Ureasil organic-inorganic hybrid as a potential carrier for combined

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Ureasil organic-inorganic hybrid as a potential carrier for combined delivery of Anti-inflammatory and Anticancer Drugs Beatriz Bernardes Caravieri, Natana Aparecida Martins de Jesus, Lilian Karla de Oliveira, Marina Diniz Araujo, Gabriele Pedroza Andrade, and Eduardo Ferreira Molina ACS Appl. Bio Mater., Just Accepted Manuscript • DOI: 10.1021/acsabm.8b00798 • Publication Date (Web): 17 Apr 2019 Downloaded from http://pubs.acs.org on April 18, 2019

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ACS Applied Bio Materials

Ureasil organic-inorganic hybrid as a potential carrier for combined delivery of Anti-inflammatory and Anticancer Drugs

Beatriz B. Caravieri,1 Natana A. M. de Jesus,1 Lilian K. de Oliveira,2 Marina D. Araujo,1 Gabriele P. Andrade,1 and Eduardo F. Molina1* 1Universidade

2UEMG

de Franca, Av. Dr. Armando Salles Oliveira 201, 14404-600 Franca, SP, Brazil

- Universidade do Estado de Minas Gerais, Unidade de Passos, Av. Juca Stockler 1130, Passos,

MG, Brazil

*Corresponding author e-mail: [email protected]

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ABSTRACT There continues to be a need to develop controlled release systems loaded with multiple drugs with distinct pharmacological activities, such as anti-inflammatory and anticancer effects, which are able to provide the desired release of each drug, as a function of time. To this end, an elegant strategy was developed for the incorporation, in a one-step process, of the anti-inflammatory drug naproxen (NAP) and the anticancer drug 5fluorouracil (5FU) into an ureasil organic-inorganic hybrid matrix. An ureasilpoly(oxyalkylene) (UPEO) matrix was prepared using a sol-gel route to obtain a versatile

dual-drug

delivery

system.

Small-angle

X-ray

scattering

(SAXS)

measurements and Fourier transform infrared spectroscopy (FTIR) demonstrated that UPEO network is preserved upon loading with the two drugs NAP and 5FU. There was excellent agreement between the macroscopic swelling behavior (water uptake) and surface wettability (determined using contact angle measurements), with this behavior being closely correlated with the release profiles and playing an important role in the sustained delivery of both drugs from the hybrid matrix. The amounts of both drugs released simultaneously could be finely controlled by adjusting the pH of the aqueous medium, with the release presenting stimulus-responsive behavior. In an aqueous PBS medium, the dual UPEO release system presented excellent potential as a vehicle for the release of the water-soluble 5FU and water-insoluble NAP drugs, at identical rates, using a single carrier. This novel and adjustable dual-drug delivery UPEO system is a promising hybrid material carrier with the ability to simultaneously incorporate a wide range of therapeutic agents for the treatment of various diseases, including cancers.

Keywords: Ureasil-poly(ethylene oxide), hybrid materials, dual-drug delivery systems, swelling.


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1. Introduction

The use of controlled release systems has attracted large attention in recent years, due to their wide range of applications in areas including drug delivery, disease diagnosis, catalysis, cell imaging, and environmental protection.1-5 However, over the past decade, one of the main technological challenges in the field of drug delivery devices has been the development of multi-drug loading for combination chemotherapy.6-8

All

cancer

treatment

technologies,

such

as

radiotherapy,

chemotherapy, thermotherapy, surgical resection, and others, still present their own limitations. For example, the failure of chemotherapy is, in most cases, due to cancer chemoresistance.9 In this situation, the use of dual-drug delivery systems can offer advantages such as i) enhanced therapeutic efficacy, ii) reduced side effects, and iii) retardation of the development of cancer chemoresistance, due to the synergistic or combined effects of different drugs.10 Nguyen et al.7 described the dual release of doxorubicin and cisplatin from a polymer-caged nanobin (PCN). The PCN dual system could deliver both drugs simultaneously to the cancer cells, attenuating the acute toxicity of the drugs and providing enhanced synergy. Yang et al.11 reported a dual-drug delivery device based on a nano-injectable hydrogel (NHG) containing combretastatin-A4 phosphate (CA4P) and doxorubicin (DOX). The hydrogels were used for sequential delivery of both CA4P and DOX for antiangiogenesis-anticancer combinatory therapy, with in vitro release assays of the drugs demonstrating different sustained release profiles from the injectable NHG hydrogel. Mesoporous silica nanoparticles are among the materials most extensively studied as controlled-release platforms, due to their high stability, biocompatibility, mesopore size control, and easye surface modification.12,13 Moorthy et al.14 prepared mesoporous organosilica-based carriers for the dual release of drugs with different 3 ACS Paragon Plus Environment


