Effect of polysaccharide nanocrystals on structure, properties, and drug release kinetics of alginate-based microspheres
Graphical abstract
Highlights
► Polysaccharide nanocrystals were firstly introduced into alginate microspheres. ► Mechanical strength and drug release behavior were enhanced and regulated. ► Nanocrystals increased the stability of the crosslinked network structure. ► Release kinetics and transport mechanisms were analyzed and recognized.
Introduction
Biopolymers from natural sources have been studied and utilized in the pharmaceutical and biotechnological industries for many years. Recently, microcapsules and microspheres derived from alginate have attracted attention for the development of controlled and sustained release drug-delivery systems due to their good biocompatibility, biodegradation, nontoxicity upon in vivo administration [1], [2], and good stability of the encapsulated drug. Furthermore, alginate-based microspheres showed pH-dependent swelling and controlled drug release functions attributed to the pH sensitivity of the alginate component. Alginate is an easily available polysaccharide obtained from brown marine algae. It is a linear copolymer, composed of 1,4-linked-β-d-mannuronic acid and α-l-guluronic acid residues, that gels in the presence of divalent cations such as calcium, due to the stacking of guluronic acid (G) blocks and the formation of “egg-box” calcium linked junctions [3]. Alginate polymers are hemocompatible, they do not accumulate in any major organs, and they show evidence of in vivo degradation [4]. In addition, due to the mild gelation process within the matrix and the high biocompatibility, alginate is well suited to form the matrix for the microencapsulation of various drugs. In previous works, we have explored pH-sensitive alginate/soy protein [5], alginate/carbon nanotube nanocomposite microspheres [6], and alginate-based magnetic microspheres [7] as drug transporters, which showed obvious differences in swelling and drug release. Because of the limited mechanical stability, durability, and high-diffusion rates resulting from the high porosity [8] (which results in low encapsulation efficiency and limited control over the kinetics of drug release) the practical applications of alginate as a drug delivery system are hindered. To improve the properties of alginate-based microspheres and to cover shortages of drug transporters, many different materials have been proposed to mix with alginate, including both synthetic [9], [10], [11], [12] and natural polymers [13], [14], [15], [16], [17], [18], [19]. The attempts utilized in these studies however, could either not combine effective reinforcement of the structural strength of microspheres with biocompatibility [20], or they involved the use of organic solvent or organic crosslinking agents [21], [22], [23].
Polysaccharide nanocrystals (PNs) derived from natural sources, such as cellulose nanocrystals (CN), chitin whiskers (CHW), and starch nanocrystals (SN), have been widely used in the research of biomaterials and bionanocomposites [24], [25], [26], [27]. PNs are rigid and highly crystalline nanoparticles with uniform structure; and they possess many outstanding characteristics, for example they are readily available, highly reactive, easily processed, biodegradable, biocompatible, and non-toxic [28], [29]. After removing the amorphous regions of natural cellulose, chitin, and starch using acidic or alkaline hydrolysis, the remaining particles are individualized, nanosized, and highly crystalline [30]. By virtue of their unique nanoscale effects, as well as the active functional groups on the surface of the nanocrystals, PNs have been applied to many matrices and materials to improve properties and enhance performance of nanocomposites, nanopolymer electrolytes [31], and labeled nanocrystals used for spectrofluorometry, fluorescence microscopy or flow cytometry [32]. In other work, PNs were introduced into supramolecular hydrogels self-assembled by α-cyclodextrin (α-CD) and poly(ethylene oxide) (PEO)-block-poly(propylene oxide)-block-PEO (EPE) and successfully formed composite supramolecular hydrogels [33]. The introduction of PNs not only enhanced mechanical strength and stability, but also improved the sustained release profile of the drug [33].
