β-cyclodextrin (β-CD) as cyclic oligosaccharide can be widely employed for preparation of controlled delivery of drugs. Hence, we synthesized a novel β-CD-based nanocarrier with superparamagnetic and molecular recognition properties for controlled release of doxorubicin (DOX) drug. The nanocarrier was prepared by using a facile ultrasonic-assisted method and through surface reversible addition fragmentation chain transfer (RAFT) copolymerization of core-shell Fe3O4@SiO2 nanoparticles onto vinylated β-CD. The spherical amino-functionalized Fe3O4@SiO2 nanomaterials were synthesized easily by a co-condensation green process of Fe3O4 nanoparticles with tetraethyl orthosilicate (TEOS) and (3-Aminopropyl) trimethoxysilane (APTES). The structure and composition of the as-prepared drug delivery nanocomposites were studied by FTIR, SEM, TEM, XRD, and VSM. Then, the loading and releasing behaviors of DOX drug have been investigated in detail. First of all, the loading of DOX was confirmed by UV-Vis spectra and SEM and TEM images of drug-loaded samples. The results also exhibited that the drug loading efficiency is found to be dependent on initial drug concentration, β-CD content and temperature. The drug loading capacity of nanocarrier was also compared with pure β-CD. Moreover, it was revealed that in vitro release rate of DOX was dependent on physiological solution pH. Finally, the drug release kinetics data were well fitted to the Higuchi model. In addition, biological characterizations were tested by MTT assay, which approved the high performance of the nanocarriers in killing cancerous cells. Due to its unique and distinct advantageous and properties, the synthesized nanocarriers can be utilized as a potential and promising biodegradable drug carrier for controlled and sustained release of various drugs.
Research Article
Ultrasonic-assisted synthesis of amino-functionalized Fe 3 O 4 @SiO 2 magnetic β- cyclodextrin nanocarrier for controlled release of doxorubicin anticancer drug
https://doi.org/10.21203/rs.3.rs-2474535/v1
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Nanocomposite
β-Cyclodextrin
Doxorubicin
Drug delivery
Ultrasound
Stimuli-responsive targeted drug delivery systems (DDSs) offer promising advantages due to their unique properties (Qiu, 2001; Zhanfeng at al., 2019). In order to prepare an ideal DDS with excellent therapeutic efficiency as well as the lowest toxicity of drugs, surface-modified drug carriers based on nanomaterials have been usually synthesized (Mallakpour & Khodadadzadeh, 2014). Among different nanomaterials, nanoparticles especially magnetic Fe3O4 nanoparticles have been recently used due to their superparamagnetic behavior, easy preparation method, large surface area, biocompatibility and stability properties (Frey et al., 2009; Wu et al., 2015). These pure nanoparticles, however agglomerated easily (Zhu et al., 2011). Therefore, it is very necessary to overcome this problem via surface modification of magnetic Fe3O4 nanoparticles by organic and inorganic materials (Pooladi et al., 2021; Ulbrich et al., 2016). Silica layer modification is one of the best modification methods due to this fact that the silica itself can be further functionalized with various compounds (Ding et al., 2012; Chae et al., 2016; Hui et al., 2011). In addition, DDSs based on Si nanoparticles, i.e. SiO2 are very stable and have high free silanol groups with tunable pore sized, which allows easy functionalized and the attraction for different drug molecules (Ding et al. 2019; Li et al., 2016; Wang et al., 2020). In summary, using Fe3O4 and SiO2 nanoparticles as core and shell could be very suitable in controlled drug delivery (Zhu & Tao, 2015; Deng & Lei, 2013; Liu et al. 2017; Molaei & Salimi, 2022; Romdoni et al., 2023). This core-shell structure, however could not be loaded drugs very well. So, this layer should be more modified for obtaining an ideal DDS.
