key: cord-1026770-fnv7uz67 authors: Olejnik, Anna; Goscianska, Joanna title: On the importance of physicochemical parameters of copper and aminosilane functionalized mesoporous silica for hydroxychloroquine release date: 2021-09-17 journal: Mater Sci Eng C Mater Biol Appl DOI: 10.1016/j.msec.2021.112438 sha: abcad8ef44d36fc9777c984ede00e7845f25f26f doc_id: 1026770 cord_uid: fnv7uz67 Recently, great attention has been paid to hydroxychloroquine which after promising in vitro studies has been proposed to treat the severe acute respiratory syndrome caused by SARS-CoV-2. The clinical trials have shown that hydroxychloroquine was not as effective as was expected and additionally, several side effects were observed in patients cured with this medicament. In order to reduce them, it is suggested to deliver hydroxychloroquine in a controlled manner. Therefore, in this study non-modified (SBA-15, SBA-16) and modified with copper and aminosilane mesoporous silica materials were applied as novel nanocarriers for hydroxychloroquine. First, pristine and functionalized samples were synthesized and characterized by X-ray diffraction, low-temperature nitrogen sorption, transmission electron microscopy, X-ray photoelectron spectroscopy, infrared spectroscopy, laser diffraction. Then the influence of physicochemical parameters of materials obtained on the adsorption and release processes of hydroxychloroquine was analyzed. The mechanism of hydroxychloroquine binding to non-modified silicas was based on the formation of hydrogen bonds, while in the case of copper and aminosilane functionalized materials the complexes with drug molecules were generated. The release behavior of hydroxychloroquine from silica samples obtained was determined by different factors including pH conditions, textural parameters, surface charge, and presence of surface functional groups. The greatest differences in hydroxychloroquine release profiles between materials were observed at pH 7.2. The amount of drug desorbed from silica decreased in the following order: functionalized SBA-15 (84%) > functionalized SBA-16 (79%) > SBA-15 (59%) > SBA-16 (33%). It proved that a higher amount of drug was released from materials of hexagonal structure. primary care practices [15, 16] . Currently, more than 200 trials of hydroxychloroquine/chloroquine or both and in connection with other medicaments are registered globally. It was reported that hydroxychloroquine improved outcomes in a small number of patients infected with coronaviruses [17] . However, the efficacy of HCQ was not as good as it was expected. The results proved that the treatment with HCQ of adults suffered from COVID-19 did not ameliorate the clinical status of the patient compared with placebo [18] . It was shown that hydroxychloroquine neither increased nor reduced the risk related to intubation or death in the case of COVID-19 [19] . From a chemical point of view, HCQ is an aminoquinoline that has an amino group attached to a quinoline ring and it contains a hydroxyl group at the N-ethyl end (Table 1) . Hydroxychloroquine sulfate is a less toxic derivative of chloroquine that has an additional hydroxyl group. HCQ sulfate is available as film-coated tablets for oral administration (200 mg of the active ingredient is used per tablet). Dosage applied is different depending on the treatment indication. Hydroxychloroquine is absorbed within 2 to 4 hours after oral administration [20] in the upper part of the intestinal tract. HCQ is metabolized in the liver by cytochrome p450 [21] and 3 metabolites such as desethylchloroquine, desethylhydroxychloroquine and bisdesethylhydroxychloroquine are formed [22] that also exhibit pharmacological activities. Afterward, the metabolized and unchanged hydroxychloroquine is expelled through urine or excrement. In general, HCQ presents a good safety profile, however, it also exhibits some negative effects. The most common one is wide application of hydroxychloroquine may cause cutaneous adverse reactions and hepatic failure [25] . HCQ can have also other side effects such as hair loss, hives, bronchospasm, muscle weakness, and unusual bleeding or bruising. Additionally, the reports proved that the treatment with hydroxychloroquine may induce the exacerbation of psoriasis [26] . In order to reduce the side effects of HCQ and to deliver this drug in a controlled manner, it is proposed to apply nanocarriers. So far ordered mesoporous silica (OMS) have been utilized as vehicles for various active compounds [27] [28] [29] . Due to their nontoxicity, high stability, welldeveloped surface area and great pore volume mesoporous silica can be recommended as an ideal candidate for drug hosting. Recently, hollow mesoporous silica spheres with polyelectrolyte multilayers have been applied as a delivery system for ibuprofen [29] . In another study biomimetic diselenide-bridged mesoporous organosilica nanoparticles were used as a carrier for doxorubicin in chemotherapy [30] . This drug was also delivered by using mesoporous silica nanoparticles conjugated with TAT peptide [31] . The presence of silanol groups on their surface enables to perform their modification using various organic groups. The introduction of amino-functional groups may enhance the sorption abilities of materials while the presence of copper may generate acid-base active centers on the surface of J o u r n a l P r e -p r o o f Journal Pre-proof materials. It should be also highlighted that at trace concentrations copper is curial for life and takes part in enzymatic reactions in humans [32] . Moreover, copper exhibits antiviral and antibacterial activity [33] [34] [35] , therefore the impregnation of mesoporous materials with copper(II) chloride is fully justified. So far colloidal silica was applied as an excipient for HCQ [36] . In another study, hydroxychloroquine-loaded hollow mesoporous silica nanoparticles (HMSN) were obtained to increase the therapeutic effectiveness of radiotherapy in cancer treatment. It was proved that HMSN accelerated the drug delivery to tumors and inhibited their growth [37] . However, there are no literature data concerning the application of modified OMS as carriers for hydroxychloroquine sulfate. Therefore, the aim of this study is to assess the importance of physicochemical properties of copper and aminosilane functionalized OMS during the adsorption and release of HCQ sulfate. The small-angle X-ray scattering was performed by X-ray diffractometer (Empyrean, PANalytical) with the copper Kα1 radiation (λ = 1.5406 Å) and the copper Kα2 radiation (λ = 1.5444 Å). The step size was 0.0001°. All materials synthesized were characterized by using powder X-ray diffraction (D8 Advance Diffractometer, Bruker, U.S.) with the copper Kα1 radiation (λ = 1.5406 Å). The XRD analyses were performed at room temperature with a step size 0.05° in the high-angle range. The samples were placed on a grid with a carbon film and analyzed by transmission electron microscope (JEOL 2000) operating at 80 kV. The pore structure of the OMS was determined based on low-temperature nitrogen adsorption-desorption isotherms using a sorptometer Quantachrome Autosorb iQ (U.S.). Before starting the measurements, pristine materials (SBA-15 and SBA-16) were degassed in a vacuum at 300 °C for 5 h, while modified OMS samples were degassed at 150 °C for 5 h. The XPS analyses were performed by an UHV SPECS spectrometer. The experiments were carried out with the use of Al Kα radiation by a PHOIBOS HSA3500 analyzer, working in the FAT scan mode with a pass energy of 20 eV. The XPS spectra were recorded and in the next step calibrated by using the C 1s peak at 284.5 eV as an internal standard. Core-level peaks were examined by non-linear Shirley-type background subtraction. The data processing was performed by the CasaXPS program. The accuracy of the binding energy values was assessed to be ± 0.1 eV. Particle size distribution (PSD) of the mesoporous materials was determined by Mastersizer FT-IR spectra of the OMS before and after HCQ adsorption were registered by using spectrometer (Bruker IFS 66v/S, U.S.). The samples were mixed with anhydrous KBr (1 mg of silica per 200 mg KBr). The infrared spectra were recorded in a wavenumber range of 4000-400 cm -1 . In order to perform the adsorption process of HCQ onto OMS materials, series of aqueous drug solutions with concentrations from the range of 6.25 to 125.00 mg/dm 3 were prepared. Where F t is the fraction of HCQ released over a certain time, t (h); F 0 is the initial amount (mg) of HCQ in OMS materials, and k 0 , k, k H, k KP , k HC correspond to release constants of particulate kinetic models. Furthermore, R 2 was estimated to determine which mathematical model follows the particular release profile. The structure of OMS materials was assessed by small-angle X-ray scattering (SAXS). Based on the SAXS profiles, it was observed that SBA-15 silica is a material with a highly ordered mesoporous structure ( Fig. 1 A) . The pattern of SBA-15 contains a characteristic peak of hexagonal pore arrangement detected at 2θ around 1° that corresponds to the plane (100) [41] . Additionally, two peaks were observed at 2θ  1.7° and 1.9° representing the (110) and (200) planes, respectively [42] . These three well-separated reflections indicate the hexagonal two-dimensional mesoporous structure (space group P6mm) [41, 43] . The SAXS pattern of Cu/SBA-15-AS ( Fig.1 B) also reveals three characteristic peaks detected at 2θ around 1°, 1.7° AS. These results proved that the functional groups were situated not only on the outer surface of materials but also inside the channels of their mesostructures [45] . It is suggested that the modification of silica undergoes more willingly at the micropore or small mesopore openings. This may be caused by the facility of attachment at the pore apertures. Consequently, the amine functional groups may block the micropores/small mesopores that lead to lessening in the surface area and pore volume [41] . Figure S1 (Supporting Information) presents the nitrogen adsorption isotherms of non-modified and modified mesoporous silica samples. They belong to