Allantoin-loaded porous silica nanoparticles/polycaprolactone nanofiber composites: fabrication, characterization, and drug release properties

Abstract

The development of biocompatible nanocomposites for biomedical applications such as drug release has attracted increasing attention in recent years. We report porous silica nanoparticles (PSNs) immobilized polycaprolactone (PCL) nanofiber composites (PCL/PSNs) for drug delivery applications. The allantoin (model drug)-loaded PSNs were mixed well with a PCL solution and electrospun to fabricate the PCL/PSNs nanofiber composites. The PSNs were prepared from rice husk. Allantoin was loaded on the PSNs to prepare (allantoin-PSNs), and its three different concentrations (10, 20 and 30 wt%) based on PCL wt% were chosen. The biocompatibility and biodegradability of PCL, higher adsorption and nontoxicity of mesoporous silica nanoparticles and the promising results of the PCL/PSNs composite highlighted their challenging potential for controlled drug delivery applications. The prepared PSNs, PCL nanofibers and PCL/allantoin-PSNs nanofiber composites were characterized by scanning electron microscopy-energy dispersive spectroscopy (SEM-EDS), transmission electron microscopy (TEM), X-ray diffraction (XRD), X-ray photoelectron microscopy (XPS), Fourier transform infrared (FTIR) spectroscopy, and drug release analysis. The results confirmed the successfully synthesis of mesoporous nanoscopic PSNs from rice husk and controlled allantoin release profile by the resulting PCL/allantoin-PSNs nanofiber composites.

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1. Introduction

Nanotechnology has revolutionized the scientific world owing to the very small size and greater surface area of the unique nanoscopic materials. Because the historical breakthrough of nanotechnology and developments,^1–5 numerous new application domains have been applied such as filters,⁶ wipes,⁷ drug delivery systems,^8,9 battery and capacitor electrodes,^10,11 regenerative scaffolds,^12,13 biosensors¹⁴ and catalysts.¹⁵ Electrospinning has received greater recognition due to the simplicity, versatility and diversity.^16–19 The electrospun polymer nanofibers and their composites have received greater attention and versatile exploitations in various applications.^19–21 In particular, heterogeneous porous nanoparticles (PNs), such as silica (PSNs) and alumina PNs immobilized nanofiber composites, have been reported as efficient candidates for biomedical applications due to their prominent characteristics and performance compared to traditional materials.^16,22–24

The PSNs have been exploited in drug delivery applications owing to their large surface area (>700 m² g⁻¹), high pore volume (>0.9 m³ g⁻¹), tunable nanoscopic pore size within narrow range of 2–10 nm and stability against thermal and chemical agents.^22–24 For an effective and viable drug delivery system, a drug carrier needs to overcome four major problems such as loading and activated release capacity for a large group of drugs, controlled release of therapeutics at their targeted location without premature discharge, nontoxicity and cost effectiveness. Vast availability of silica in nature, cost-effective and tailorable fabrication, tunable mesoporous structure, nontoxicity, biocompatibility and controllable adsorption/desorption profile along with a greater specific surface area and pore size endow PSNs unique properties suitable for drug delivery applications.²⁵ Furthermore, tailored adsorption and release characteristics of the PSNs can be achieved by tuning its porous architecture, pore size and by surface functionalization.^26–29 These unique characteristics define wider applications of PSNs ranging from biomedical,^30,31 filtration,³² sensors³³ to imaging.^32,34–37

The surface of PSNs is composed largely of silanol groups (Si–OH) with weak acidic characteristics. Owing to the existence of these silanol groups, it can be easily modified with various silylating agents. For drug delivery applications, surface interactions between the drug and the host (PSNs) are primarily chemical interactions between the free silanol groups of PSNs and functional groups in the drug molecules. For the loading and unloading of drug molecules, PSNs posses open entrances and ordered channels for entrance, a homogenous distribution and release of drug molecules.³⁷ However, it is necessary to consider the functional interactions and molecular size vs. pore size between the to-be delivered drug and PSNs;²⁵ a drug with molecular size larger than the pore size of PSN would not be a successful case.