On the other hand, the oligosaccharide, β-Cyclodextrin (β-CD) with internal hydrophobic and external hydrophilic surface are expected as excellent biodegradable and biocompatible natural polymer to apply in design of a DDS with low cytotoxicity, leading to the higher loading efficiency as well as better solubility of lipophilic and hydrophilic drugs (Toomari et al., 2015; Kanjickal et al., 2005; Xu et al., 2010; Machín et al., 2012). Additionally, β-CDs can be modified with large number of reactive functional groups for various types of drugs and protecting them from the external environment (Chen, 2015; Liu et al., 2013; Ajkidkarn et al., 2017). For example, Pourjavadi and Tehrani reported the synthesis of poly(N-isopropylacrylamide)-coated β-cyclodextrin-capped magnetic mesoporous silica nanoparticles for controlled release of DOX (Pourjavadi & Tehrani, 2017). In another example, Tan et al. covalently grafted hydroxyapatite on β-CD to improve the drug loading capacities and prolong the release of Ofloxacin drug (Tang et al., 2013).
Conclusively, there are remarkable efforts on preparations improved and novel DDSs with acceptable loading and controlled-releasing behaviors for various drugs (Mbituyimana et al., 2022; Amoyav et al., 2021; Yadav et al., 2022; Wang et al., 2022; Zhang et al., 2022; Ojagh et al., 2021). Herein, a novel drug carrier on the basis of β-CD nanocomposites was prepared via a facile ultrasonic-assisted reaction of Fe3O4@SiO2 nanoparticles with carboxylated β-CD. In this regard, the effects of some major factors on drug loading and releasing capacities were investigated in detail. In addition, the kinetics and the mechanism of drug release were studied in vitro.
Materials
The chemical compounds of β-Cyclodextrin (β-CD), ferric chloride hexahydrate (FeCl3.6H2O), ferrous chloride tetrahydrate (FeCl2.4H2O), azobisisobutyronitrile (AIBN), N,N′-dimethylformamide (DMF), tetraethyl orthosilicate (TEOS), (3-Aminopropyl) triethoxysilane (APTES), 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDC), N-hydroxysuccinimide (NHS), p-toluene sulfonyl chloride (TsCl), maleic anhydride (MA), 2,2′-tetrabutylammonium hydrogen sulfate, carbon disulfide were of analytical grade and used without further purification. MTT powder and dialysis tubing Cellulose Membrane (33mm*21mm) were supplied by Sigma-Aldrich Company. Doxorubicin hydrochloride (DOX) drug with purity≥98.0% were obtained from Sigma-Aldrich and used as received (Figure 1). Distilled water was used for preparation of all experimental solutions.
Synthesis of Fe3O4 nanoparticles
Magnetic Fe3O4 nanoparticles were prepared by co-precipitation method (Zhaoz et al., 2008). In summary, 1.8 mmol of FeCl3.6H2O and 1.2 mmol of FeCl2.4H2O were dissolved in 50 mL of distilled water. Then, 11 mL of 25% NH4OH was added to the mixture for 1 h at 70 ° C. These produced black magnetic nanoparticles were separated by using a magnet and then washed with distilled water. Finally, the Fe3O4 nanoparticles were dried in a vacuum oven at 80 °C for 24 h.
Synthesis of Fe3O4@SiO2-NH2
In this step (Step 1 in Scheme 1), we firstly prepared SiO2 components bonded to magnetic Fe3O4 nanoparticles (Fe3O4@SiO2). So, 1.3 g of the powdered Fe3O4 nanoparticles was sonicated in 20 mL ethanol/H2O (2:1) for 1 h. Then, 0.5 mL of TEOS was added and the mixture was stirred for 12 h. The resulted black product was separated by a magnet, washed and dried. For the amination of Fe3O4@SiO2 by using APTES, 0.05 g of Fe3O4@SiO2 was dispersed in 100 mL of water and 0.2 mL of APTES. The resulting mixture was stirred for 1h at 50 oC. The resulted Fe3O4@SiO2-NH2 product (Product A in Scheme 1) was removed by using a magnet, washed and finally dried in an oven at 70 oC.
Synthesis of RAFT agent
As simply shown in Step 2 in Scheme 1, the RAFT agent was then prepared. The S,S′-bis(α,α′-dimethyl-α′′-acetic acid)-trithiocarbonate (BDATC) RAFT agent was obtained by using the methods reported previously with some modification (Nakabayashi & Mori, 2013). Briefly, 9.57 mL of carbon disulfide, 41.33 mL of chloroform, 36.21 mL of acetone, and 1.65 g of tetrabutylammonium hydrogen sulphate were mixed with 60 mL of toluene. Then, 102.48 g of NaOH was added to the mixture and the solution was mixed for 12 h. In the next step, 200 mL of H2O was added to separate the produced organic layer. At the final step, the aqueous layer was acidified with HCl solution and the synthesized RAFT agent (Product B in Scheme 1) was dried in an oven (40 °C).
