Dual-functional SFP/PAN based nano drug release system for treatment and nutrients

Abstract

Nano drug delivery systems can control the ordered release of drugs. To achieve the target of supplying therapeutics and nutrients at the same time, a novel nano drug delivery system with a core–shell structure was prepared by coaxial electrospinning. Polyacrylonitrile (PAN) has been used to produce a drug release scaffold in the shell section, mixed with absorbable silk fibroin peptide (SFP) as a nutrient. Ciprofloxacin (CPFX), a broad-spectrum antibiotic, was used as the core, as well as an antibacterial agent. Owing to its low molecular weight, using a pure SFP thin solution to manufacture nanofibers by electrospinning is still technically challenging. Thus, different ratios of PAN to SFP were used in the shell electrospinning solution. In this research, a novel nano dual-functionality drug delivery system has been successfully prepared. In vitro testing demonstrated that nanofibers could supply more nutrients with increasing SFP in shell solutions; however, the ability to maintain controlled release was reduced. It was found that the nanofiber membrane had the best controlled drug release capability for a PAN-to-SFP mass ratio of 95:5. Overall, most ciprofloxacin was released in the first 12 h, while the release of SFP was constant throughout the first 24 h. Our modeling demonstrated that the release of CPFX and SFP is best described using a first-order kinetic model. The developed drug delivery system is designed to release antimicrobial drugs in a controlled manner and provide absorbable nutrients simultaneously.

Keywords

Silk fibrion peptide nano drug delivery system coaxial electrospinning drug release model core–sheath structure

A sustained release of drugs is an important drug delivery process for all types of dosage system.^1,2 Compared with other drug release systems, sustained drug delivery systems can improve patient compliance by reducing the total dose administered, dosing frequency, and treatment failure rates, as well as the spread of bacterial resistance. In the past half-century, almost all of the novel techniques have been used to develop drug-sustained release technology to treat materials.³^–5 With the advent of nanotechnology, new forms of pharmaceutical, including nanoparticles, nanobeads, and nanofibers, have been widely used in drug release systems.^6–8

The application of nanotechnologies in drug therapy delivery can enhance a controlled release and improve the absorption and availability of drugs.^9,10 Medicated nanofibers have primarily been created by electrospinning.^11–15 With the advancement of technology, a core–sheath structure can be created using some novel form of electrospinning, such as coaxial electrospinning,¹⁶ modified tri-axial electrospinning,^17,18 or coaxial electrospraying.¹⁹ All these technologies have provided a wide variety of opportunities to tailor drug-controlled release profiles^20,21 and produce nanofibers by loading various elements into the core and shell parts.

Owing to its easy operation and controllable parameters, coaxial electrospinning has been widely studied by researchers.²²^–24 This novel technology also gives an opportunity for some low molecular weight unspun natural polymer to be applied in nanofiber-based drug delivery systems.²⁵ In particular, the development aims in producing electrospun functional nanofibers are higher than before; however, the synthesis of multifunctional nanofibers is a major challenge for researchers.

Silk fibroin peptide (SFP) is a small-scale protein-derived material with better hydrophilicity and is better absorbable than silk fibroin. The main component of SFP is glycine, which is a nutrient and basic peptide, known to decrease undesirable stimulation of the gastrointestinal tract.²⁶ For these reasons, SFP is an ideal supplementary medical material and food additive.²⁶^–29 Thus, SFP is an excellent choice of nutritional supplement in the nano drug delivery system. However, spinning SFP with low molecular weight in the nano drug delivery system remains technically challenging. Polyacrylonitrile (PAN) is a well-studied water-insoluble polymer, which has been widely used in electrospinning.^22,30^–32 Moreover, PAN can improve the spinability of some hydrophilic polymers.³⁰ Thus, PAN is widely used as a drug delivery agent and medical material because of its excellent chemical stability. Lee et al.³³ used an electrospun PAN nanofiber membrane as a basic material to manufacture a layer-by-layer antithrombogenic drug release membrane and found it an ideal choice for hemodialysis. Lian et al.³⁴ chose pH-sensitive polyacrylonitrile nanoflowers as drug-loaded carriers in designing a potential target drug delivery system used in colon tissue, producing a cumulative release rate of about 83% after 260 h.