the IV type of isotherms according to the IUPAC classification characteristic for mesoporous materials [46] . Elemental analysis was used to identify the chemical compositions of materials obtained. It gave information about the content of nitrogen in the functionalized samples. These experiments were also carried out to confirm the effectiveness of surface modification. The results were shown in Table 3 . The contents of nitrogen, carbon, and hydrogen significantly increased in both aminosilane functionalized mesoporous silica compared to the pristine samples. It was also noticed that a higher amount of nitrogen was determined for Cu-SBA-15-AS that could have an influence on HCQ adsorption and release processes. eV, [48] ), C 1s (286 eV, [49] ) and N 1s (~400 eV, [50] ) were determined. The small peaks derived from Cl 2p were also observed. Further analysis revealed that copper was present on the surface of both Cu/SBA-15-AS and Cu/SBA-16-AS. Based on the XPS survey it could be stated that the modification of pristine materials was effective. intensity 2:1) are assigned to Cu 2p 3/2 and 2p 1/2 , respectively, that correspond to Cu(I). These results are in accordance with studies reported by Li et al. [54] . Additionally, two peaks at a binding energy of 936.3 eV and 956.5 eV were found in the spectrum that correspond to Cu 2p 3/2 and Cu 2p 1/2 , respectively, that are assigned to Cu(II) [55] . The existence of satellite peaks in the spectra was determined at 943.9 eV and 963.3 eV. The detailed spectral characteristics for the samples are presented in Supporting Information in Table S2 . (Fig. S2 B) , the signal of C 1s was decomposed into three components. The main peak at 285.2 eV (25.4%) corresponds to C-C bonds [58, 59] that are assigned to the propyl chain in the AS moiety. Another component determined at 286.5 eV (5.9%) is attributed to C-N [60] . The last C 1s peak at 288.8 eV (3.8%) originates from C-Si. It is supposed that due to the relationship between copper ions and AS moiety the binding energy was shifted. The same components were observed for Cu/SBA-16-AS (Fig. S3 B) , however, the atomic concentrations were slightly different than for Cu/SBA-15-AS (Table S2 ). The Cl 2p XPS spectra in The atomic concentration of Cl 2p was at a very low level for both samples. The particle size distributions of OMS materials are depicted in Figure 6 . Particles with the smallest sizes (0.5 to 120 m) were observed for SBA-15 of hexagonal structure. Its functionalization with APTES and impregnation with copper(II) chloride led to increasing in particle sizes (0.5 to 800 m). Similar results were obtained for silica of cubic structure. The pristine SBA-16 had a relatively small particle size ranging from 2 to 700 m, while modification of its surface with amine groups and copper ions caused a significant shift towards larger particle sizes. Table 4 Additionally, the zeta potential of modified and non-modified OMS at various pH was determined. Zeta potential gives information about the surface charge of selected nanomaterial that is useful to explain the behavior of samples at different conditions. It was observed that the zeta potential value of each silica material is strongly dependent on the pH J o u r n a l P r e -p r o o f Journal Pre-proof of the medium (Fig. 7) . For SBA-15 at pH value from 1.8 to 7.8 the electrokinetic potential was negative. It is suggested that Si-Ospecies are formed because a proton detached from the silanol groups that are localized on the silica surface. Therefore, the pristine material of hexagonal structure acted as a weak acid [61] . After modification with aminosilane and impregnation with copper(II) chloride, the surface charge significantly changed. At pH ranging from 1.5 to 4.9 the zeta potential values were positive. It is assumed that NH 3 + species were formed because the aminosilane functional groups tend to gain proton. For Cu/SBA-15- to the theory regarding strong and weak acids and bases, copper ions exhibit tendency to bind with N atoms of amine groups [63] . The proposed mechanism for the formation of complexes between Cu(II) and aminosilane functionalized silica materials are presented in Fig. S4 (Supporting Information). other studies [65, 66] . The region around 3300 cm -1 and 3290 cm -1 is characteristic for asymmetric and symmetric stretching modes of NH 2 [67] . Additionally, the C-N stretching vibration should be detected in the wavenumber of range 1000-1200 cm -1 . However, it was overlapped with Si-O-Si, Si-O-C and Si-C found at 1200-1100 cm -1 . Another confirmation that the amine groups were attached to the surface of silica materials is a weak peak at 673 cm -1 that corresponds to the bending of N-H bond [68] . In order to confirm that the HCQ was efficiently adsorbed on the surface of OMS, FT-IR spectra of organic-inorganic hybrid systems were recorded (Fig. 9 ). This technique enables to study intermolecular interactions between drug and nanomaterials. Apart from bands Lewis acid/base adducts are formed between copper ions and hydroxychloroquine. Based