Different cation-exchanged (K+, Na+ & Ca2+) nano-zeolites withi magnetite nanocomposites were synthesized and their suitability for drug loading was studied. Nanocomposites with different Fe3O4 contents were synthesized by adding magnetic Fe3O4 nanoparticles to the zeolite crystallization solution. The zeolite and its nanocomposites had high surface areas and enough adsorption capacity to load and release sufficient amounts of the chemotherapeutic doxorubicin. None or the zeolites or nanocomposites showed toxicity to SKBr3 or MCF-7 cancer cells. However, DOX@zeolite inhibits cell growth more than the non-encapsulated drug. Thus zeolites and their magnetite nanocomposites show potential as biocompatible medical devices.
Biocompatibility, mechanical stability and high drug loading capacity are necessary for drug delivery systems and for slow controlled release. Inorganic carriers have recently been used as drug release systems, but there are few reports of porous matrices as drug carriers [1,2,3,4]. Zeolites’ low toxicity, high dispersibility, good capacity and surface silanols make them good biomaterials with various applications. They have microporous structures with ordered cages and channels [5,6]. The size and dimensions of the pores, channels and cages, as well as the numbers, sites and types of structural cations affect their drug loading properties [7,8,9,10,11,12], and drug functional groups can interact with the surface silanols of the zeolites. Zeolites and their composites are used as catalyst supports , anticancer drug encapsulants [14,15,16], antibacterial agents [7,17,18], antihelminthics , and anti-inflammatory drugs . Doxorubicin is a cytotoxic and cytostatic drug with a low therapeutic index, used in cancer chemotherapy [21,22,23,24]. Zeolites have been reported as slow release carriers [7,24]. For example, zeolite Y is commonly used for encapsulating dichlorvos (2,2-dichlorovinyldimethylphosphate), ibuprofen (anti-inflammatory) , 5-fluorouracil , erythromycin, carbamazepine, levofloxacin , and aspirin (acetylsalicylic acid) . Clinoptilolite is a natural zeolite used to carry erythromycin in topical acne therapy , aspirin , and sulfamethoxazole . Zeolite A is an important moleculor sieve due to its high adsorption and easy sodium exchange for cations (calcium, potassium, iron, etc). [31,32]. There have been few studies of zeolite A as a drug carrier [33,34].
Magnetic drug targeting using magnetite core-shell composites to achieve biocompatiblity and porosity for drug adsorption or encapsulation is an emerging improvement over convenaional cancer treatment methods. A magnetic field is applied to direct The composite to the tumor proximity. This can significantly reduce the necessary dose and minimize side effects .
Magnetite-zeolites may prove effective drug delivery composites because of the zeolite properties as well as preventing magnetite agglomeration. There has been only one report; magnetite-FAU zeolite was prepared by mechanical activation but no toxicity results were reported [34,35]. A novel magnetic zeolite as a potential MR imaging agent has been recently reported .
The purpose of the present work was to examine the nano-zeolites (KA, NaA, CaA) and nano-magnetite zeolite (Fe3O4/NaA) as in vitro magnetite drug delivery systems for the anticancer drug doxorubicin (DOX), on two different breast cell lines, SKBR3 and SCF7.
Ferrous chloride (FeCl2·4H2O), ferric chloride hexahydrate (FeCl3·6H2O), sodium aluminate, sodium hydroxide, CaCl2, and KCl were purchased from Merck and local clinoptilolite was used. SKBR3 and SCF7 human breast cancer cell lines were purchased from the National Cell Bank of Iran, Pasteur Institute of Iran, Tehran, Iran. MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl- tetrazolium bromide) and Cell Death Detection ELISAPLUS kit were purchased from Roche Diagnostics GmbH, Mannheim, Germany.