On the other hand, PCL as a base polymer has been chosen owing to its vast applicability and characteristics suitable for biomedical applications. The material is a semi-crystalline aliphatic polyester with lower T_g (−60 °C) possessing broader in vivo and in vitro bio-compatibility. It has been reported to be biocompatible and bio-resorbable material for both soft and hard tissues.^38,39 The U.S. Food and Drug Administration has approved PCL for substantial number of drug delivery and other biomedical applications.⁴⁰

In this study, the PSNs were synthesized from rice husk. Although several other methods of PSNs preparation are available; however, a new method for PSNs preparation from rice husk has been developed. This technique of PSNs preparation from rice husk has two-fold advantages such as environmental problems of rice husk disposal and pollution can be solved along with the effective utilization of an extensively available natural resource. Burning rice husk in air produces large quantities of environmental pollutants, such as CO₂, SO_x and NO_x, and its untreated discarding results in airborne breathing problems due to its low density.^41,42 The second advantage of silica nanoscopic particle synthesis from rice husk is the very low preparation cost compared to its highly sophisticated applications.⁴³

Although sufficient study has been done on nanoporous silica particles and PCL; however, very little literature is available on the synthesis of PSNs from rice husk and it's composite with PCL as drug carrier. Therefore, our study on electrospun nanocomposite mats composed of PCL/PSNs loaded with allantoin (Fig. 1) as a guest drug is reported. For optimization, three concentrations (wt%) of allantoin loaded PSNs (10%, 20% and 30%) were used. The results obtained from SEM, TEM, XRD, XPS, EDS, FTIR and drug release analysis confirmed the nanocomposite mat to be suitable for the controlled release of allantoin for biomedical applications with a tunable release profile.

Fig. 1 Chemical structure of PCL (a) allantoin (b).

Owing to excellent biocompatibility and nontoxicity of PCL, the nontoxicity of mesoporous PSNs, the PCL/PSNs nanocomposite can be considered as a nontoxic and viable drug carrier medium. Therefore, it can be exploited suitably in drug delivery systems, tissue engineering and other biomedical applications. Further study on PCL/PSNs nanocomposites may further unfold its candidacy for biomedical applications.

2. Experimental

2.1 Materials

Polycaprolactone (PCL, M_n: 70 000–90 000), dichloromethane (DCM), allantoin, hydrochloric acid (HCl), phosphate buffer powder (PBS, 1/15 mol L⁻¹ with pH 7.2), and dimethylformamide (DMF) were purchased from Sigma-Aldrich or Wako Pure Chemicals. All chemicals were used without further purification. The rice husks were collected from Aichi Prefecture of Japan, and processed before use.

2.2 Preparation of PSNs

The rice husk (500 g) was washed and dried at 60 °C for 24 h to remove the potassium, calcium and other metal components. The rice husk contained 55–60 wt% of cellulose and about 22 wt% of lignin out of its organic constituents.⁴³ To remove these constituents, 50 g of the dried husk was stirred in 0.1 M HCl (500 ml) at 27 °C for 24 h. The husk was then calcined in a muffle furnace at 600 °C at 10 °C min⁻¹. The resulting powder was crushed using a mortar to produce fine silica particles. Subsequently, the crushed porous silica particles were dispersed in distilled water and kept for 1 h. Finally, the PSNs were obtained by complete removal and evaporation of water.

2.3 Loading of allantoin on PSNs

The equal weights of allantoin and PSNs (0.3 g each) were added to 500 ml of water. The solution was stirred for 6 h under dark conditions. The PSNs were separated using a centrifugal separator (XX42CFO RT, Nihon Millipore K.K, Japan) at 6200 rpm. To remove the loosely held allantoin, the drug-loaded PSNs were stirred in distilled water and processed in the centrifugal separator. The drug loaded silica nanoparticles were finally dried to remove water and used to fabricate the PCL-composites.