Based on previous research, we have explored a useful method to incorporate low molecular weight SFP in a multifunctional drug delivery system by mixing with PAN and coaxial electrospinning. In addition, ciproﬂoxacin, predominantly absorbed in the gastrointestinal tract, was used as a model drug in this study.³⁵ Hence, we compared and analyzed the SFP/PAN ratio to successfully explore the nanofiber drug delivery system using PAN as a dissolution scaffold for loading the model drug and SFP as a control-release medium and nutrient. Additionally, mathematical models were applied to analyze the drug release kinetics of this novel nano drug delivery system.

Materials and methods

Experimental materials

Ciprofloxacin hydrochloride-hydrate (CPFX) and PAN (molecular weight: 85000) were purchased from Sinopharm Chemical Reagent Co. Ltd. (Shanghai, PRC), N,N-dimethylformamide (DMF) of analytical purity was obtained from Tianjin Zhiyuan Chemical Reagent Co., Ltd. (Tianjin, PRC). Silk fibroin peptide (SFP, molecular weight 300–16000) powder was purchased from Xi’an Green Spring Biotechnology Co., Ltd. (Xi’an, Shaanxi, PRC).

Preparation of electrospinning solution

To assess differences in fiber morphology at different concentrations of SFP, different masses of SFP powder and PAN powder were homogeneously dispersed in a DMF mixture using magnetic stirring (14 h at 70°C). The prepared sheath solutions for electrospinning were termed S1 (PAN: 4.75 wt%; SFP: 0.25 wt%); S2 (PAN: 4.50 wt%; SFP: 0.50 wt%); S3 (PAN: 4.25 wt%; SFP: 0.75 wt%); S4 (PAN: 4.0 wt%; SFP: 1.00 wt%); and S5 (PAN: 3.75 wt%; SFP: 1.25 wt%). An electrospinning core pre-solution was prepared (PAN: 9 wt%; CPFX: 1 wt%); PAN, SFP, and CPFX powder were dispersed in DMF using magnetic stirring for 14 h at 70°C.

Preparation of core–sheath nanofiber membranes

After the electrospinning solution was prepared, core–sheath nanofibers were prepared using a coaxial electrospinning spinneret purchased from Hefei Sipin Technology Co., Ltd. The inner and outer diameters of the inner tube were 0.30 and 0.60 mm, respectively, and the inner diameter of the outer tube was 1.20 mm. The flow rate was set to 0.40 mL/h and 1.20 mL/h for the core and shell, respectively. The applied voltage was set at 20.0 kV to produce a stable Taylor cone. Briefly, a grounded stainless steel plate covered with tin foil was placed 12 cm away from the spinneret to collect nanofibers in the form of a membrane for 2 h. The samples that were spun using core solution and sheath solution S1, S2, S3, S4, or S5 were termed N1, N2, N3, N4, and N5, respectively. Figure 1 illustrates the electrospinning system.

Figure 1.

Core–sheath nano drug delivery system.

Chemical analysis of core–sheath nanofiber membranes

Fourier transform infrared spectroscopy (FTIR) was performed using a Spotlight 400 Fourier transform infrared spectrometer (Perkin Elmer Thermo Fisher Scientific Co., Ltd., Waltham, MA, USA) to obtain a characteristic peak of silk proteins and other raw materials. X-ray diffraction intensity curves were used to chemically characterize N1 nanofiber. In addition, samples were analyzed using a Bruker D8 advance X-ray diffractometer (Cu target; acceleration voltage: 40 kV; current: 150 mA; λ = 0.154 nm) with a test diffraction angle set to 2θ = 5°–50°. The analysis was carried out using Origin 2017 software (Origin Lab Corporation, Northampton, MA, USA).

Morphology of core–sheath nanofiber membranes

The morphology of nanofiber membranes was investigated using scanning electron microscopy (SEM, Quanta-450-FEG, Hillsboro, OR, USA). Samples were coated with a 10 nm gold layer to improve electrical conductivity before SEM. The core–sheath structure of the N1 nanofiber membrane was further characterized using transmission electron microscopy (TEM, FEI Tecnai G2 F20, Hillsboro, OR, USA) with an accelerating voltage of 200 kV. Transmission electron microscopy analysis was conducted by directly spinning the N1 nanofiber membrane onto a carbon membrane coated with a copper grid for several seconds. The diameters of the core and shell sections of the electrospun fibers were evaluated using Image-Pro Plus 7.0 (Media Cybernetics, Inc., Rockville Pike, MD, USA).

