Research paperElectrospun tri-layered zein/PVP-GO/zein nanofiber mats for providing biphasic drug release profiles
Graphical abstract
Introduction
Drug delivery systems (DDS) have attracted considerable attention over the past several decades due to their potential applications in various medical fields (Dong et al., 2017, Wu et al., 2016). For the ideal delivery system, it is important to maintain an effective drug concentration throughout the treatment period. However, the initial burst of drug release is frequently observe in nanoscale delivery systems (Mitragotri et al., 2014). On the contrary, too slow release couldn’t be an effective therapeutic method to whom immediately requiring medical treatment. In the case of wound dressing, a high initial burst release of drugs can prevent invading bacteria to skin that are introduced during the implantation, and a continued release is necessary to prevent the potential occurrence of a latent infection (Xue et al., 2014). Therefore, the ideal drug carrier would have a time-controlled release behavior that can systematically regulate the drug release with rapid introducing drug at initial state and subsequent slow release to prolong the effective the therapeutic treatment. Moreover, wound dressing should be durable, stress resistant, flexible, and elastic. It should be easy to apply and remove without incurring any trauma during dressing changes. As such, the mechanical properties are critical and important for applying to the wound dressing application, which could bear the stresses exerted by different parts of the body having varying contours (Kokabi et al., 2007).
Recently, many pharmaceutical studies have focused on the development of nanofiber-type drug carriers constructed through electrospinning (Kim et al., 2013, Zupančič et al., 2016). Electrospun nanofibers feature large surface area, high porosity, and high surface-to-volume ratio (Lee et al., 2016b), which make them a promising material for drug carriers and effective delivery of water-insoluble drugs (Deng-Guang et al., 2009). Also, therapeutic drugs can easily be embedded in the nanofibers during the electrospinning process. However, the easy formation of drug suspension implies that there is no lattice energy barrier to dissolution, indicating that the drug dissolution rate and solubility increase in favorable solutions. Thus, electrospun nanofibers also have poor performance in terms of sustained release due to their uncontrollable and undesirable initial burst release (Pattama et al., 2007).
To overcome this shortcoming, a biphasic release system that can perform an initial burst release followed by a relatively steady release in the later release stage has been developed by combining a fast release with the slow release component of the drug (Yu et al., 2013a). A biphasic release system utilizes the difference of diffusion pathway of drugs in different polymer matrices, leading to the time-regulated release of the drug (Wang et al., 2010). Coaxial electrospinning, in which a concentric spinneret can accommodate two different fluids, is one of methods for constructing a biphasic release system (Vellayappan et al., 2016). It can be applied to control the secondary structures of nanofibers, which is a useful method for imbedding drugs or biological agents selectively in different polymer matrices. Recently, several groups produced a coaxial electrospinning system for demonstrating biphasic drug release profiles (Yu et al., 2015). However, the coaxial electrospinning process requires that the spinning fluids having good compatibility, similar physicochemical properties, and comparable flow rate to prevent undesirable phenomena such as phase separation or coagulation (Tiwari et al., 2010). Thus, the implementation of coaxial electrospinning and also other multiple-fluid processes needs profound skills (Yu et al., 2017). A more facile and straightforward method for achieving a biphasic system is a multi-layered nanofiber system, which can provide the advantages of biphasic drug release and easy fabrication conducted by sequentially electrospinning the second polymer on the same target collector after the first electrospun nanofiber has been collected. Such a sequential spinning process can produce a hierarchically ordered structure composed of different kinds of polymer mesh. From this method, a time-regulated drug release behavior can be modulated systematically over the course of the treatment.
