Synergistic enhancement of cytotoxicity against cancer cells by incorporation of rectorite into the paclitaxel immobilized cellulose acetate nanofibers
Introduction
Paclitaxel (PTX), which was originally isolated from the bark of Taxus brevifolia in 1962, has been found to be a potent anti-neoplastic agent to be widely used to treat pancreatic, breast, gastric, ovarian, and non-small-cell lung cancers in clinics. [[1], [2], [3], [4], [5], [6]] Paclitaxel inhibits cell growth by promoting and stabilizing microtubule polymer assembly via non-covalent interaction with tubulin, thereby blocking cell replication in the late G2 mitotic phase of the cell cycle. [7,8] Nevertheless, paclitaxel treatment has severe limitations and deficiencies. [9] Oral administration of paclitaxel has a very low level of biological availability at only 6.5% due to its poor aqueous solubility (<0.03 mg/ml). [10] Absorption of paclitaxel through intravenously administration is higher but it is associated with hypersensitivity reactions, neutropenia, catheter-related infection, and extravasation. [[11], [12], [13], [14]] As the low biological availability of paclitaxel, the enhancement of antitumor activity during its utilization becomes very important for cancer treatment. Therefore, it is necessary to seek a kind of drug delivery system which can achieve synergistic effect with paclitaxel to enhance its antitumor activity.
Electrospun nanofibers as drug delivery systems possess high surface-to-volume ratio that could increase drug encapsulation efficiency and drug release stability. [15,16] It has been reported that paclitaxel-loaded poly (ε-caprolactone) nanofibers could suppress liver cancer, PTX-SA (a conjugation of paclitaxel and succinic acid) nanofibers could inhibit proliferation of lung carcinoma A549 cells more effectively than free paclitaxel, and nanofibers conjugated with the cell penetrating peptide Tat could be an effective drug carrier of paclitaxel. [[17], [18], [19]] Therefore, nanofibers could be used as an ideal template to build paclitaxel delivery system.
Cellulose acetate (CA) is a negatively charged biodegradable polymer derived from cellulose, the most abundant polysaccharide on earth. [20,21] Cellulose acetate has excellent biocompatibility and can be easily electrospun into fibrous films, which makes it suitable for immobilization of biological compounds. [[22], [23], [24], [25]] In drug delivery system, cellulose acetate could be used as a semipermeable stent facilitating the release of drugs by an osmotic mechanism. It has been suggested that cellulose acetate could be an ideal raw material to prepare multilayered scaffold for osmotic drug delivery system. [26,27] Besides, for paclitaxel, the solvent could be identical to that of cellulose acetate during the electrospinning process.
Clay materials have good intercalation capacity and therefore have been safely used for drug delivery in traditional pharmaceutical such as anti-diarrheal medicine, and in other products like antacids and cosmetics. [28,29] Rectorite (REC) is a typical type of regularly interstratified clay material with alternate pairs of dioctahedral mica-like layer (nonexpansible) and dioctahedral montmorillonite-like layer (expansible) at the ratio of 1:1. Quaternized chitosan/rectorite nanocomposites have been fabricated for gene delivery. [30,31] Chitosan/rectorite nanocomposite beads have been prepared as drug carrier, and the nanocomposite beads had higher encapsulation efficiency, more continuous and slower drug-release behavior compared with pure chitosan. [32] It has been reported that the composite films containing organic rectorite layer-by-layer assembled nanofibers displayed a stronger antitumor effect than non-organic rectorite fibers. [33]
Herein, paclitaxel-loaded cellulose acetate nanofibrous mats (CA/PTX), as well as rectorite-incorporated mats (CA/PTX/REC) were obtained via electrospinning technique. The morphology, distributions of fiber diameter, specific surface area and the thermal stability of the obtained nanofibrous mats were characterized. In vitro release profiles of paclitaxel, and the adhesion, spreading and cytotoxicity of human gastric adenocarcinoma SGC7901 cells grown on the composite nanofibrous mats were investigated. It is anticipated that with the favorable properties of rectorite, we are able to enhance the antitumor activity of paclitaxel to treat gastric cancer.
Section snippets
Materials
Cellulose acetate (Mn = 3 × 104 D) was supplied by Sigma-Aldrich Inc. (St Louis, MO, USA). Paclitaxel (99% purity) was obtained from Nanjing Zelang Medical Technology Co., Ltd. (Nanjing, China). Calcium rectorite (Ca2+-REC) refined from the clay minerals were purchased from Hubei Mingliu Inc., Co. (Wuhan, China). Acetonitrile (Sinopharm Chemical Reagent Co., Ltd., Shanghai, China) used in high performance liquid chromatography (HPLC) was HPLC grade. Other chemicals were analytical grade and
Morphology properties
The morphology of CA/PTX and CA/PTX/REC mats was examined by FE-SEM images and the distributions of fiber diameter were measured using image analyzer (Fig. 1). All the mats exhibited typical electrospun nanofibrous morphology and three-dimensional (3D) structure. The surfaces of the fibers were smooth, and there was no obvious difference in the morphology of the nanofibrous fibers. The CA mats consisted of loosely packed cylindrical fibers with the average fiber diameter of 396 ± 102 nm. After
Conclusions
In this work, CA/PTX/REC composite nanofibrous mats were successfully fabricated via co-electrospinning of paclitaxel and rectorite with cellulose acetate solutions. The nanofibrous mats were with good 3D structure and typical nanofiber morphology. The average diameter of the fibers has been decreased by incorporation of rectorite. Paclitaxel was released from CA/PTX and CA/PTX/REC nanofibrous mats at a relative slow and stable rate. Interestingly, although introduction of rectorite reduced the
CRediT authorship contribution statement
Yin Liu: Investigation, Data curation, Writing - original draft. Qin Wang: Investigation, Visualization. Yuan Lu: Methodology, Software. Hongbing Deng: Validation, Software, Writing - review & editing. Xue Zhou: Supervision, Data curation, Project administration, Conceptualization, Funding acquisition, Writing - review & editing.
Acknowledgement
This work was supported by the National Natural Science Foundation of China (Nos. 81673131, 81973000), and the National High Technology Research and Development Program of China (No. 2015AA020313).
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