Surface water contact angle of nanofiber membranes

The hydrophilicity of the nanofiber membranes was evaluated by detecting the surface water contact angle (WCA) using a drop shape analysis instrument (DSA100, Krüss GmbH, Hamburg, Germany). Droplets of 3 µL of water were placed on the sample surfaces, and the angles were recorded when the droplets were steady.

Controlled release profile of nanofiber membranes

Controlled release of the nanofiber membranes N1, N2, and N3 was measured using the second pulp method as stipulated in the Chinese Pharmacopoeia.³ Release characteristics of CPFX and SFP were tested in vitro. A 5 mg dried composite nanofiber membrane was briefly placed in a centrifuge tube containing 3 mL phosphate-buffered saline (PBS), then oscillated at constant temperature (150 r/min) at 37 ± 0.1°C to simulate in vitro release. The maximum ultraviolet absorption of CPFX and SFP was observed at λ = 300 nm and λ = 260, respectively, using a UV-1900PC ultraviolet spectrophotometer (Shanghai Meixi instrument Co., Ltd., Shanghai, PRC). After determining the drug concentration at different periods, the drug cumulative release rate was calculated as

Q_{m} = \frac{_{C_{m} V + V_{i} \sum_{i = 0}^{m - i} C_{i}}}{M_{0}} \times 100 %

where: Q _m is the drug cumulative release rate at time point n, as a percentage; C_m is the drug concentration of sample n, in milligrams per milliliter; V is the release medium volume, the first time point sample volume, in milliliters; and M₀ is the nanofiber membrane drug mass, in milligrams.

Results and discussions

Morphology and structure of nanofiber membranes

As shown in Figure 2(a) to (c), nanofibers N1, N2, and N3 had relatively narrow fiber distributions and smooth morphology. As shown in Figure 2(g) to (i), the diameters of nanofibers N1, N2, and N3 were 184 ± 56 nm, 111 ± 43 nm, and 158 ± 42 nm, respectively. However, as SFP content increased, nanofibers N4 and N5 had large numbers of electrospun beads. Electrospun beads and irregular nanofibers can be easily identified, as shown in Figure 2(d) and (e). Owing to the increase in low molecular weight SFP content of the electrospun solution, the viscosity and stability of electrospun solution N4 and N5 decreased; the average numbers of electrospun beads were 1.04/µm² and 1.64/µm², respectively. Hence, the electrospun quality deteriorated, resulting in a sheath solution diluted to spin, and electrospun beads came under an applied voltage of 20 kV.

Figure 2.

Morphological structure and diameter distribution of the nano drug delivery system: (a–e) scanning electron micrographs of nanofibers (a) N1, (b) N2, (c) N3, (d) N4, and (e) N5; (f) transmission electron micrograph of core–sheath nanofiber N1; (g–i) diameter distribution of nanofibers (g) N1, (h) N2, and (i) N3.

The inner structure of nanofibers was characterized using TEM, as presented in Figure 2(f); the core nanofiber was encased in the sheath nanofiber. Moreover, we found that, with an increase in SFP content, the nanofibers have random electrospun beads.

Chemical characterization and crystal analysis of nanofibers

Infrared spectroscopy and X-ray diffraction were used to characterize the chemical make-up of the nanostructures. Figure 3(a) shows a peak characteristic of the amide of SFP at 1627 cm⁻¹ (amide I, C=O stretching).^36–39 In the N1 infrared spectrum, the peak observed at 1627 cm⁻¹ is broader than that in SFP and is probably from CPFX, containing a C=C(Ar) observed at 1621 cm⁻¹, which strengthened the absorbance of amide I. Moreover, the cyclopropyl peak (2930 cm⁻¹) and fluorine atom peak (1333 cm⁻¹) of CPFX are apparent in the incorporated nanofiber membrane, demonstrating uptakes. The X-ray diffraction spectra indicate that electrospinning did not alter the chemical components or crystalline structure of SFP, PAN, or CPFX. Figure 3(b) shows the X-ray diffraction (XRD) spectra of the raw materials (SFP, PAN, and CPFX) and the prepared N1 nanofibers. There is a major characteristic peak for CPFX at 26.4° and 29.1°, confirming crystalline materials, as suggested by sharp peaks in the XRD spectra. Both PAN and SFP have a major characteristic peak at 16.7° and 20.6°, respectively, confirming that they both have a crystalline structure. As anticipated, nanofibers N1 had no sharp peaks in the XRD patterns, whereas the sharp peak of PAN at 16.7° became smooth and shifted to 15.4°, showing a decrease in crystallinity of PAN with N1 nanofibers. Simultaneously, the characteristic peaks of CPFX and SFP both disappeared, which means that they existed in the N1 nanofibers in an amorphous pattern. Thus, all the raw materials were transferred into an amorphous physical state in N1 nanofibers and lost their original crystalline state. These results suggest that SFP, PAN, and CPFX were well mixed in an electrospun solution, and amorphous drug–polymer nanocomposites were formed.

