used as an attractive reinforcement material in hydrogels due to its distinguished intrinsic properties such as high crystallinity, desirable mechanical properties, biocompatibility, biodegradability, and non-toxicity [6]. However, conventional hydrogels are not efficient enough for targeting and retaining a drug at the specific site. To use hydrogel in pharmaceutical technology with higher efficiency, the development on magnetically responsive hydrogel was considered as one of the most effective technique. It was important to note that the benefit of magnetic responsive hydrogel was involved on controllable concept of hydrogel at specific site under external applied magnetic field. Novel triple-responsive hydrogel was therefore developed based on pH, temperature and magnetic responsive properties. Thus, to approach this concept, magnetic targeting is a powerful method to directly deliver a drug to a desirable site even under various conditions by incorporation of magnetic nanoparticles (MNPs) into drug delivery systems together with the application of an external magnetic field. This method is also advantageous to reduce a drug amount required to achieve a particular concentration at the targeted site and to minimize adverse effect of the drug at non-targeted sites [7]. Among MNPs, magnetic iron oxide nanoparticles, especially magnetite (Fe3O4), are the most widely used in biological applications because of their particular magnetic properties, biocompatibility, and relative non-toxicity when coated with appropriate surface coatings [8]. Furthermore, the drug release from delivery systems can be controlled by a magnetic field [9,10].

In present research work, the fabricating feasibility and ability of a triple-responsive magnetic composite hydrogel (Mag-H) consisting of gelatin, BC, and gelatin-coated MNPs (Gel-MNPs) was evaluated. The prepared Mag-H were assessed for their physicochemical, thermal, mechanical, rheological, and magnetic properties by X-ray diffractometry (XRD), Fourier transform infrared spectroscopy (FTIR), thermogravimetric analysis (TGA), texture analyzer, rheometer, and vibrating sample magnetometer (VSM), respectively. Furthermore, the effect of external stimuli conditions including temperature, pH, and magnetic field on the swelling and in vitro drug release behaviors of Mag-H was investigated. In drug loading and release studies, methylene blue (MB) was used as a model drug. All characterizations were also carried out with gelatin hydrogel (Gel-H) and gelatin/BC composite hydrogel (Gel/BC-H) so as to compare with Mag-H.

Section snippets

Materials

Iron (II) chloride tetrahydrate (FeCl2·4H2O, ≥99.0%) and glutaraldehyde (25%, w/w) were purchased from ACROS Organics. Iron (III) chloride hexahydrate (FeCl3·6H2O, 99.0–102.0%), hydrochloric acid fuming (HCl, 37.0–38.0%), and sodium hydroxide (NaOH,  99.0%) were purchased from Merck. Methylene blue (MB, molecular weight of 319.85 Da) was purchased from Sigma-Aldrich. Gelatin (188 bloom) was of pharmaceutical grade and purchased from Union Chemical. Bacterial cellulose was extracted from nata de

Particle size and zeta potential of Fe3O4 particle

Fe3O4 particle was successfully synthesized via an aqueous co-precipitation method under oxygen-free atmosphere. The obtained aqueous suspension had a black color as a result of the formation of magnetite nanoparticles (Fe3O4). The Fe3O4 particle in aqueous suspension had a mean hydrodynamic diameter of 108 ± 9 nm and a zeta potential of −23.4 mV, similar to previous report [18].

XRD analysis

The XRD spectra of Fe3O4 particle and composite hydrogels (Gel-H, Gel/BC-H, and Mag-H) are displayed in Fig. 1. Seven

Conclusion

The triple-responsive composite hydrogel was successfully prepared as the form of Mag-H, which was composed of gelatin, BC, and Fe3O4 particle, by chemical crosslinking of glutaraldehyde with gelatin chains. The BC and Fe3O4 particle could serve as reinforced materials, which greatly enhanced the thermal and the mechanical stabilities of Gel-H. The multiple-responsive features of Mag-H to external stimuli included temperature, pH, and magnetic field. This composite hydrogel had the best

Acknowledgements

The authors gratefully acknowledge the financial support provided by Thammasat University under the TU New Research Scholar, Contract No. 28/2557. The appreciation was extent to Plastic Institute of Thailand. The appreciation was extent to financial support from National Research Council of Thailand (Fiscal year 2016). The authors would also like to acknowledge Center of Scientific Equipment for Advanced Research, Thammasat University (TU-CSEAR) for a TGA/DSC 3+ Thermogravimetric Analyzer

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