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hydrophobicity, with ibuprofen and 5-fluorouracil being incorporated together in a single material. Selective release was obtained for each individual drug, since the mesoporous organic silica carrier was pH-sensitive. However, a limitation of many of these systems is that they incorporate and release multiple species simultaneously.15-17 There is still a demand for the development of controlled-release systems loaded with multiple drugs that present distinct pharmacological actions, such as anti-inflammatory and anticancer activities, which enable fine tuning of the amounts of each drug released, as a function of time. An elegant strategy for the development of dual-drug delivery devices is to combine distinct components, such as organic and inorganic phases, into a single material at the molecular or nanoscale level, enabling the design of multifunctional hybrid materials.18,19 In the present work, a strategy is described for the incorporation and release of the anti-inflammatory drug naproxen (NAP) and the anticancer drug 5-fluorouracil (5FU), which present differences in terms of hydrophobicity and the mechanisms of therapeutic action, employing a single organicinorganic hybrid matrix, namely ureasil-poly(ethylene oxide) (UPEO). The strategy included the design of a dual-drug delivery system, based on UPEO, in which the matrix could be generated in the presence of the two drug molecules, in a one-step process. Organic-inorganic ureasil-based materials offer mechanical flexibility, transparency, fine control of hydrophilicity, good adhesion, versatile shape, easy solution manipulation, and biocompatibility.20-23 Furthermore, this class of hybrid materials has a wide range of applications, being used in ionic conductors,24 solid-state electrochromic devices,25 full color displays,26 luminescent solar concentrators,27,28 and adsorbents for the efficient removal of dyes and metal ions from solution.29,30 Notably, in the past decade, ureasil hybrid matrices have attracted much attention as drug delivery systems. Santilli et al.31 described, for the first time, the 4 ACS Paragon Plus Environment

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use of ureasil-polyether for controlled release of the drug sodium diclofenac. Subsequently, these matrices have been widely studied for the treatment of many diseases and for the delivery of various drugs with different therapeutic activities.32-39 Considering the importance of dual-drug delivery, the aim of this study was to investigate use of the UPEO hybrid matrix for such a purpose. Although we have extensive experience in use of the sol-gel process to prepare ureasil hybrids for drug delivery,20, 22, 32, 33, 36-39 these matrices have not, to the best of our knowledge, so far been investigated as dual-drug delivery systems. In this study, the production of UPEO containing both the hydrophobic non-steroidal drug naproxen and the hydrophilic anticancer therapeutic agent 5-fluorouracil, using a one-pot process, would be able to improve the sustained release of the two drugs. In order to test this material, UPEO was prepared with specified amounts of NAP and 5FU, followed by in vitro release assays performed under a range of pH conditions. The nanostructures of the unloaded and drug loaded UPEO, together with the NAP and 5FU release profiles and the swelling degrees of the hybrids, were conducted in a systematic way using small-angle X-ray scattering (SAXS), Fourier transform infrared (FTIR) spectroscopy, contact angle measurements, and ultraviolet-visible spectrophotometry (UV-Vis).

2. Experimental Materials: Jeffamine ED-2003 O,O’-bis-(2-aminopropyl) polypropylene glycolblock-polyethylene

glycol-block-polypropylene,

3-(triethoxysilyl)propylisocyanate

(ICPTES), tetrahydrofuran (THF, HPLC grade), EtOH (HPLC grade), 5-fluorouracil (5FU), and sodium naproxen (NAP) were purchased from Sigma-Aldrich. Synthesis of the organic-inorganic precursor: An established procedure previously reported in literature31,37 was used to prepare the ureasil precursor (see 5 ACS Paragon Plus Environment