Figure 3.

(a) Fourier transform infrared spectra of polyacrylonitrile (PAN), silk fibroin peptide (SFP), ciprofloxacin hydrochloride-hydrate (CPFX), and N1 nanofibers; (b) X-ray diffraction spectra of PAN, SFP, CPFX, and N1 nanofibers.

Characterization of controlled release of nanofibers

Silk fibroin peptide has excellent hydrophilicity. With an increase in sheath nanofiber concentration, the hydrophilicity of nanofiber membranes will be enhanced; however, the nanofiber drug delivery system’s efficiency will decrease. The WCA of nanofiber membranes decreased with an increase in SFP content, leading to a better hydrophilicity for N3 nanofiber membranes than for N1 and N2 nanofiber membranes, as shown in Figure 4. However, with the increasing hydrophilicity of nanofiber membranes, nanofibers became dissolved more easily and lost their ability to control drug release. As presented in Figure 5(a) and (b), the N3 nanofiber membrane had a blast release. Moreover, increasing the concentration of SFP resulted in greater corrosion of the sheath structure of the nanofiber. Overall, close to 80% of the model drug CPFX was released within 5 h, demonstrating the membrane’s ability to quickly release the drug; however, the release of SFP and CPFX is different. As presented in Figure 5(c) and (d), SFP release could be characterized as more isometric than CPFX. The release of SFP was constant from 0 h to 24 h, whereas most CPFX was released between 0 and 12 h. Moreover, N1 nanofibers performed best in the controlled release of CPFX and SFP and have excellent potential for application in clinical settings. Additionally, the minimum release concentration of CPFX as a model drug for N1 nanofiber in processing the controlled release was 0.83 µg/mL, which is larger than its minimal effective range of 0.20–0.25 µg/mL.⁴⁰ In addition, 1 mg of nanofiber membrane could release 0.05 mg glycine in the entire release, demonstrating its usefulness in nutrient supplementation.²⁶^–29 Overall, the developed nanofiber can achieve its expectant function in the entire drug release stage.

Figure 4.

(a) Water contact angle of nanofiber membranes for different silk fibroin peptide (SFP) contents; (b–d) water contact angle images of nanofibers (b) N1, (c) N2, and (d) N3.

Figure 5.

Release of ciprofloxacin hydrochloride-hydrate (CPFX) and silk fibroin peptide (SFP) from nanofiber membranes: (a) in vitro CPFX model drug dissolution results; (b) comparison of CPFX release percentage; (c) in vitro SFP dissolution; (d) comparison of SFP release percentage.

The release process of CPFX and SFP from nanofiber membranes is best described as a degradation consisting of three main steps, as shown in Figures 6 and 7. Figure 6(b) shows that the first dissolution occurred in the sheath nanofiber; after 1 h of dissolution in PBS solution, some pores formed on the nanofiber surface, wherein hydrophilic portions of the SFP dissolved. After that, most of the model drug was released from the core of the nanofiber. As shown in Figure 6(c), after 4 h of dissolution, more hydrophilic SFP degraded from the sheath nanofiber, which increased the size of pores, and more drug was released. Overall, the developed membranes have released SFP and CPFX in a controlled manner over time.

Figure 6.

Scanning electron micrographs for dissolution situation of nano drug delivery system after different durations: (a) 0 h;(b) 1 h; (c) 4 h.

Figure 7.

Dissolution of silk fibroin peptide (SFP) and ciprofloxacin hydrochloride-hydrate (CPFX) dissolution from the nano drug delivery system.

