Functionalization of ginger derived nanoparticles with chitosan to design drug delivery system for controlled release of 5-amino salicylic acid (5-ASA) in treatment of inflammatory bowel diseases: An in vitro study
Graphical abstract
Introduction
Inflammatory bowel disease (IBD) is among the most frequently occurring diseases around Asian countries which are associated either with genetic disorders caused by mutation and other environmental factors or due to the imbalance of immune response that fails to protect the cell linings of intestine from inflammation [1,2]. The conventional medicine used for the treatment of IBD is 5-ASA, but its daily intake of heavy dose and non-specific absorption to uninfected tissues develop severe adverse effects. It is, therefore, important to design site-targeted and controlled drug delivery carriers to release the drug to the inflamed cell linings [[3], [4], [5]]. Nanocarriers derived from naturally occurring compounds have shown potential in healing the infections by enhancing the immunity of the patients. Such natural compounds are quite rich in bio-proteins, carbohydrates, and also in biologically active chemical constituents which themselves act as drug against the infected cells [6,7].
Chitosan is a linear polysaccharide transformed by deacetylation of chitin which is extracted from crab shells and shrimps. This cationic biopolymer has been extensively used as a drug loading vehicle for the treatment for various kinds of diseases [8]. It forms one of the best drug delivery systems due to its non-toxic, biocompatible, and biodegradable nature [9]. Since chitosan has a high drug loading capacity, as reported by many researchers, integrating it with plant extracts may increase the efficiency of loading and release of the drug. Thus, realizing the vast pharmaceutical potential of chitosan it has been used to functionalize ginger extract (Zingiber officinale) which is being used traditionally since ancient times in the treatment of the IBD due to its high medicinal value. Various researches have shown that the carbohydrate content in ginger is as high as 68% of its total composition [10]. It also contains 22.2% amylose, which is a polysaccharide [11]. Ginger works as an anti-inflammatory agent and binds successfully with IBD drugs such as 5-ASA [12,13]. In the present work, drug 5-ASA is being used as a model drug which is commercially available as Mesalamine. 5-ASA is known to help in the reduction of inflammation by inhibiting the action of enzyme cyclo‑oxygenase [14].
From compositional point of view, ginger is known to contain a series of bioactive compounds such as gingerols, paradols, and shogaols which have been identified in ginger and suggested to play significant roles in both flavoring and health contributions. Gingerols are known to form a series of chemical homologues which are differentiated on the basis of the length of their un-branched alkyl chains. Among various gingerol members, [6] gingerol (IUPAC name: (S)-5-Hydroxy-1-(4-hydroxy-3-methoxyphenyl)-3-decanone, molecular formula (C17H26O4),) is the most abundant and major pungent component in the ginger oleoresin from fresh rhizome [15].
Since chitosan is a cationic polyelectrolyte and ginger derived nanoparticles possess negative charge [16], the chitosan macromolecules may couple with [6] gingerol via electrostatic attraction and this strategy seems to be a rational approach to design chitosan bounded ginger derived nanocarriers (C-GDNC). Furthermore, tailoring 5-ASA drug to the C-GDNC is expected to be more effective in healing the inflamed cell lining of the intestine.
Section snippets
Materials
5-amino salicylic acid (Mesacol, Mesalamine Delayed-release tablets USP 400 mg) and chitosan (CAS 9012-76-4) were procured from Merck, India while fresh ginger was purchased from the local market. Analytical grade chemicals and Millipore water were used throughout the experiments.
Preparation of chitosan bounded ginger derived nanocarriers (C-GDNC)
The reaction scheme for the preparation of C-GDNC is shown in Fig. 1 (A) which involves non-covalent interactions between cationic chitosan macromolecules and [6] gingerol. For preparing C-GDNC, fresh ginger rhizomes (
1H NMR analysis
1H Nuclear Magnetic Resonance analysis was conducted for the structural confirmation of prepared nanocarriers using Bruker's Avance-III 500 MHz spectrometer.
FTIR microscopy
Fourier Transform Infrared spectral analysis of the native (without 5-ASA) and drug loaded (D-C-GDNC) nanoparticles was performed using FTIR-8400S, Shimadzu Spectrophotometer within the range of 4000 to 400 cm−1.
Dynamic light scattering based size and potential analysis
Malvern DLS (dynamic light scattering) Zetasizer 90, Malvern Instruments, UK was used to determine the size (d.nm) and surface
Chemical integrity of 5-ASA
To determine the stability of D-C-GDNC in different chemical environments, the UV spectra were recorded and compared in three different media of pH 7.4, 6.8 and 1.2, respectively. The UV spectra of drug unloaded nanocarriers (C-GDNC) were also recorded.
1H NMR
The 1H NMR spectrum of the prepared nanocarriers is depicted as Fig. 2 which shows a small absorption peak at δ 11.0 which confirms the presence of carboxylic protons of drug 5-ASA (5-amino-2-hydroxy benzoic acid). In the present nanocarriers, all the aromatic protons are supposed to have different chemical environments (due to ionic interactions), which therefore gives multiple number of peaks in the aromatic region in the range of δ 6.7 to 7.2 which implies for the presence of benzene rings
Chemical integrity of 5-ASA
UV spectrum of C-GDNC is given in Fig. 11 (a) showing its λmax at 293 nm which was recorded in PBS [43,44]. The UV spectrum of C-GDNC was recorded to correlate the shifting of wavelength after drug loading as well as verify the chemical integrity of 5-ASA in gastrointestinal pH. Fig. 11 (b) shows the UV spectra of drug loaded nanocarriers (D-C-GDNC) with a λmax at 300 nm at pH 7.4, the shifting of λmax from 293 nm to 300 nm might be due to the loading of 5-ASA. Fig. 11 (c) and (d) represent the
Conclusions
The aim of this research work is to synthesize a non-toxic, nano-sized, pH-sensitive drug delivery system for slow and controlled release of 5-ASA using polysaccharides based nanocarriers. Chitosan bounded ginger derived nanocarriers (C-GDNC) are synthesized using a simple procedure and loaded with 5-ASA drug with ~50% drug loading and entrapment efficiency. The 1H NMR and FTIR spectra confirm the binding of chitosan to ginger derived nanocarriers loaded with the drug 5-ASA. The size of GDNC
Acknowledgements
The authors are grateful to St. Aloysius College, Jabalpur, India for FTIR and in vitro cytotoxicity, UGC-DAE Consortium for Scientific Research, Indore, India for XRD analysis, Central Instrumental Facility of Jiwaji University, Gwalior, India for TEM and TGA, and IIITDM Jabalpur, India for SEM analysis.
Submission declaration and verification
Submission of an article implies that the work described has not been published previously (except in the form of an abstract, a published lecture or academic thesis, see ‘Multiple, redundant or concurrent publication‘for more information), that it is not under consideration for publication elsewhere, that its publication is approved by all authors and tacitly or explicitly by the responsible authorities where the work was carried out, and that, if accepted, it will not be published elsewhere
Funding
This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.
Declaration of Competing Interest
The authors do not have any conflicts of interest.
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