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Scheme 1). In brief, Jeffamine ED-2003 (10 mmol) was dissolved in THF and ICPTES was added in a 1 : 2 molar ratio. The mixture was refluxed at 70 °C for 24h and then cooling to room temperature; followed by removal of THF by rotary evaporation. It was reported by Brik et al.40 that the reaction between Jeffamine-ICPTES resulted in a 100% yield, according to quantitative NMR analysis. Synthesis of the UPEO hybrid matrix: The sol-gel process was initiated by adding EtOH (3 mL), HCl (2 M, 0.036 mL) and distilled water (0.1 mL) to ureasil precursor (1.5 g). The sol was stirred for 5 min and then transferred into a polypropylene mould. Samples were aged for 3 days, at room temperature, resulting in a gel. To complete the drying process the gel was maintained for 24 h in desiccator at 70 °C, under vacuum. Drug-loaded UPEO samples were prepared by addition a defined mass of the drug 5-FU and/or NAP (0.015 g) in the same sol reported above, in order to prepare UPEO containing 1 wt% of 5-FU, NAP, or both drugs.

2.1. Characterization and release assays Fourier transform infrared spectroscopy (FTIR): FTIR spectra were measured on a Perkin Elmer Frontier spectrometer and collected over a range of 3500-400 cm-1, with a resolution of 4 cm-1, with averaging of 12 scans by ATR mode. Samples were dried under vacuum at 50 °C for 24 h, in order to decrease the levels of solvent and adsorbed water. The contact angles of the UPEO matrix were measured on OCA (Dataphysics) contact angle instrument in sessile drop mode. In this case, the droplet volume was about 7.0 μL - deionized water, and then a droplet of liquid was delivered onto the UPEO surface. Contact angle values and image were obtained using the drop shape 6 ACS Paragon Plus Environment

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analysis software which is described by the Young-Dupré equation, assuming a smooth and homogeneous surface41. The nanostructural behavior of the loaded and unloaded UPEO were studied by small-angle X-ray scattering (SAXS). The data was collected at the SAXS1 beamline of the National Synchrotron Light Laboratory (LNLS, Campinas, Brazil). The beamline was was equipped with an asymmetrically cut and bent Si(111) monochromator that provided a λ = 0.1608 nm. A 2D PILATUS 300K detector located ~900 mm from the sample was used to record the scattering intensity, I(q), as a function of the modulus of the scattering vector q = (4/λ)sin(ε/2), where ε is the X-ray scattering angle. The data were normalized considering the varying intensity of the direct X-ray beam, detector sensitivity, and sample transmission. Because of the cell windows and vacuum, the parasitic scattering was normalized from the total scattering intensity. Drug Release Measurement: UV-Vis spectrometry was used to evaluate the temporal evolution of the in vitro drug release of NAP and 5FU drugs. In brief, 0.5 g of drug-loaded UPEO xerogel was immersed in 100 mL of aqueous medium (deionized water, HCl solution pH 1.2 and PBS solution pH 7.4) at 37 °C. The pH value of deionized water used during the in vitro release essays was around 5.6. Thus, the in vitro release studies using water as aqueous medium was in slightly acidic conditions. The accumulated amount of NAP and 5FU released into the solution was measured in situ using a Varian Cary50 spectrophotometer connected to an immersion probe (optical path length of 2 mm). A fully spectrum was recorded (200 – 600 nm) using a scan rate of 400 nm min-1. For quantitative determination of the cumulative release of NAP (λmax = 229 nm) and 5FU (λmax = 265 nm) standard solutions at different concentrations were used. A comparison between UVvis spectra of a prepared drug solution (NAP and 5FU) and UVvis spectra of the drug-loaded-UPEO after immersion in the aqueous medium 7 ACS Paragon Plus Environment


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was provided to demonstrate that the drug molecules release by the matrix are the same of the pristine drugs (Supporting Information Figures S1-S3). All the release experiments were performed with two independent samples and the results were presented as averages of the data.