Herein, we demonstrate a biphasic structure using tri-layered electrospun nanofiber meshes to achieve an effective time-regulated drug release system. The drug release profiles of the resultant nanofibers were evaluated using in vitro release assay. Two different polymer matrixes – zein and polyvinylpyrrolidone (PVP) – were used as the top/bottom layer and middle layer, respectively. Ketoprofen (KET), one of the non-steroidal anti-inflammatory drugs, was exploited as the model drug, which was loaded into each nanofiber. It is an effective anti-inflammatory agent for patient with phlogistic diseases (Park and Lee, 2011). As a renewable and biodegradable material, zein have been investigated as drug carriers to protect drugs from stomach acid (Cao et al., 2017). Zein is a mixture of proteins with different molecular weights in corn gluten meal. Zein is a mixture of proteins with different molecular weights in corn gluten meal (Lai and Guo, 2011). Dong et al. (2004) reported the good ability of zein films to proliferate both human liver cell and murine fibroblast cells, which implies that zein can be a promising biomaterial with good biocompatibility (Dong et al., 2004). PVP is a well-known hydrophilic biocompatible polymer and has been extensively used in pharmaceutical industry (Yu et al., 2013b). PVP has significant commercial utility and potential applications in a wide variety of fields, such as medicine, food, pharmaceuticals and cosmetics (Yu et al., 2010). The PVP fiber is also utilized as a fast-dissolving drug system due to its hydrophilic character, which improves the dissolution profiles of poorly water-soluble drugs for possible oral delivery applications. Graphene oxide (GO) is used as a therapeutic carrier by incorporating it into PVP nanofiber. GO has a unique chemical structure that contains numerous hydroxyl and epoxide functional groups, which provide sufficient capacity to carry drugs via surface adsorption and increase the dispersibility of drug in nanofiber (Zhang et al., 2017). Furthermore, GO exhibits excellent biocompatibility and can improve the mechanical properties of nanofiber (Rana et al., 2011). Owing to its unique properties, it has led to many potential applications in the biomedical engineering field, including adsorption of biomolecules, and biosensors, and drug delivery. The biocompatibility of GO was investigated by Zhi et al. (2013), they reported the effect of GO and PVP/GO on dendritic cells, T cell and macrophages in vitro and found that combination of PVP and GO improve the immunological biocompatibility of GO in vitro, and the PVP-GO sheets can enhance the immunologic function of lymphocytes to some extent (Zhi et al., 2013). Generally, nanofiber mats have very poor mechanical properties, but such shortcomings can be overcome by incorporating GO (Uddin et al., 2015). We successfully fabricated a tri-layered nanofiber structure – zein, PVP/GO and zein – and monitored its biphasic release behavior showing a delayed initial burst of drug, implying that it can be an effective time-regulated drug carrier.
Section snippets
Materials
PVP (Mw = 1300 kg mol−1) was purchased from Sigma-Aldrich. Zein (purity of 98%), ethanol (99.5%), KET (98%), and phosphate buffer solution (PBS, pH 7.4) were obtained from Wako Pure Chemical Industries, Ltd. (Japan). Graphene oxide solution (GO, 2 mg/mL in water) was purchased from Sigma-Aldrich, and the DI-water was highly purified.
Tri-layered nanofiber fabrication
Multilayered drug-loaded nanofibers were fabricated using sequential electrospinning with two different types of polymer solutions – zein and PVP. The drug-loaded zein
Morphology and structure of nanofibers
Cross-sectional SEM images of tri-layered nanofiber meshes and the morphology of each layer are presented in Fig. 2. From the cross-sectional images, the boundary between zein and PVP/GO nanofiber-loaded drug can be clearly observed, and the thicknesses of the fabricated nanofibers were 83 ± 19 μm for the zein and 51 ± 11 μm for the PVP/GO. The top, middle and bottom layers were collected for 1, 4, and 1 h, respectively (Fig. 2a). The first and the third layers of zein are thicker than that of PVP
Conclusions
The facile fabrication of tri-layered nanofiber mesh was successfully demonstrated via sequential electrospinning in this work. Sequential electrospinning was comprised of several construction process: (i) the drug-loaded zein nanofiber was electrospun for a designated amount of time as the bottom layer, (ii) the drug-loaded GO/PVP nanofiber was electrospun for 4 h as the middle layer, and then (iii) the drug-loaded zein nanofiber was electrospun again, the same as the first layer. Results of
Funding sources
This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.
Acknowledgments
H. L. gratefully acknowledges the support from Division of Frontier Fibers, Institute for Fiber Engineering (IFES), Interdisciplinary Cluster for Cutting Edge Research (ICCER) at Shinshu University. This research was supported by Basic Science Research Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Science, ICT & Future Planning (2014R1A1A3A04049595).
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