on the computational approaches performed by Rezaee et al. [70] , it is assumed that complexes can be generated near the electron rich sites in HCQ molecules such as N-, O-and Cl-groups. It is expected that these sites may donate the lone pairs to 3d and 4s orbital of copper atoms. Furthermore, the N of pyridine ring and oxygen of hydroxyl group of HCQ will have the highest affinity to interact with Cu 2+ ions of modified silica materials. The FT-IR spectra proved that interactions between functionalized silica and drug occurred. Before HCQ adsorption a band at around 1500 cm -1 of N-H groups was detected and after its loading the intensity of band was significantly reduced. Similar attractions between molecules were observed when magnetic metal-organic frameworks were applied for extraction of HCQ [72] . On the other hand, the drug loading efficiency depends to a large extent on textural features such as pore volume, pore diameter and surface properties of mesoporous materials [73] . It can be observed that the total pore volume of materials was a crucial parameter that had influence on hydroxychloroquine loading. These results are consistent with literature data [74] . The highest amount of HCQ was adsorbed on SBA-15 with the highest pore volume (0.61 cm 3 /g) compared to other silica materials obtained. Therefore, for this sample, multilayer adsorption can take place. This can be an explanation why the saturation in the case of non-modified materials was not observed. The total pore volume of SBA-16 was 0.25 cm 3 /g consequently the drug loading was lower than for silica of hexagonal structure. In turn, the functionalization with aminosilane and then impregnation with copper(II) chloride reduced significantly both the BET surface area and total pore volume and thus the HCQ loading capacity at high drug concentration was lower compared to non-modified analogues. It was possible to determine the maximum sorption capacities for Cu/SBA-15-AS and Cu/SBA-16-AS, which were 37.1 mg/g and 37.7 mg/g, respectively. J o u r n a l P r e -p r o o f The release studies of HCQ from OMS materials were performed in three media simulating gastric fluid (pH 1.2), intestinal fluid (pH 5.8) and saliva (pH 7.2). In order to calculate the percentage of HCQ released from each mesoporous silica, initially the UV spectra at certain interval of time were recorded and the results obtained at pH 7.2 were presented in Fig. 11 . The data registered at pH 5.8 were depicted in Fig. S5 (Supporting Information) . It can be observed that depending on the type of material applied the absorbance over time increased. Based on these results the cumulative percent of drug released from modified and nonmodified mesoporous silica was calculated and the graphs are presented in Fig. 12 . It was observed that pH conditions had influence on the drug release profiles. For SBA-15 the highest cumulative release was achieved at pH 5.8, 99% of HCQ was detected in receptor J o u r n a l P r e -p r o o f fluid within 2.5 h (Fig. 12 A) . In turn, at pH 1.2 the initial burst release within first 30 minutes was noticed, followed by a steady diffusion that lasted till the end of experiment. The lowest amount of drug was released from SBA-15 at pH 7.2 (ca. 50%). This could be related to the fact that at physiological pH HCQ has a positive charge [75] while according to the zeta potential measurements, SBA-15 has a negative charge on its surface. Therefore, it could be suggested that interactions between drug and nanomaterial were based on attractions of organic and inorganic components of hybrid system. The cumulative release of HCQ at pH 7.2 was much lower compared to other media conditions because the interactions between HCQ and SBA-15 were stronger than those obtained at another pH, so hydroxychloroquine could not be easily released to the receptor fluid. It should be also added that depending on pH values different ionization forms of HCQ can be created (Fig. 13 ). Hydroxychloroquine is a weak base that accumulates within acidic lysosomes [76, 77] . There are three basic functional groups in the structure of HCQ with pK a values below 4.00, 8.27, and 9.67 [78] . Hydroxychloroquine is fully protonated at low pH (around 4) as H 2 HCQ 2+ , while at neutral conditions there are two types of species protonated H 2 HCQ 2+ (ca. 66%) and monoprotonated HHCQ + (ca. 34%). Whereas in alkaline solution, the proportion of HHCQ + significantly increased to ca. 83%. At high pH there is also HCQ in its neutral form [79] . According to Parvinizadeh and Daneshfar [80] the pH value of the medium has an influence on the adsorption mechanism of HCQ. It was observed that at acidic condition the nitrogen atoms of hydroxychloroquine and the amino groups of APTES attached to the surface of silica materials were protonated, and the formation of hydrogen bonds was hindered. At a higher pH value, the hydrogen bond formation was enhanced, because other hydroxychloroquine species were also present than at lower pH [72] . Therefore, it is suggested that these electrostatic