3. Results and Discussion 3.1 Characterization of loaded and unloaded UPEO The influence of loading with the drugs on the structural properties of the hybrid matrixes was evaluated by SAXS and FTIR. Figure 1 shows the SAXS curves of the unloaded and UPEO loaded with naproxen (UPEO-NAP), 5-fluorouracil (UPEO-5FU), and both drugs simultaneously (UPEO-NAP-5FU). The SAXS curves for the unloaded and loaded UPEO hybrids displayed a single broad peak located at qmax of ~1.4 nm-1, which was characteristic of the entangled siloxane cross-linking with a spacing dependent of the PEO chain length.39 Incorporation of the individual drugs (Figure 1, blue and red circles) and NAP and 5FU simultaneously (Figure 1, green circles) in the UPEO hybrid did not affect the average correlation distance between two adjacent nodes (ζd ~4.50 nm, as determined using the equation ζd = 2π/qmax). However, the SAXS curves of the drug-loaded UPEO hybrid showed a less intense I(q) of the peak, which decreased the electronic contrast between the siloxane nodes and the PEO phase. This feature could be attributed to the solvation of the drug molecules in the UPEO matrix, since NAP and 5FU were loaded in the open spaces between the polymeric chains. Hence, the UPEO containing both drugs (Figure 1, green circles) presented a less intense I(q) and a broader peak, compared to all the other UPEO matrices, due to the simultaneous solvation of NAP and 5FU. In addition, the transparency of the unloaded and loaded UPEO hybrid samples evidenced i) that the inorganic phase (ICPTES) was


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covalently bonded and homogeneously distributed within the polymeric network,42 and ii) that there was good solubilization of the individual and combined drugs (Figure 1 inset). Figure 2 shows the FTIR spectra of the unloaded and drug-loaded UPEO xerogels, in the spectral ranges between 1500 and 1800 cm-1 (Figure 2a) and from 800 to 1400 cm-1 (Figure 2b), indicating assignment of the well-known main FTIR bands of the UPEO matrix.43 The spectral signatures of the urea linkage (1500-1600 cm-1) and the PEO backbone (800-1400 cm-1) could provide valuable information about NAP and 5FU solvation by different functional groups present in the UPEO hybrid network. The region between 800 and 1400 cm-1 corresponded to the CH2 rocking mode and the C–O and C–C stretching modes (Figure 2b), for which the bands are very sensitive to conformational changes in the polymer backbone.43,44 The bands with maxima at 1374, 1359, and 1242 cm-1, related to CH2 wagging and twisting modes, as well as the most intense band at 1105 cm-1, assigned to C-O stretching vibration, showed similarities between the unloaded and drug-loaded UPEO matrixes. These bands did not shift following incorporation of 1 wt% of NAP and 5FU, individually or simultaneously, indicating that the PEO chains structural properties was not changed in the presence of the drugs in the hybrid matrix. According to Bermudez et al.43, the region between 1500 and 1800 cm-1 corresponds to the “amide I” and “amide II” vibrational modes, assigned to C=O stretching, C-N stretching, C-C-N deformation vibrations, N-H in-plane bending, and C-C stretching, as shown in Figure 2a. The IR bands in the 1500-1800 cm1

region for the unloaded (black line) and NAP-loaded UPEO (blue line) were very

similar, with no shift of the wavenumber, suggesting that NAP was dissolved in the matrix, without interaction with the functional groups of UPEO. However, there was a clear band at ~1694 cm-1 in the spectra for UPEO-5FU (red line) and UPEO-NAP-5FU



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(green line). Fu et al.45 tentatively ascribed the components at around 1690 and 1655 cm-1 to the vibration of urea-poly(ether) hydrogen-bonded structures. The greater intensity of the band at 1694 cm-1 for UPEO-5FU and UPEO-NAP-5FU, compared to the unloaded UPEO, suggested that a fraction of the 5FU molecules could have interacted by hydrogen bonding with urea groups present in the hybrid matrix (Figure 2c). Similar interactions between 5FU and diurea groups connected to pyridine moieties (DUPy) in a bi-silylated organosilane precursor have been reported previously.14

3.2 Wettability behavior and drug release Figure 3a display the water absorption (Δw/wd) of the UPEO xerogel in water (at ~25°C) as a function of immersion time. The hydrophilic nature of the UPEO hybrid, due to the PEO chains, resulted in a high water uptake of around 300%. Water uptake equilibrium was reached after 60 min, evidencing the rapid formation of a fully waterembedded UPEO matrix (inset of Figure 3a). The influence of the pH of the medium on the water uptake (Δw/wd) of the UPEO1900 xerogel, as a function of immersion time, was evaluated using solutions of HCl (pH 1.2) and PBS (pH 7.4) (Supporting Information Figure S4a and S4b). The profiles of water uptake by the UPEO were very similar and were independent of the pH of the aqueous medium, with equilibrium reached in ~60 min. The surface wettability of the UPEO, as a function of time, was investigated using static contact angle measurements (Figure 3b). The value of θ for UPEO after contact with the water droplet was 65 ± 0.4°, due to the existence of hydrophilic moieties such as the urea groups and PEO chains in the hybrid matrix. As expected from the hydrophilic nature of the PEO, the θ values decreased as a function of time, from 65 ± 0.4° (at 0 min) to 11 ± 0.2° (at 30 min). After 30 min of the assay, the water was spread over the entire surface of the UPEO, evidencing the complete wetting