Synthesis of vinylated and carboxylated β-cyclodextrin
In the step 3 (Scheme 1), we firstly prepared tosilated β-cyclodextrin (β-CD-TsCl) substrate by the method of Pooresmaeil and Namazi with a little change (Pooresmaeil & Namazi, 2018). Firstly, β-CD (2.0 g) and NaOH (1.5 g) were dissolved in distilled water (30 mL). After 20 min of vigorous stirring, 3.0 g of TsCl dissolved in 10 mL of acetonitrile was added dropwise within 30 min to the mixture under nitrogen atmosphere. The reaction mixture was ultrasonicated at room temperature for 5 h. After that, the optained white precipitate, namely mono-6-OTs-β-CD was cooled down in an ice-water bath. Then, the mono-6-OTs-β-CD was recrystallized in water-acetone solution mixture and dried in the vacuum. For the preparation of vinylated and carboxylated β-cyclodextrin (β-CD-COOH), 0.5 g of mono-6-OTs-β-CD was reacted with 2.5 mmol of maleic anhydride (MA) dissolved in anhydrous DMF. After carrying out the reaction for 10 h and at 70 °C, the β-CD-COOH with -C=C- double bond (Product C in Scheme 1) was obtained by the precipitation in CHCl3 solution and finally washed in acetone for three times (Mohamed et al., 2011).
Synthesis of magnetic nanocomposite drug carrier
For the preparation of the final drug delivery system, 1.5 g of Fe3O4@SiO2-NH2 (Product A) was firstly added to 1.0 g of RAFT agent (Product B) and the mixture was sonicated for 1 h. Then, 0.1 g NHS and 0.2 g EDC were added to the solution and the reaction was continued for 2 h. The resulting product D was finally RAFT polymerized with product C by using 2.0 mg of AIBN initiator. In this step, the solution mixture was ultrasonicated for 45 minute period under ultrasonic power of 500 W. The obtained final product (Product E in Scheme 1) was washed several times with 1,4 dioxane and diethyl ether, and dried at 50 oC upto kept constant weight.
Characterization
Fourier transformed infrared (FTIR), scanning electron microscopy (SEM), transmission electron microscope (TEM), vibrating sample magnetometer (VSM) and X-ray diffraction (XRD) analysis methods were used to confirm the structure and compositions of the synthesized samples and products in the present work. Furthermore, MTT assay was applied to study the cytotoxicity and anti-cancer features of the nanocarrier.
Drug loading experiments
The DOX loading in the nano-carriers was carried out by immersing powdered sample (10 mg) drug solution (2 mL, 2 mg mL-1). After shaking for 6 h, the mixture was centrifuged, washed then finally air-dried. The DOX-loading efficiency percentage (LE%) was measured using UV-Vis spectrophotometer at λmax of 480 nm by using the following equation:
where A is the amount of loaded DOX and B is the total mass of DOX-loaded nano-carrier.
Drug releasing experiments
The DOX releasing behaviors of the nano-carriers were studied by immersing the DOX-loaded samples into 100 mL of buffer solutions (pH 2.0, 5.0 and 7.4) at 25°C for 24h. At specific times, 3 mL of the solution were removed from the drug buffer solution. The solution (2 mL) was then placed in a locked tube before it was measured using UV–Vis spectroscopy at 480 nm. It should be noted that the total volume of solutions were kept constant with addition of buffer solution to the mixture. The drug release percent (DR%)was calculated by using the following equation:
where Rt and L represent the final amount of drug released and the initial amount of drug loaded at time t, respectively. The average standard deviation of measurements was 0.03 %.