2.4 PCL/PSNs solution preparation

Dichloromethane (DCM) and dimethyl formamide (DMF) at three w/w ratios 8 : 2, 6 : 4 and 4 : 6 were used as the solvent for polycaprolactone (PCL). Three different PCL concentrations (8%, 10% and 12% by weight) were mixed with each solvent formulation for an optimal electrospinning solution. The results (Fig. S1–S3†) showed that a 10% PCL concentration and 6 : 4 DCM : DMF ratio produced smooth and regular PCL nanofibers without beads in the structure along with the lower mean diameter. The lower diameter of nanofibers allows higher permeability⁴⁴ for liquids along with increased specific surface area, which enhances the adhesion among the fibers. In the other PCL and solvent formulations, undesirable results (beads, ruptures, surface and structural irregularities) were observed. Therefore, a 10% PCL concentration and 6 : 4 DCM : DMF was used for further experiments and PCL/PSNs nanofiber composite formation. Subsequently, three allantoin containing silica particle concentrations (10, 20 and 30 wt%) were added to the PCL solution. The PCL/allantoin-PSNs solution was then stirred for 12 h to obtain a homogeneous solution.

2.5 Electrospinning process

For electrospinning, Har-100*12, Matsusada Co., Tokyo, Japan, electrospinning apparatus with grounded rotary drum collector covered with aluminium foil was used. The applied voltage was 10 kV and the needle tip to collector distance was 15 cm.

2.6 Drug release test

The drug releases characteristics of the prepared samples were investigated by immersing the nanofiber composites into 50 ml of PBS (pH 7.2) and thermostatically shaken (100 rpm) at 36 °C for 5 days. To determine the drug concentration, 4 ml of the test solution was taken at particular time intervals; 4 ml of new test solution was then added for capacity adjustment. After drug release test, the samples were vacuum dried for 24 hours. A UV-visible spectrophotometer (V-530, JASCO, Japan) was used to determine concentration of the allantoin released from collected test solution. To determine the concentration of allantoin, a calibration curve from the ultraviolet-visible absorption spectrum of allantoin was prepared in advance.

2.7 Characterization

The morphology of the electrospun mats was investigated by SEM-EDS (Hitachi 3000H SEM). For a morphological study of the nanofibers and silica nanoparticles, FE-SEM (S-5000, Hitachi Co., Japan) and TEM (JEOL model 2010 Fas TEM) were used. An X-ray photoelectron spectrometer (KratosAxis-Ultra DLD, Kratos Analytical Ltd, Japan) and EDS were used to confirm the elemental composition of the silica. FTIR analysis (IR Prestige-21, Shimadzu, Japan) was carried out to study chemical structure of the surface of the porous silica particles. The specific surface area of the samples was determined using the Brunauer–Emmett–Teller (BET) method (BELSORP-max, BEL Japan, Inc.). In addition, the test temperature was maintained at 36 °C using a thermostat (SLI-200, EYELA, Japan). During the drug release test, the tested sample was immersed in the test solution using a shaker (NX-20, NISSIN, Japan) at 100 rpm.

3. Results and discussion

3.1 Characterization of rice husk and PSNs

After the HCL treatment, the color of rice husk became to paler and lighter compared to its darker colored precursor, which confirms the removal of the impurities from rice husk, such as lignin, cellulose and others (Fig. S4†). The macro structure of the husk and porous silica (Fig. 2a and b) revealed their uneven surface. The PSNs surface can be observed with lower crests and falls compared to its precursor. The smoother surface of the husk (Fig. 2c) and porous structure of silica (Fig. 2d) confirmed formation of fine pores in the later. The magnified SEM images of PSNs (Fig. 2f) further confirmed its porous structure.

Fig. 2 SEM images of rice husk (a, c, and e) and PSNs (b, d, and f).