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of the matrix. The excellent agreement between the macroscopic water uptake (Figure 3a) and the surface wettability (Figure 3b) provided evidence of the uniformity and equilibrium of the hydration process (after 30 min), with the rapid formation of a fully water-embedded UPEO matrix. The hydrophilic behavior presented by the UPEO hybrid, with consequent high water uptake, played an important role in determining the release profiles of the drugs incorporated into this matrix. The released amounts of NAP and 5FU from UPEO using water at 37 °C were determined by the characteristic wavelength (λmax) of each drug molecule (λmax = 229 and 265 nm for NAP and 5FU, respectively). Figure 4 shows the cumulative profiles for release of the individual drugs from the UPEO samples loaded with NAP (1 wt%) and 5FU (1 wt%). The polyether hydrophilic character and the high water uptake by the UPEO xerogel facilitated the dissolution and release of NAP and 5FU. The cumulative release amounts of 5FU were 96% in a short period of time (~70 min) and then reach a near-equilibrium state. In the case of the NAP-loaded UPEO sample, only 20% of the drug was released in the same period of time, followed by a slow increase of the NAP amount in the water, reaching about 56% drug release after 420 min (equilibrium state). As seen in Figure 4, the release of NAP was different from 5FU due to the different hydrophobicity characteristics of the drugs, given the hydrophilic nature of 5FU and the hydrophobicity of NAP. The excellent agreement between the water uptake and the quantity of hydrophilic 5FU released at equilibrium (after ~60 min, see Figures 3a and 4) evidenced that the diffusion of 5FU through the UPEO matrix was much faster than the NAP dissolution rate, resulting in two different release profiles. The cumulative profiles for dual-release of NAP/5FU from the UPEO matrix during immersion in water and at pH 1.2 (HCl) and pH 7.4 (PBS), at 37 °C, are shown in Figures 5a-5c. It was evident that in all cases, the amounts of both NAP and 5FU



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simultaneously released from the UPEO hybrid were lower, compared to the release of the drugs individually (Figure 4). With the incorporation of both drugs into the UPEO hybrid matrix, it is important to note that in water at 37 °C, (i) the amount of 5FU released decreased from 96 to 67% (comparing Figure 4 and Figure 5a - blue circles) and (ii) the amount of NAP released decreased from 56 to 40% (comparing Figure 4 and Figure 5a - green circles). Similar cumulative release behavior was observed using the aqueous HCl medium at pH 1.2 (Figure 5b). However, using the aqueous PBS medium (pH 7.4), the amounts of NAP and 5FU simultaneously released were ~60% after 90 min, with a sustained release profile observed, as a function of time. The sustained dualrelease behavior of NAP/5FU (Figures 5a-5c) suggested that both drug molecules were well embedded within the UPEO and could be selectively released by tuning the pH of the medium. The differences in the release behaviors (individual or dual-release systems) could be mainly attributed to the hydrophobicity effects and dissolution of the drugs at the flexible PEO moieties of the hybrid matrix. The decreased release of NAP and 5FU in the dual-release system, compared to the conventional system (individual release) suggested combinations of the following effects: (1) different distributions of NAP and 5FU within the hybrid matrix; (2) dissolution of 5FU mainly by hydrogen bonding interactions with urea groups (see Figure 2c); (3) no change of the structure of the UPEO hybrid due to solubilization of NAP in the matrix (see Figures 2a and 2b). The presence of NAP in the inner spaces of the UPEO hybrid suggested the formation of a hydrophobic layer that restricted the water flux, resulting in delayed or obstructed release of 5FU located deep within the matrix. When the UPEO hybrid loaded simultaneously with NAP and 5FU was immersed in the aqueous medium (Figures 5a5c), the solute (drug) species near the surface of the monolithic xerogel began to dissolve. The dissolved solute was extracted from the UPEO surface towards the