After considering all the advantages of alginate and polysaccharide nanocrystals, novel sodium alginate (SA)/PNs nanocomposite microspheres have been produced by the method of the “green” ionic gelation of SA with divalent calcium ions. Gelling of alginates occurs when divalent cations take part in interchain binding between guluronic acid blocks leading to a three-dimensional network structure. This structure was expected to inhibit the self-aggregation of PNs, and hence improve their dispersion in aqueous media and produce stable nanocomposite sols. With the introduction of rigid nanoscale PNs, the alginate-based nanocomposite microspheres would possess excellent mechanical properties. At the same time, because they both belong to the polysaccharide family, the similar chemical structures of alginate and PNs provide good compatibility for the resultant microspheres as drug carriers. The aim of this study was to develop a pH-sensitive microsphere-based controlled release system for drug delivery. These microspheres were composed of three highly crystalline polysaccharide nanocrystals and sodium alginate forming semi-interpenetrating polymeric networks (semi-IPN). Theophylline was chosen as the model drug for studying release characteristics and was entrapped in the nanocomposite microspheres. It should be pointed out that all the components in this system are derived from nature, and a green ionic crosslinking method that avoids the use of organic solvents or organic crosslinking agents was utilized. The mechanical stability of alginate-based sols was investigated by rheological testing. The structure, composition, and crystalline properties of these bionanocomposite microspheres were characterized by Fourier transform infrared (FT-IR) spectroscopy and X-ray diffraction (XRD). The morphology and dispersibility of the PNs in the presence of alginate were verified by transmission electron microscopy (TEM), while the surface and cross-section of the microspheres were observed by scanning electron microscopy (SEM). Finally, the swelling and drug release behaviors of the nanocomposite microspheres were investigated, and the release kinetics and mechanisms were recognized and discussed. This paper reports and discusses the results of these studies. As far as we know, this is the first study on the introduction of polysaccharide nanocrystals to alginate-based biomaterials and its use in the field of drug delivery. The conclusions thereof create the basis for selective production of such microspheres for future application studies.
Section snippets
Materials
Sodium alginate (SA) was purchased from the China Medicine Group Co., Ltd. (Shanghai, China). Theophylline, with a purity of 99%, was purchased from Hangzhou Biological Engineering Co., Ltd. (Hangzhou, China). The linter was kindly supplied by Hubei Chemical Fiber Co., Ltd. (Xiangfan, China). Ocean Biochemical Co., Ltd. (Yuhuan, China) supplied the shrimp shell chitin. Pea starch, composed of 35% amylose and 65% amylopectin and with an average granule size of about 30 μm, was supplied by
Morphologies and crystalline properties of PNs
Rod-like morphology was observed in the cellulose nanocrystals (CN) and chitin whiskers (CHW) in this work (as shown in the TEM photos inserted in Fig. 1A and B), which was consistent with previous reports [33], [38]. The CN had a length of 200–300 nm and width of 10–20 nm with an aspect ratio (L/d) of about 20; the CHW nanocrystals possessed a higher aspect ratio of ca. 30 with a length of 300–400 nm and width of 10–20 nm. Starch nanocrystals (SN) exhibited platelet morphology (as shown in Fig. 1C
Conclusions
This work was undertaken in order to find a new and simple way of decreasing the release rate of drugs and overcoming the frequently observed problem of burst release of drugs from hydrogel matrices. Three nanocrystals, all derived from natural polysaccharides, were introduced into alginate-based microspheres and novel SA/CN, SA/CHW, SA/SN bionanocomposite microspheres were successfully prepared by simultaneously carrying out traditional crosslinking of Ca2+. The presence of alginate
Acknowledgements
The research work was financially supported by the Program of Energy Research and Development (PERD) of Natural Resources Canada; the Pulse Research Network (PURENet) through Agriculture, Agri-Food Canada's Agriculture Bioproducts Innovation Program (ABIP); National Natural Science Foundation of China (50843031); 973 Projects of Chinese Ministry of Science and Technology (2007CB936104 and 2009CB930300); Fundamental Research Funds for the Central Universities (Self-Determined and Innovative
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