Characterization
FTIR analysis
Figure 2 depicts the FTIR spectra of Fe3O4 nanoparticles, Fe3O4@SiO2 core-shell, Fe3O4@SiO2-NH2, RAFT agent, β-CD, vinylated β-CD, and magnetic nanocomposite drug carrier. The appeared peak at 602 cm-1 in the FTIR pattern of Fe3O4 nanoparticles (Figure 2-a) can be attributed to the stretching vibration of Fe-O bonds (BabuL & Rami Reddy, 2020). The FTIR spectra of Fe3O4@SiO2 (Figure 2-b) depicts a new characteristic peak at 1036 cm-1 which be assigned to the Si-O-Si asymmetric stretching vibration mode (Poor Heravi et al., 2022). A new peak shown at 2975 cm-1 in the FTIR spectra of Fe3O4@SiO2-NH2 (Figure 2-c) is related to –CH2- group of aminopropyl of APTES reagent. Of course, it should be also noted that the characteristic peak of –NH stretching vibration was overlapped with the broad peak of –OH functional groups.
The FTIR spectrum of the RAFT agent demonstrated the bands of C–H, C=O, C=S, and C–S at 2959, 1698, 1058, and 871 cm−1, respectively (Figure 2-d). In the FTIR spectra of β-CD (Figure 2-e), the characteristic peaks are observed at 897, 1082 and 1172 cm-1 which can be attributed to the 1,4-bond skeleton vibration, anti-symmetric glycosidic (C-O-C) and coupled (C-C/C-O) stretch vibrations of β-CD (Abarca et al., 2016). In the carboxylate β-CD (Figure 2-f), two new adsorption peaks at 1571 and 1733 cm-1 are assigned to the –COOH groups. Moreover, vinylated β-CD demonstrates a peak at1229 cm-1 that can be related to the -C=C- vinylic bands. The successful reaction between products A and B was confirmed by the new band in the FTIR spectra of D at 1676, which correspond to C=O stretching vibration of –CONH2 functional groups (Figure 2-g). In the spectra of the final nanocarrier (Product E), we observed most of the characteristic peaks of the synthesized components including β-CD, Fe3O4@SiO2-NH2 and RAFT agent (Figure 2-h) with a small shift, which prove successful reacting of vinylated β-CD (Product C) with Fe3O4@SiO2-NHCO-RAFT agent (Product D).
XRD analysis
The crystalline structure of the samples, i.e. β-CD, Fe3O4, Fe3O4@SiO2 and nanocarrier were characterized by X-ray diffraction (XRD) spectra (Figure 3). As clearly seen from the Figure 3(a), the main peak of rare β-CD shows
a specific peak at 2θ = 9.7°. The XRD pattern of Fe3O4 nanoparticles (Figure 3-b) shows diffraction peaks at at 2θ = 30.43°, 34.91°, 44.1°, 56.77° and 62.21° which are related to the (220), (311), (400), (511) and (440), respectively (Zhou et al., 2010). Moreover, the XRD spectra of the Fe3O4@SiO2 (Figure 3-c) indicated that the characteristic peaks of Fe3O4 nanoparticles remained unchanged. This result indicates that the crystalline structure of Fe3O4 nanoparticles has been preserved during the core-shell formation. However, in the XRD curve of nanocarrier (Figure 3-d), the relatively amorphous structure of the nanocomposite is observed, which is due to the growth of polymer on the surface of nanocomposite and change the crystalline structure of the β-CD.
VSM analysis
The magnetic properties of β-CD, Fe3O4 and Fe3O4@SiO2 and drug nanocarrier were studied by VSM analysis method (Figure 4). According to the figure, the magnetization saturation values were measured to be 61, 32, 19 and 0.4 emu.g-1 for Fe3O4 nanoparticles, Fe3O4@SiO2, nanocarrier and β-CD, respectively. This magnetic property of the prepared nanocarriers, however was tested by applying a magnet near the nanocarrier sample, which confirms the acceptable separation capability of product after each adsorption process. This behavior is due to the presence of Fe3O4 nanoparticles within the structure of nanocarriers. It should be also noted that the β-CD has no magnetic behavior and the magnetic value of Fe3O4@SiO2 sample is low due to the presence of non-magnetic SiO2 nanoparticles on the surface of Fe3O4 nanoparticles.
Morphological analysis
The morphology of the samples β-CD and nanocarrier is investigated by SEM and TEM microscopic methods. The SEM images are illustrated in Figure 5. The SEM micrograph of β-CD shows a flat, rigid and rough surface of the monomer with various groups of on β-CD substrate. Furthermore, the SEM micrograph of nanocarrier reveals that the presence of Fe3O4 nanoparticles within the network of the nanocarrier structure. On the other words, this SEM image depicted the strong interactions between the Fe3O4 nanoparticles and various functional groups of β-CD due to the distribution of nanoparticles in the surface of product.