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solution, leading to the rapid release of both drugs in the first 90 min of the assays. However, after this time, solute release was delayed by the hydrophobic layer and the flow of water though the matrix decelerated, until reaching an apparent equilibrium stage. The greater amount of NAP released (~60%) at equilibrium using PBS (Figure 5c), compared to the amounts released (~40%) in water and aqueous HCl (Figures 5a and 5b), was due to the higher pH value (pH 7.4), at which the carboxyl groups of NAP could be ionized, hence facilitating dissolution of the drug and its transfer from the matrix to the solution. Xia et al.8 described a dual-drug delivery system based on mesoporous bioactive glass/PBLG-g-PEG nanomicelle composites. At acid pH, the NAP entrapped in the cores of the nanomicelles was minimally ionized, leading to slow release, while fast release of this drug was achieved in an alkaline aqueous medium, due to the progressive formation of ionized NAP species. The transport mechanisms governing the release kinetics of the individual and dual-release systems based on the UPEO hybrid were studied using a model proposed by Korsmeyer et al.46 This model (Eq. 2) uses a power law dependence to describe diffusion-controlled (Fickian) and swelling-controlled (Case OII transport) mechanisms: 𝑀𝑡 𝑀∞

= 𝑘 𝑡𝑛

(2)

where Mt/M∞ is the fractional drug release, t is the release time, k is the pre-exponencial factor characteristic of the drug/matrix system , and n is an exponent that characterizes the mechanism of release, with values of n = 0.43 for Fickian diffusion and n = 1 for Case II transport (zero order drug release). Values of n between 0.50 and 0.90 can be regarded as an indication of the existence of both phenomena. The plots of log (Mt/M∞) against log t for the individual and dual delivery of NAP and 5FU from the UPEO matrix are shown in Figures 6 and 7. The multimodal 13 ACS Paragon Plus Environment


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profiles for the individually-loaded and dual-loaded UPEO could be fitted by straight lines (two or three) with different slopes, indicating that the release kinetics (n) was dependent on the release time. The experimental n values (see Table 1) corresponding to the early (ne), advanced (na), and later (nl) stages were obtained from linear fitting of the slopes of the curves. The individual releases of NAP and 5FU from the UPEO in water presented two and three stages, respectively. In the case of NAP, the first stage (na) was attributed to diffusion, with a zero order rate (n = 0.7), indicating that the amount of drug released was controlled by the penetration of the solvent-swollen front. The second stage (nl) showed a low n value of 0.04, characteristic of the equilibrium state. In the case of 5FU, three stages were observed, with the first one (corresponding to the early stage, with ne = 0.25) being attributed to diffusion of the drug from the solution near to the surface, followed by anomalous transport consisting predominantly of a Case II mechanism (na = 0.91), and finally equilibrium (nl = 0.02) (Figure 6a, Table 1). The kinetics of release of the drugs from the dual-loaded UPEO matrix in water (Figure 6b) showed a two-stage process for NAP and a three-stage process for 5FU, similar to the results obtained for the individual systems (Figure 6a). The individual and dual-release n values for NAP in water indicated that the kinetics of the processes were the same. On the other hand, the release kinetics of 5FU in the dual system, using water as the aqueous medium, reflected a mechanism dominated by rapid diffusion (ne = 0.43), followed by a decrease of the n value (na = 0.13), characteristic of slow diffusion of the drug molecules, and finally attainment of the equilibrium state (nl = 0.04). We suggested that in the dual-release system, a hydrophobic layer was created by the solubilization of NAP, which delayed or obstructed release of the fractions of both drugs present deep within the matrix. This effect of restricted water flux, due to the hydrophobic NAP loaded into the UPEO hybrid matrix, was evident in the case of the