2.2 Synthesis of nano-zeolites
Nano-zeolite NaA was synthesized hydrothermally from annealed local clinoptilolite after crushing, drying, screening and washing. Clinoptilolite, sodium hydroxide, sodium aluminate and distilled water were mixed for 6h (aging). The resulting gel was treated by ultrasound for 6h, transferred to a Teflon-lined stainless steel autoclave, and heated at autogenous pressure in an air oven at 353 K. After a suitable time (the pH reached 7) the suspension was centrifuged several times and the product was dried. For the preparation of CaA (5A) and KA (6A) nano-zeolites, calcium and potassium hydroxide replaced the sodium hydroxide. The products were characterized and their adsorption properties examined.
For synthesis of nano-magnetic NaA, magnetic Fe3O4 was synthesized by co-precipitation from an alkaline solution of Fe2+ and Fe3+ salts and added to the carrier gel  after the ultrasound treatment. The next steps were same as the synthesis of nano-zeolite NaA. Nanomagnetite NaA with different Fe3O4 loadings (0, 2.1, 4 and 7.7 wt.%) was prepared by varying the amount of nano-Fe3O4 and designated as Mn4A (n=0, 2.1, 4 & 7.7).
2.3 Doxorubicin standard solutions preparation
Standard solutions of doxorubicin (5, 50, 100 mgL–1) in deionized water were prepared quickly and kept in the dark because light immediately changes doxorubicin to a toxic material.
2.4 Preparation of drug loaded nano-zeolites
20 mg of each nano-zeolite was added to 20 mL of the standard doxorubicin solutions and stirred for 24 hours at room temperature. The white zeolite changed to the red doxorubicin color as the drug entered the zeolite pores and the loading was complete. Doxorubicin disappearance was confirmed by supernatant absorbance measurement with a Shimadzu UV-240 spectrophotometer at 485 nm. After there were no further changes in the liquid phase concentration it was assumed that the loading capacity had been reached. The reddish solid was separated by filtration, air-dried for 24h and designated DOXn@ZA (n= 0, 5, 50, 100 & 500).
Desorption was examined at 37ºC, but the loaded nanocomposite was first washed and dried to remove non-adsorbed doxorubicin. The release profile was obtained by dispersing 100 mg of dried drug-loaded nano-zeolite in 50 mL of buffer (pH= 7.4, 5.5). As in the uptake experiments, the concentration of doxorubicin in the particle-free liquid was determined at fixed time intervals.
A Siemens D500 diffractometer with Cu Kα radiation (λ=1.5418 Å and θ=4-80°) was used to characterize the powders. Functional group absorption bands were studied with a Bruker Tensor 27 FTIR as KBr pellets. Gold-coated particle morphology, size and elemental composition were analyzed with a Philips XL30 SEM. SEM was done at 5Kv while EDX analysis was at 15Kv.The BET surface area was measured by N2 adsorption–desorption isotherms at liquid nitrogen temperature a using N0VA2000 (Quantachrome, USA). TEM and EDX of the samples were performed on a Zeiss LEO 912 Omega at 120 kV. TEM specimens were made by evaporating one drop of ethanolic solution on carbon-coated copper grids and blotted dry on filter paper. Magnetic properties were investigated at room temperature using a 7400 vibrating sample magnetometer.
2.6 MTT assay
The effects of concentrations of the carrier, drug and drug-loaded carrier on cell viability were investigated using identical methods.
SKBR3 and SCF7 cell lines were grown in sterile RPMI-1640 media containing 10% fetal bovine serum, streptomycin (100 μg/mL), amphotericin B (0.25 μg/mL) and penicillin (100 U/mL) at 5% CO2 in a humidified 37°C incubator. Then 200 μL/well of supplemented medium and 12×103 cells were incubated in 96-well plates for 24 hours at 37°C and 5% CO2. The cells were divided into four groups in triplicate: blank, drug, carrier and drug-loaded carrier supplemented.
A Cell Death Detection ELISAPLUS kit was used according to the manufacturer’s protocol to induce cell apoptosis and necrosis. Briefly, supernatants and cell lysates were prepared and incubated in microtiter plates coated with an antihistone antibody then analyzed at 405 nm.