3.1.1 XPS and EDS analyses. The surface of PSNs largely contains silanol groups (Si–OH), whereas the rice husk constitutes of organic materials along with some minerals. These chemical constituents in both were confirmed by XPS and EDS in Fig. 3 and 4, respectively. The XPS spectra of porous silica (Fig. 3a) showed peaks for O 1s, Si 2p and Si 2s at 530 eV, 100 eV and 145 eV, respectively, whereas the husk (Fig. 3b) showed peaks for C 1s and K 2s at 280 eV and 400 eV, respectively. The absence of C 1s and K 2s peaks in PSNs confirmed the removal of potassium and organic ingredients. The EDS results (Fig. 4) further confirmed reduction of carbon and increase of silicon and oxygen.

Fig. 3 XPS spectra for porous silica (a) and rice husk (b).

Fig. 4 EDS spectra of porous silica (a) and rice husk (b).

3.1.2 FTIR analysis. The distinct features of PSNs are its internal structure composed of Si–O–Si with silanol group (Si–OH) at its surface (Fig. S5†). The FTIR results (Fig. 5) for PSNs and rice husk showed respective peaks. The peaks at 1027 cm⁻¹ and 793 cm⁻¹ prove the existence of Si–O–Si. The peaks of the organic components at 3000–2870 cm⁻¹ and at 1430–1250 cm⁻¹ present in rice husk (Fig. 5b) disappeared in the spectrum of porous silica (Fig. 5a), which confirms the removal of organic components. At nearly 945 cm⁻¹, a shoulder peak of Si–O–Si could be observed. These products were from Si–OH, which indicates the presence of Si–OH on the surface of porous silica and the internal structure composed of Si–O–Si.

Fig. 5 FTIR spectra of PSNs (a) and rice husk (b) demonstrating enlarged Si–OH peaks in the two figures at the bottom.

3.1.3 XRD analysis. Crystalline silica (Group 1) is carcinogenic to humans, whereas non-crystalline silica (Group 2) is non-carcinogenic and safe for humans. Group 2 silica, owing to its biocompatibility is used widely as an additive in medical applications. The XRD result of porous silica prepared in this experiment (Fig. 6) showed a gentle peak at 2Θ = 22.5°, which proves it to be non-crystalline⁴⁵ and thus safe for the human body.³⁶

Fig. 6 XRD pattern of porous silica.

3.2 Porous silica nanoparticles

3.2.1 TEM analysis. In the TEM images of silica nanoparticles (Fig. 7), voids derived from fine pores in the particles can be observed, which confirms the presence of fine pores in the pulverized porous silica. The particle size distribution of silica nanoparticles obtained through light dynamic scattering method is described in Fig. 8. The pulverized porous silica solution without a supernatant (Fig. 8b) contains coarser particle, while wherein the supernatant was added after three hours (Fig. 8a) contains fine particles with an average diameter of 220 nm and polydispersity index (PDI) of 0.221. The particles were uniformly dispersed (monodisperse).

Fig. 7 TEM image of porous silica nano particles.

Fig. 8 Particle size distribution of PSNs when supernatant added after 3 (a) and PSNs dispersion without supernatant (b).

3.2.2 Analysis of pore characteristics. The surface area and pore size of PSNs can be measured by the nitrogen gas adsorption–desorption isotherm method (BET method). From the nitrogen gas adsorption and desorption isotherms measured by the automatic specific surface area measuring device, the specific surface area was found to be 334 m² g⁻¹ and the average pore size was 3.57 nm, proving that the porous silica is mesoporous.

Considering the previous FE-SEM image (Fig. 2), pores with a pore size from several nanometers to several tens of nanometers can be observed. Combining FE-SEM image (Fig. 2) and the nitrogen gag adsorption–desorption results (Fig. 9 & 10), it was clear that the surface and the internal parts of porous silica had a porous structure. The results indicated a tubular pore shape and uniform porous structure of PSNs.

Fig. 9 Nitrogen adsorption–desorption isotherm.

Fig. 10 BJH porous distribution.