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NAP/5FU dual-release UPEO system in HCl as the aqueous medium (Figures 7a and 7b). The NAP and 5FU release kinetics values for the early stage (ne) were different, with n = 0.14 and n = 0.75, respectively (Table 1). This evidenced that the two drugs were released according to different mechanisms in this early stage, with NAP showing diffusion, while 5FU showed an anomalous mechanism (Fickian diffusion + Case II transport). In the advanced stage, the na values were similar for the two drugs (2.24 and 2.44) and were characteristic of a mechanism controlled by the penetration of the solvent-swollen front47 (the hydrogel layer). For both curves (Figures 7a and 7b - green and blue circles), a striking effect observed in this stage was a short plateau followed by a rapid increase of release of the drugs, and then a slower increase during the advanced stage of the assay. The first plateau (t = 30 min), characterized by a deceleration and immediately followed by increased release of the drugs, was indicative of the existence of restricted water flux caused by solubilization of the hydrophobic NAP by PEO moieties. Therefore, the plateau suggested that the hydrophobic barrier hindered the mobility of the drug molecules, leading to a constant rate of release of the drugs during this period. This effect was also apparent during the time intervals 45 ≤ t ≤ 50 min and 75 ≤ t ≤ 80 min, after which it was no longer evident. These results corroborated the water uptake equilibrium (Figure 3a), with the formation of a fully water-embedded UPEO matrix after ~60 min. Molina et al.32 identified an osmotic flow in the water uptake when the antitumor cisplatin (CisPt) drug was incorporated into UPEO. After 20 min of the release assay, depletion of CisPt on the surface of the matrix caused shrinkage, due to a more ordered hydrocarbon structure, indicative of hydrophobic interactions in the CisPt-loaded UPEO. In the present work, during the later stage, the nl values for 5FU and NAP were the same (nl = 0.07) and indicated that the equilibrium state had been reached (Table 1 and Figure 7a).



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Figure 7c shows the release kinetics of the drugs from the dual-loaded UPEO matrix, using PBS as the aqueous medium. There was an absence of the early stage (ne), while the advanced (na) and later (nl) stages were observed for both NAP and 5FU. The ne and nl values were similar, indicating that for both drugs, the release mechanism was according to the zero order model, followed by the equilibrium stage (Table 1). Hence, when PBS was used as the aqueous medium, the dual-release UPEO system presented excellent potential as a vehicle for releasing both water-soluble (5FU) and waterinsoluble (NAP) drugs, at identical rates, using a single carrier (Figures 5c and 7c). This class of hybrid materials based on UPEO matrix present high stability due to the siloxane nanodomains covalently linked at the polyether backbone. Zaldivar et. al,48 showed that the thermal stability of UPEO, by thermogravimetry analysis, present a main degradation starting at ~ 310°C attributed to the formation of more compact siloxane aggregates dispersed in the matrix for UPEO hybrids made with HCl. Thus, based on the thermal stability and nanostructural properties of the UPEO, the molecular structure of the NAP and 5FU is preserved in the sol-gel route used to synthesize the drug-loaded UPEO hybrid matrix. Furthermore, in vivo biocompatibility experiments of ureasil membranes demonstrated that the UPEO synthetic biomaterial can be used to assist in the processes of bone regeneration and the membranes exhibited a smaller level of inflammatory cells comparing to collagen commercial membranes.49,50 Based on the biocompatibility of the UPEO hybrids21,49,50 this dual-drug delivery concept can be applied to cancer therapy.

Conclusions In summary, this work demonstrates the feasibility of using the ureasilpoly(ethylene oxide) hybrid as the basis for a new dual-drug delivery system that can be


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prepared by a simple sol-gel route. In-depth analysis using contact angle measurements, SAXS, and water uptake determinations enabled correlation of the data with the results of release assays, with excellent coherence between the amounts of naproxen and 5fluorouracil released and the mechanisms responsible, as a function of time. It was found that two drug molecules with distinct activities (anticancer and anti-inflammatory effects) could be incorporated into the UPEO hybrid, with satisfactory solubilization of both drugs. The hydrophilic behavior (water uptake and surface wettability) presented by the UPEO hybrid played an important role in determining the release profiles of naproxen and 5-fluorouracil incorporated individually or simultaneously in the UPEO matrix. The release of the drugs from the UPEO followed multimodal patterns that were kinetically governed by diffusion/dissolution and the zero-order model. The creation of a hydrophobic barrier by the NAP molecules in the dual-release UPEO system, together with varying the nature of the aqueous medium, enabled fine tuning of the quantities of NAP and 5FU simultaneously released, as a function of time. Use of an aqueous PBS environment (pH 7.4) with the dual UPEO system resulted in the water-soluble (5FU) and water-insoluble (NAP) drugs being released at identical rates from a single carrier system. This study represents the first steps towards a broader application of these hybrid materials that have the ability to simultaneously incorporate a wide range of therapeutic compounds into the UPEO matrix for delivery purposes.

Conflicts of interest There are no conflicts of interest to declare.