After incubation the used media were discarded and the wells washed with pH 7.4 phosphate-buffered saline. 50 μL of 2 mg/mL MTT solution and 150 μL culture medium were added to each well. The cells were incubated at 37°C and 5% CO2 for 24 hours; then the media was removed and 200 μL of dimethyl sulfoxide and 25μL Sorenson solubilizer buffer added to each well. Finally, an ELISA plate reader (BioTeck, Bad Friedrichshall, Germany) was used to read the absorbance at 405 nm. All results were analyzed relative to the untreated cells then normalized.
The conducted research is not related to either human or animals use.
3.1 Characterization of DOX@ZA
Figure 1A shows the pXRD of zeolite 4A before and after DOX loading. All characteristic peaks of zeolite 4A are shown. In Figures 1A(b-d), 4.7ppm, 42.5ppm and 80ppm DOX were loaded. XRD pattern similarity before and after drug loading indicates that the framework did not change. However, overall reduction in the peaks’ intensity indicated a slight decrease in zeolite crystallinity following drug adsorption which is more obvious at higher drug loadings. The XRD patterns of the other zeolites are similar.
The XRD show only characteristic 4A zeolite and Fe3O4 peaks; no other structures or changes in cell parameters were observed (Figure 1B). The XRD of the DOXn@M44A (n = 42.5ppm and 80ppm; Figures 1B (a-c)) were similar to the M44A XRD with reduced peak intensities.
TEM and SEM examined nano-zeolite morphology before and after loading. The DOX@ZA with the lowest DOX concentration (5 ppm) is shown in Figure 2a. The morphology and structure were unchanged after drug loading. As DOX is larger than the nano-zeolite pores, it is adsorbed on the outer surface. Drug and zeolite -OH and –NH2 groups hydrogen bond causing aggregation. The average particle size of the starting 4A was about 50-100 nm (Figure 2b) and 80-120 nm for M4A (Figure 3a).
3.2 Loading efficiency and release
4A zeolite (94% of DOX5@ZA) has significantly higher loading efficiency than 3A and 5A zeolites (86% and 79%) as shown in Figure4a. The higher amounts of DOX in the 4A zeolite suggest higher drug loadings in the pores due to different pore sizes. The initial red of the DOX solution became colorless after a few minutes of zeolites contact; respectively, 92%, 84% and 74% of the initial DOX was adsorbed in 30 min by 4A, 3A and 5A (Figure 4a). Adsorption of the remaining DOX was slower and saturation was complete in approximately 120 min. DOX solution UV spectral changes after contact with zeolites were not significant, indicating that their interaction is only physical
Hydrogen bonding of the DOX ‒NH2 (δ+) groups to the zeolite ‒OH (δ‒) groups causes drug loading.
At higher DOX concentrations (DOX50@ZA and DOX100@ ZA), loading efficiency was lower (Figure 4b). The mean pore size of the A zeolites is 0.87 nm which is much smaller than the DOX molecule, so adsorption occurred only on the external surface as a poremouth phenomenon . The 4A BET external specific surface area of 5.27 m2/g means that although the nanocomposite has a considerable DOX storage capacity, the composite surface area (≈ 220-255 m2g–1) will not be fully occupied. Its loading may come from physical attachment rather than encapsulation.. Substrate surface electronic structure and charge transfer dynamics can strongly influence interactions with the adsorbate.
The DOX concentration in DOX5@ZA is very low; after 24 h approximately 60% of the loaded drug (4.7 ppm from 5 ppm) way released.
Initial DOX uptake by magnetite-zeolite nanocomposites (M4A) was very fast, with 94% adsorption in 30 min. Drug saturation was completed in approximately 2h. At higher DOX concentrations drug loading was lower for all the composites (Figure 4c). As shown in Figure 4, drug loading increased with increased Fe3O4 percentage but at the highest percentage (7.7%) the loading decreased. At 4 wt% Fe3O4, maximum adsorption was achieved because the iron oxide was well dispersed into the zeolite pores, caused by strong interactions between the zeolite oxygen atoms and Fe3O4. Increasing the Fe3O4 content blocked the channels, reducing adsorption.