3.3 PCL/PSNs nanofiber composite

3.3.1 SEM and TEM analyses. With the incorporation and subsequent addition of PSNs with PCL to form PCL/allantoin-PSNs nanofiber composites, the nanofiber diameter of the composite increased and cobb-like projections were observed (Fig. 11). The TEM images (Fig. 12) showed PSNs enveloped inside the PCL nanofibers, which also confirms the aggregation of the porous structure. Cobb-like projections of the silica particles at the surface of the nanofiber structure were also observed in the PCL/allantoin-PSNs composite.

Fig. 11 SEM images and diameter distribution of PCL/allantoin-PSNs nanofiber composite with PSNs with 0 wt% (a), 10 wt% (b), 20 wt% (c) and 30 wt% (d).

Fig. 12 TEM images of PCL/allantoin-PSNs nanofiber composite, PSNs enveloped in the nanofibers (a) and cobb-like projections of PSNs (b).

3.3.2 FTIR evaluations of PCL/PSNs and PCL/allantoin-PSNs. The FTIR spectra of PCL/PSNs and PCL/allantoin-PSNs are described in Fig. 13. For all samples, the characteristic peaks of PSNs⁴⁶ can be observed at 1110 cm⁻¹, 2850 cm⁻¹ and 2925 cm⁻¹. In addition, PCL characteristic peaks⁴⁷ can be observed at 720 cm⁻¹, 850–1480 cm⁻¹ and at 1725 cm⁻¹. In case of PCL/allantoin-PSNs, the characteristic peaks of allantoin overlapped completely with the absorption bands of PCL and PSNs so that these bands are unavailable for differentiation.

Fig. 13 FTIR spectrum of PCL/allantoin-PSNs 10% (a), 20% (b), 30% (c) and PCL/PSNs 10% (d), 20% (e) and 30% (f).

3.3.3 Allantoin release analysis. The cumulative allantoin release from PSNs reached equilibrium in about one hour (Fig. 14). The allantoin release results from the PCL/allantoin-PSNs nanocomposite are given in Fig. 15.

Fig. 14 Cumulative allantoin release from PSNs.

Fig. 15 Cumulative allantoin release from PCL/allantoin-PSNs nanofiber composite.

For the pure PCL nanofibers, rapid allantoin release was observed in first 10 hours, which then slowed down, resulting in the release of 80% after 120 hours. The comparative higher release rate of allantoin can be attributed to allantoin adsorption on the surface of the PCL nanofibers, and because allantoin is a polar molecule and has high affinity for DMF, whereas the PCL and DMF have low affinity with each other. As a result, during the electrospinning process, the DMF concentration of the PCL solution changed on volatilization and allantoin moves to the PCL nanofiber surface. Therefore, the rapid release of allantoin is observed at the beginning. A sustained releasing agent will help to obtain the sustained release of the drug, which was successfully accomplished via PSNs in this study.

The presence of PSNs in the PCL/allantoin-PSNs composite nanofibers may be considered a sustained releasing agent. The allantoin released in the first 10 hours of the process was 20%, 15% and 5% with the allantoin loaded PSNs of 30 wt%, 20 wt% and 15 wt%, respectively. The sustained release of allantoin by the incorporation of PSNs may be due to the Si–OH functional groups and polarity of the Si–O–Si bond in its structure. These groups prevented the migration of allantoin onto the surface of the PCL nanofibers during electrospinning of the composite. However, the increased release of allantoin with further addition of PSNs (20% and 30%) are probably the result of their increased density and projection outside of the nanofiber surface, as confirmed by SEM and TEM (Fig. 11 and 12).

Further evaluation of the results showed that for the first 30 hours of the process, PCL nanofibers without the PSNs released more than 60% of allantoin, whereas the PCL/PSNs composite nanofibers released less than 30% with a prominently lower release rate by 10% silica nanoparticles. The results confirmed the excellent performance of PCL/PSNs nanofiber composites for medical applications such as wound healing, with the possibility of tailoring the release rate via controlling the silica contents and thus tailoring the size and area of silica nanoparticles in the composite. Thus compilation of the results of current study encapsulates the successful synthesis of PCL/allantoin-PSNs nanofiber composite for sustained drug release. Some of the study carried out by other researchers is further discussed below.