Figure 6 displays TEM photographs of Fe3O4 nanoparticles and nanocarrier samples. The TEM images of Fe3O4 nanoparticles showed that the nanoparticles have mean diameter of 15–30 nm. It is also evident from the TEM images of nanocarrier that the Fe3O4 nanoparticles in the nanocarrier with some aggregates were randomly diffused in the structure especially on β-CD backbones. Moreover, the size of most incorporated Fe3O4 molecules were approximately observed between 10 upto 20 nm. Similar morphologies have also been reported for magnetic β-CD-based nanocomposites by other researchers (Shirke et al., 2022; Wang et al., 2022; Bosu et al., 2022).
Drug loading studies
In the drug delivery systems, the drug loading capacity is a very important practical factor. Firstly, we used the UV-Vis, SEM and TEM techniques to confirm the acceptable drug loading in the synthesized nanocarrier. As seen from Figure 7, the UV-Vis spectra of pure DOX drug was depicted two main adsorption peaks at 241 and 287 nm. These peaks can be attributed to the n→π* and π→π* transitions, respectively. In the UV-Vis spectra of the DOX-loaded nano-carrier, however the intensities of the absorption wavelength of the drug were greatly decreased due to the loading of DOX within the structure of the carrier. Figure 8 shows the SEM and TEM images of the nanocarrier before and after drug loading. As seen, the drug carrier has a large number of pores and holes, which are naturally suitable places for absorbing DOX molecules. As it is also clear from the figure, these empty available spaces are mostly occupied by drug molecules after the adsorption process. Moreover, this issue is proven by TEM analysis method. The TEM images in Figure 8 demonstrated that after drug loading process, the core-shell Fe3O4@SiO2 nanoparticles were agglomerated and the particle size of the nanoparticles was also increased.
After these preliminary drug loading investigations, we studied the effect of important and influential factors on the drug loading capacities, which will show the obtained results in the following sections.
In this series of experiments, the effect of DOX concentration, β-CD content, and temperature on the LE% was investigated and the results shown in Figure 9. As clearly seen from Figure 9(a), the LE% of drug DOX was increased with the increase of drug concentration due to the more drug accessibility nearby the nanocarrier molecules.
The LE% of drug in nanorarriers was also significantly affected by the β-CD content. According to Figure 9(b), with increasing the content of the β-CD, the amount of loaded DOX is linearly increased by an increase in amount of the β-CD due to increasing of adsorbing and reacting functional groups attached on the surface of the monomer. For further study of this issue, we also compared the LE% of the nanocarrier with the net β-CD (Figure 9(c)). As it can be seen, the β-CD alone is able to absorb a good amount of DOX in comparison with the main nanocarrier, and this depicts the main role of β-CD in adsorbing drug molecules.
The effect of drug solution temperature on LE% of DOX was also studied and the obtained results were summarized in Figure 9(d). It was observed that due to providing the required kinetic energy of the drug molecules, the amount of loading increases with temperature increasing. However, higher increasing the temperature leads to a decrease in the amount of DOX loading, which the main reason of this result is the release of some loaded drug molecules.
Drug releasing studies
Effect of pH on drug releasing
According to Figure 10(a), the percentage of DOX drug release (DR%) in acidic environment (pH=5.8), which is actually the simulated environment of cancer cells, is much more than the basic environment (pH=7.4). Two main reasons for this observation can be mentioned: Firstly, the hydrophilicity of the drug increases in acidic environment, and secondly, the attractive interactions between the drug and the nanocarrier are broken faster and more in acidic conditions, and as a result, the amount of DOX drug release increases. It should be noted that the initial burst DOX release in both pH solutions is due to the un-complexed and weakly loaded DOX molecules on the surface of nanocarrier. This novel nanocarriers, therefore, has the ability for a pH-controlled and targeted drug release. Hence, by activating the drug in the acidic environment of cancerous cells, the targeting mechanism lessens the drug’s toxic impacts on healthy cells.