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Acknowledgments This work was supported by the Brazilian agencies: Coordenação de Aperfeiçoamento de Pessoal de Nível Superior – (CAPES) – Finance Code 001, Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq) – n° 306271/2017-6, and Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP, grants 2013/20455-2 and 2015/02802-2). The authors wish to thank the Brazilian National Synchrotron Light Laboratory (LNLS) for providing access to the SAXS1 beamline, and the SAXS staff for helping during the measurements. We would like to thank Huntsman Performance Products for donating the Jeffamine® reagents. The authors gratefully acknowledge Celso V. Santilli and Sandra H. Pulcinelli for allowing us to use their laboratory facilities (IQ-UNESP/Araraquara) during the contact angle measurements.

Supporting Information: Comparison between UVvis spectra of the drug solutions and UVvis spectra of the release molecules after immersion of loaded UPEO in aqueous medium. Macroscopic (Δw/wd) expansion ratio curves for the UPEO xerogel in (a) HCl and (b) PBS aqueous media.

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TABLE

Table 1. Release kinetics parameter n for the early (ne), advanced (na), and later (nl) stages of individual and dual release of NAP and 5FU from the UPEO hybrid. The values in parentheses are the values of the 5FU release kinetics n parameter for the dual system in different aqueous media.

Sample

ne

na

nl

UPEO-NAP

-

0.70

0.04

UPEO-5FU

0.25

0.91

0.02

UPEO-NAP-5FU (water)

- (0.43)

0.73 (0.13)

0.04 (0.04)

UPEO-NAP-5FU (HCl)

0.14 (0.75)

2.24 (2.44)

0.07 (0.07)

UPEO-NAP-5FU (PBS)

- (-)

1.35 (1.30)

0.04 (0.05)



Page 24 of 39

FIGURE CAPTIONS

Scheme 1. Synthetic route for the preparation of unloaded and loaded-UPEO containing NAP and 5FU drugs. (R1 = -CH2-CH3). Figure 1. SAXS curves for the unloaded and loaded UPEO containing naproxen (UPEO-NAP), 5-fluorouracil (UPEO-5FU), and both drugs (UPEO-NAP-5FU). Inset: photographs of the unloaded UPEO xerogel and UPEO loaded with NAP and 5FU. Figure 2. FTIR spectra of the UPEO, UPEO-NAP, UPEO-5FU, and UPEO-NAP-5FU matrices in the spectral ranges (a) 1500-1800 cm-1 and (b) 800-1400 cm-1. (c) Schematic illustration of the proposed mode of interaction of the UPEO hybrid matrix with the 5FU molecules. Figure 3. (a) Time dependence of the macroscopic expansion ratio (Δw/wd) for the UPEO xerogel in water. Inset: Photographs of the UPEO xerogel before and after 300 min of contact with water. (b) Contact angle measurements, as a function of time, for the UPEO1900 xerogel. Inset: Contact angle images of the UPEO at different times. Figure 4. Temporal evolution of cumulative individual release of NAP and 5FU from UPEO using water as aqueous medium at 37 °C. Figure 5. Temporal evolution of cumulative profiles for dual-release of NAP/5FU from the UPEO matrix during immersion in different aqueous media at 37 °C: (a) water, (b) HCl solution (pH 1.2), and (c) PBS solution (pH 7.4). Figure 6. Plots of log (Mt/M∞) against log t for (a) individually-loaded UPEO and (b) dual-loaded UPEO, using water as the aqueous medium, at 37 °C. Figure 7. (a) Temporal evolution of cumulative profiles for dual release of NAP/5FU from the UPEO matrix during immersion in the aqueous HCl medium. Plots of log (Mt/M∞) against log t for the dual-loaded UPEO hybrid matrix in (b) the aqueous HCl medium and (c) the aqueous PBS medium, at 37 °C.


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254x190mm (96 x 96 DPI)

ACS Paragon Plus Environment


SCHEME 1 254x190mm (96 x 96 DPI)


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FIGURE 1 254x190mm (96 x 96 DPI)



FIGURE 2 254x190mm (96 x 96 DPI)


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FIGURE 3A 254x190mm (96 x 96 DPI)



FIGURE 3B 254x190mm (96 x 96 DPI)


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FIGURE 5C 254x190mm (96 x 96 DPI)


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FIGURE 7C 254x190mm (96 x 96 DPI)


Ureasil organic-inorganic hybrid as a potential carrier for combined

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