Yuvakkumar et al.⁴⁸ synthesized porous silica nanoparticles from rice husk by alkali (NaOH) extraction followed by acidic extraction. The researchers claimed higher purity of silica using 0.5 N, 1 N, 1.5 N, 2 N, and 2.5 N NaOH with highest purity obtained using 2.5 N NaOH. They claimed the preparation of silica nanoparticles with a ∼25 mean size, specific surface area of 274 m² g⁻¹ and 1.46 nm pore size. The study did not report a further study for the suitability of the nanoparticles for biomedical applications such as drug delivery.

In another study, Hu et al.⁴⁸ successfully synthesized silica nanoparticles (nonporous) from rice straw using potassium silicate (KOH filtrate) by precipitation with polyethylene oxide (acidified) followed by calcination at 500 °C for purification. The study prepared nonporous spherical silica nanoparticles with a 100 to 120 nm particle size. The study did not report any extension for further study on the application of these silica nanoparticles. Ahmad et al.⁴⁹ reported the successful synthesis of silica micro and macro particles from a miscanthus crop, cereal residues (pellets) and wheat straw. The biomass was treated thermo-chemically to produce the silica particles. The biomass was leached with H₂SO₄ (5 M) followed by thermal treatment in a muffle furnace. The study claimed the highest silica content and specific surface area of 245 m² g⁻¹ from cereal pellets. The study does not further discuss the application and suitability of the meso and macro silica particles for biomedical applications. Kashanian et al.⁵⁰ fabricated mesoporous silicon (pSi) encapsulated in biodegradable PCL microfibers by electrospinning to produce a nonwoven pSi/PCL mat for biomedical applications. The results of the study evinced the successful encapsulation of pSi in the PCL microfibers by electrospinning and further disclosed the biocompatibility of the mat with the epithelial cells of rats. The study suggested the possibility of controlled release kinetics by modifying the Si surface. Singh et al.⁵¹ successfully prepared a multilayered mesoporous silica and PCL based nanoscopic biomatrix for bone regeneration and controlled loading and release capacity of the guest molecules. The polycaprolactone nanofibers were electrospun and coated with mesoporous silica using a sol–gel technique. The mesoporous silica coating improved the wetting, ionic reactivity and mechanical characteristics of the composite for bone regeneration. In addition, the mesoporous surface allowed the capability for the loading of proteins and drug molecules along with sustained drug release profile over an extended time period. Although a little study is available on silica synthesis from different biomasses and agricultural waste; however, the method of synthesis of mesoporous silica nanoparticles from rice husk extends a wider domain of research for the efficient and useful utilization of natural resources and synthesis of highly sophisticated materials for the safety and survival of human life on the planet.

4. Conclusions

This study reported a successful method of PSNs synthesis from rice husk resulting in the suitable utilization of a natural resource along with the mitigation of ecological problems from its untreated dumping in environment. The prepared PSNs, loaded with allantoin as the sample drug, were fabricated successfully with PCL to produce PCL/PSNs nanofiber composite for sustained drug release. The guest loaded PSNs were added in three wt% concentrations with PCL (10%, 20% and 30%) and then electrospun into a composite mat. The results revealed 10% PSNs in the composite producing a slower release rate, which subsequently increased with the further addition of PSNs. Therefore, the results showed that controlled drug release profile can be achieved by tuning PSN wt% in PCL/PSNs nanofiber composite. Thus, confirms the PCL/PSNs composite as a sustained drug delivery nanofiber mat.

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Footnote

† Electronic supplementary information (ESI) available: SEM images and BET isotherm curves are provided. See DOI: 10.1039/c5ra22199d

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