Mechanisms of drug release from nanofiber membranes

A drug delivery agent is responsible for drug diffusion and polymer dissolution, which govern the basic drug release mechanisms from polymers.^41,42 To investigate the release mechanisms and quantitatively analyze the release of CPFX model drug and SFP from N1 nanofiber membranes, several mathematical models were applied. The relationship between the cumulative rate of drug release and time was fitted using a zero-order kinetic model, first-order kinetic model, and Higuchi kinetic model.⁴³ The Ritger–Peppas model was also used to obtain more information regarding the type of diffusion mechanism;⁴³ the release or diffusional exponent, n, obtained from this model indicates the drug release mechanism. If n < 0.5, the release mechanism follows Fickian diffusion, and for 0.5 < n < 1, the drug release follows a non-Fickian model, indicating irregular transport of the film. For n > 1, the mechanism of drug release is regarded as super Case-II transport.⁴⁴, ⁴⁵

Table 1 shows the release behavior of the CPFX model drug in N1 nanofiber membrane model fitting results. The first-order kinetics describing the release of CPFX are shown in Figure 8(a). The data fit well using a first-order kinetic model. Therefore, the rate of drug release of the developed nanomaterial was constant over time.⁴³ For the result obtained using the Ritger–Peppas model, the equation of CPFX is

Q = 38.7943 \cdot t^{0. 3339} (R^{2} = 0. 9074)

Table 1.

Fitted equations for describing different drug release models of ciprofloxacin hydrochloride-hydrate in N1 nanofiber membranes

Drug release model	Fitted equation	R ²
Zero-order kinetics model	Q = 3.5777·t + 37.4591	0.7989
First-order kinetics model	Q = 100.0864 · (1 − e^−0.2637t)	0.9922
Higuchi kinetic model	Q = 21.8391 · t^0.5 + 12.0144	0.8598
Ritger–Peppas model	Q = 38.7943 · t^0.3339	0.9074

Figure 8.

First-order kinetics describing the release of (a) ciprofloxacin hydrochloride-hydrate (CPFX) and (b) silk fibroin peptide (SFP) from the N1 nanofiber membrane.

where n = 0.3339 for n < 0.5. The release of CPFX follows Fickian diffusion. Hence, the release rate of CPFX was affected by the drug concentration, and its release occurred in an ordered and controlled manner.

Table 2 presents a fitting analysis of SFP from nanofiber membranes, while the first-order kinetics describing SFP release is shown in Figure 8(b). Overall fitting results demonstrate that the mechanism of release differed from that of CPFX.⁴³ Using the Ritger–Peppas model, the equation for SFP is

Q = 7.2795 \cdot t^{0.8214} (R^{2} = 0.9891)

Table 2.

Fitted equations of drug release models describing the release of silk fibroin peptide from N1 nanofiber membranes

Drug release model	Fitted equation	R ²
Zero-order kinetics model	Q = 4.12t + 4.1366	0.9888
First-order kinetics model	Q = 172.4127·(1 − e^−0.0341t)	0.9951
Higuchi kinetic model	Q = 21.3869·t^0.5 − 15.0097	0.9525
Ritger–Peppas model	Q = 7.2795·t^0.8214	0.9891

where n = 0.8214 for 0.5 < n < 1. The release of SFP follows non-Fickian diffusion. Thus, the release of SFP fitted well using a first-order kinetic model, similar to the release of CPFX. However, the initial release stage of SFP lagged behind that of CPFX, and the nanofiber membrane developed can be used for both inflammation and nutrient supplementation.

Conclusions

In this work, coaxial electrospinning was used to construct a drug delivery system with a core and sheath section. The hydrophilic polymer SFP was placed on a sheath layer to create a drug release scaffold. Overall, core–sheath electrospun membranes have dual functionality, with the ability to deliver an antibacterial agent and nutrients that have great potential in treating gastrointestinal tract disease and supplying nutrients. The developed method can also be applied to other sustained release systems that require dual functionality to treat diseases.

Footnotes

Declaration of conflicting interests

The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Funding

The authors disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: This work was supported by the National Natural Science Foundation, China (Grant Number 52073224), the Natural Science Basic Research Program of Shaanxi, China (Grant Numbers 2017JQ5054 and 2020JQ-819), the Shaanxi Provincial Education Department, China (Grant Number 18JS041), the Thousand Talents Program of Shaanxi Province, and the Sanqin Scholar Foundation of Shaanxi Province, China.

ORCID iDs

Ling Han

Wei Fan

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