attractions may affect the release of active compound from OMS materials. This phenomenon was noticed when pristine materials (SBA-15 and SBA-16) were applied as vehicles for HCQ. Additionally, the influence of material type on the drug release process was also discussed. For this purpose, the obtained results were presented at different pH conditions for all were very similar regardless of the type of silica material used. At pH 5.8 the highest amount of drug was released from SBA-15 and the lowest from SBA-16. For both modified materials Cu/SBA-15-AS and Cu/SBA-16-AS similar HCQ dissolution profile was noticed (Fig. S6 B, Supporting Information). The biggest differences in the HCQ release profiles were found at pH 7.2 (Fig. 14) . This could be related not only to the surface charge of these materials but also to their textural properties and the type of their structure. It can be perceived that at pH 7.2 the lowest amount of HCQ was released from SBA-16. Negatively charged surface of SBA-16 interacted with diprotonated HCQ and therefore drug diffusion was limited. Moreover, it was found that higher amount of drug was released from modified silica materials compared to the pristine samples. The initial burst release was detected within 1 hour of the experiment. It is expected that due to the presence of copper ions and aminofunctional groups on Cu/SBA-16-AS, the HCQ was mainly adsorbed on the outer surface of silica. These findings were also proved in other studies performed by Song et al. [81] . It should be noted that the total surface area of SBA-16 was higher than that of hexagonal material SBA-15. This finding could have also influence on its better sorption capacity and thus it had impact on drug release. Higher amount of HCQ was released from SBA-15 compared to SBA-16 due to the difference in pore diameter. The material of hexagonal J o u r n a l P r e -p r o o f structure was characterized by larger pore diameter (4.52 nm) than material of cubic structure (2.84 nm). When pores are larger, higher amount of hydroxychloroquine was released because the interactions between walls of material and drug molecules were weaker. Five mathematical models were used to fit the experimental data of HCQ release from nonmodified and modified OMS materials. In Table 5 , the calculated kinetic values of release constants (k), correlation coefficients (R 2 ) and release exponent (n) were presented. The graphs presenting the fitting of HCQ release data to kinetic models are included in Supporting Information (Figures S7-S9 ). For all materials obtained and, in all media applied, the highest Table 5 . Kinetic models applied to describe the release of HCQ from mesoporous materials. The results obtained proved that the modification of mesoporous silica with APTES and impregnation with copper(II) chloride was successfully achieved. Based on SAXS profiles and TEM images it can be stated that pristine SBA-15 and SBA-16 had highly ordered mesoporous structures. In turn, for the aminosilane and copper(II) chloride modified materials the degree of mesostructure ordering decreased. A similar relationship was observed in the case of textural parameters. OMS modification significantly reduced their specific surface area and pore volume. The obtained data revealed that the adsorption process of HCQ was more efficient on the surface of modified materials only at low drug concentrations. It was found that pore volume is the crucial parameter that had influence on the sorption capacity. J o u r n a l P r e -p r o o f The highest amount of HCQ was adsorbed on SBA-15 with the largest pore volume (0.614 cm 3 /g) compared to other OMS materials synthesized. The release behavior of HCQ from mesoporous silica nanocarriers was highly determined by the pH conditions and it could be regulated by the introduction of functional groups on the surface of materials. The release of drug from OMS was best fitted to Korsmeyer-Peppas model and the release mechanism followed Fickian diffusion. The presented study is crucial to understand the relationship between the physicochemical properties of mesoporous silica nanocarriers and antiviral drug molecules. The proposed delivery systems can be successfully applied in any antiviral therapy. It should be noted that despite the development of various types of vaccines, in the long term, finding appropriate antiviral drugs incorporated into carriers designed using nanotechnological solutions will be a priority. Especially considering the rate at which viruses mutate. The appropriately selected antiviral drug delivery system can reduce the frequency of drug daily dosage and in this way decrease its toxicity. Therefore, synthesized OMS can be used as a smart vehicle for HCQ that will allow a controlled release of the antiviral drug at the chosen location of the body. It is expected that introduction of copper on the surface of mesoporous materials will enhance their antiviral and antibacterial activity. The biological studies will be performed in the future. 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