In vitro cellular cytotoxicity assay
In this section, we used MTT assay test for investigation of the anticancer activity of the synthesized nanocarrier. The procedure of the MTT assay technique was similar to previous published papers (Ojagh et al., 2021; Rasouli et al., 2013). The in vitro cell viability of the K562 cancer cells after 48 h incubation with the free DOX, DOX-loaded nanocarrier and un-loaded DOX nanocarrier were shown in Figure 10(b). The experiment was done in triplicate, and the average of three trials is demonstrated in each column. According to this figure, the cell growth inhibition rate of DOX-loaded nanocarrier at various cell concentrations (2-12 µg.mL-1) is lower than both free DOX and net nanocarrier. For example, the Cell viability was about 89%, 77% and 98% for free nanocarrier, free DOX and DOX-loaded nanocarrier, respectively. The figure proves a sharp reduction in cell viability percentage in DOX-loaded nanocarriers compared to other samples. This can be attributed to the controlled DOX release with good efficiency, due to the nanocarriers’ ability to deliver the drug to the targeted tissue, which demonstrated that the nanocarrier had no cytotoxicity activity.
Kinetics of drug releasing
In general, various models or mathematical relationships can be used to show the rate or kinetics of drug release. In this part, we used three famous and well-known models of zero-order, first-order and Higuchi, which are defined based on the following equations, respectively (Modi & Anderso, 2013):
where F is the fraction of DOX release in time t. The K0, K1 and K2 are rate constants of the zero-order, first-order and Higuchi models, respectively. The summarized results in Table 1 depict that the Higuchi model with the higher correlation coefficient (R2) is the best kinetics model for fit the experimental DOX release data with the theoretical ones. These results prove that mechanism of drug release from the as-prepared nanocomposites is a diffusion controlled mechanism.
Table 1. Kinetics parameters for the DOX release from the prepared nanocarriers
|
DOX (mg.mL-1) |
zero-order |
first-order |
Higuchi |
|||
|
K0 |
R2 |
K1 |
R2 |
K2 |
R2 |
|
|
1 |
0.008 |
0.8392 |
0.0011 |
0.8999 |
0.012 |
0.9919 |
|
2 |
0.011 |
0.8136 |
0.0019 |
0.9101 |
0.017 |
0.9964 |
|
3 |
0.007 |
0.8892 |
0.0015 |
0.8745 |
0.018 |
0.9975 |
|
4 |
0.004 |
0.8979 |
0.0021 |
0.8184 |
0.014 |
0.9992 |
For further study about the effect of time on releasing kinetics, we recorded the UV-Vis spectra of the solution of DOX at various releasing times from nanocarrier. Figure 11 simply and clearly shows that the rate of drug release from the nanocarrier increases as the drug release time increases from 5 to 120 minutes. According to this figure, the absorption intensity at the λmax of the drug in the spectrum increases with the passage of time, due to the release of the drug into the solution and the increase in its concentration.
In the present work, a novel drug-loaded β-CD-based nanocarrier with magnetic Fe3O4@SiO2 core-shell has been fabricated by using a facile ultrasonic-assisted method for controlled release of DOX. The structure and composition of the nanocarriers were evaluated by FTIR, SEM, TEM, XRD, and VSM instrumental analysis methods. The synthesized nanocarriers were used for drug delivery application. So, the drug loading behaviors of nanocarriers mainly including the effects of various affecting parameters were investigated in detail. Furthermore, the release profiles of embedded drugs from the nanocarriers were found to be dependent upon the solution pH. The results of the relevant investigations showed that the prepared nanocarriers have high drug loading and controlled drug releasing capabilities. The MTT assays were also depicted the anti-cancer properties of the prepared drug-loaded nanocarriers. According to the reported results, it can be concluded that these nanocomposites with above-mentioned properties can be useful for designing as novel controlled drug delivery systems in real applications.
Funding declaration
None
Data availability
The datasets produced during the present study are not publicly available due to ongoing research, but are available upon reasonable request from the corresponding author.
Author Contribution
Hossein Hosseinzadeh wrote the main manuscript text. Ziba Jahanbakhsh and Bakhshali Masoumi prepared all figures. All authors reviewed the manuscript.
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Scheme 1 is available in the Supplementary Files section.
No competing interests reported.