The dried nanocomposite contains more than 75% drug. Its release was measured by desorption and diff usion into pH 7.4 buff er; released DOX % is given by:
22% (9.24 ppm), 26% (11.06 ppm), 22% (9.02 ppm) and 21% (9.55 ppm) of the DOX on the 3A, 4A, 5A zeolites and M44A nanocomposite was released in 24 h. However, at the lower cancer cell pH (5.4), more desorption from DOX50@ ZA occurred (70-80%). The release profiles of DOX5@ZA are the same. There was no dependence of the (DOX@ZA) characteristics on the storage time.
Arruebo et.al reported magnetite/Y zeolite prepared by milling as a potential DOX delivery vehicle. They found 92% of DOX adsorbed in 25 h and 77% of the load was released in 12.6 h .
3.3 Cytotoxicity of the combination of nanozeolite with doxorubicin
For breast cancer, the required DOX dosage is 50 mg/m2 times the Mosteller value for the BSA (body surface area) :
For a 170 cm, 65 kg female the required DOX dosage is 87.7 mg. Her total body water (TBW) is calculated by Watson’s formula :
Therefore, the DOX concentration should be 2.73 μg/mL. Based on the DOX = 5 ppm loading and release profiles, we achieve this concentration in 25 min from 4A and 20 min from M44A, respectively. DOX@ZA was selected for the rest of the study.
Zeolites should have small or no effect on cell viability to achieve a suitable delivery system. Investigation of the starting zeolites’ cytotoxicity was carried out with the SKBr3 & MCF-7 cell lines. Different DOX5@ZA concentrations (0.50, 1.00, 2.50 and 5.00 mg/mL) were suspended in the culture medium (RPMI 1640) and treated with ultrasound for 2 min before use for better homogeneity.
Figure 6 illustrates the effect of increasing carrier amounts (zeolites and composites) on cell viability determined by the MTT assay (P> 0.05). The insignificant differences between controls (no zeolite) and zeolite concentrations tested show that 3A, 4A & 5A zeolites are not cytotoxic over the 24h incubation period. All of the zeolites and composites gave similar results for a 48 h incubation. For magnetite zeolites containing 7.7% Fe3O4 cell viability decreased, but very mild toxicities appeared. M44A magnetic nanocomposites had no cytotoxicity suggesting biomedical application.
The effects of DOX5@ZA concentration and zeolite type (3A, 4A, 5A & M3.44A) on SKBr3 & MCF-7 cell viability were investigated. When the DOX5@ZA concentrations (0.5, 1.0, and 2.5 mg/mL) increased, cell growth inhibition was observed in both cancer cell lines (Figure7). Loading doxorubicin on zeolite improves tumor inhibition over doxorubicin alone.
This increased efficacy may be due to slow release. We believe that like other systems [33,40,41,42], zeolite delivery systems increase the bioavailability and promote DOX entry into the cell, explaining this increase in potency. Upon exposure to the acidic endosomes/lysosomes environment, DOX is released intracellularly, resulting in efficient apoptotic cell death . Figure 7 shows the treatment-induced apoptosis (> 80%) and necrosis (< 20%), obtained from ELISA analysis for the SKBR3 line.
As shown in Figure 8, the cytotoxicity of delivery with type A zeolite (1.0 mg/mL) was more pronounced for 4A and M44A, which have greatest loading and release capacity.
Figure 9 shows the M44A magnetization curve at room temperature. The nanocomposite showed superparamagnetism and the curve’s coercivity was negligible. The saturation magnetization and susceptibility values for the nanocomposite were found to be 43.4 emu/gFe and 17.65 emu/gFe kOe, respectively.
Linde type A zeolites and their magnetite nanocomposites can be used for efficient loading and slow release applications. Parent zeolites and their nanocomposites were nontoxic to SKBr3 and MCF-7 cells. DOX@4A and DOX@M4A had higher tumor inhibition efficiency compared to other DOX@zeolites and doxorubicin alone.
This work was financially supported by the Iran National Science Foundation: INSF (Grant No. 92012004).
Conflict of interest: The authors state no conflict of interest.
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