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Synergistic action of curcumin and cisplatin on spinel ferrite/hierarchical MCM-41 nanocomposite against MCF-7, HeLa and HCT 116 cancer cell line

Abstract

Background

Platinum-based drugs are widely used in cancer therapy, but are known for toxic side effects and resistance. Combinational drug delivery represents an effective chemotherapeutic strategy, but often leads to an increased toxicity. Aim of this study is to test the co-delivery of cisplatin with natural antioxidants on hierarchial porous large surface area hexagonal nanocarriers for synergistic action.

Results

A series of structured mesoporous materials were impregnated with magnetic spinel ferrite (30% CuFe2O4) and then coated with curcumin (25% wt/wt). Mesosilicalite and MCM-41 with high curcumin release abilities were functionalized with cisplatin (5% wt/wt) for synergistic effect of combinational drugs. The cytotoxic efficiency of our nanocomposites was tested on cell viability of MCF7 (human breast cancer), human cervical cancer (HeLa), colorectal cancer (HCT116), and HFF (human foreskin fibroblasts) cell lines using the MTT cell viability assay. At a concentration of 0.1 mg/ml, CuFe2O4/mesosilicalite/curcumin/cisplatin resulted in 89.53% reduction in viability in MCF7, 94.03% in HeLa, 64% in HCT116 and 87% in HFF; whereas, CuFe2O4/MCM-41/curcumin/cisplatin resulted in 76% reduction in viability in MCF7, 64.46% in HeLa, 64% in HCT116 and 24% in HFF. The EC50 for CuFe2O4/mesosilicalite/curcumin/cisplatin was 81.23 µg/ml in MCF7, 47.55 µg/ml in HeLa, 48.96 µg/ml in HCT116 and 76.83 µg/ml in HFF. The EC50 for CuFe2O4/MCM-41/curcumin/cisplatin was 72.51 µg/ml in MCF7, 58.6 µg/ml in HeLa, 62.58 µg/ml in HCT116 and 154.2 µg/ml in HFF. Furthermore, cells treated with both nanocomposites had a high number of cleaved Caspase 3-positive cells suggesting that the reduction in cell viability was triggered by activating the apoptotic signaling pathway.

Conclusion

Our results show that CuFe2O4/MCM-41/curcumin/cisplatin is a better candidate for combinational drug therapy due to its lowest EC50 value and the wider difference in EC50 (a fold change) between cancerous and non-cancerous cell line.

Introduction

In recent years, magnetic nanoparticles in nanomedicine research have been steadily rising for developing targeted drug delivery system for various biomedical applications (Amiri et al. 2019). Spinel ferrite-based nanocomposites have been widely studied in biomedical applications such as hyperthermia, contrasting agents in tumor imaging, drug delivery and magnetic separation of biological specimens (Kefeni and Mamba 2020). The use of magnetic nanocomposites in drug delivery has been reported to increase the targeted drug delivery, reduce the dose, and enhance patient compliance (Ghosh et al. 2019). Among the different types of spinel ferrites, CuFe2O4 is an interesting magnetic nanoparticle due to its superparamagnetic nature, strong T2 MRI contrast, ability to be guided by an external magnetic field, tunable particle size, low synthesis cost, and its eco-friendly characteristics (Khanna et al. 2019). CuFe2O4 was composed of a cubic inverse spinel structure in the Fd3m space group (Dippong et al. 2021). Several nanocarriers with functionalization property based on hydrogels, alginate, clay, liposomes and polymeric species based therapeutic tools have been reported for treating chronic diseases (Li et al. 2019; Mantha et al. 2019; Abduljauwad and Ahmed 2019; de Lima et al. 2018). Mesoporous hexagonal structured silica MCM-41 with superior textural features with high surface area (~ 500–1000 m2/g) has been used as catalyst in fine chemical synthesis and gas adsorption (Beck et al. 1992; Lanzafame et al. 2020; Chen et al. 2020). The large hexagonal shaped pore size of Si-MCM-41 is built with amorphous silica framework. ZSM-5/MCM-41 hybrid composite material that are derived from zeolite contains crystalline framework with presence of micropore and mesopores (Ravinayagam and Jermy 2019; Odedairo et al. 2012). The framework of such hierarchical hexagonal structure of composite is stable due to nanozeolitic building units (Jermy and Ravinayagam 2019).

Recently, using multiple drug-loaded nanoparticles had attracted interest as a cancer treatment option to overcome drug resistance. Xylan, a polysaccharide biopolymer modified with a redox-sensitive conjugate disulfide linker, has been explored as a drug delivery system. The delivery of curcumin and 5-fluorouracil using xylan nanoparticles resulted in a significant inhibition of cell viability in the colon carcinoma cells HT-29 and HCT-15 (Sauraj et al. 2020). Biocompatible polymers involving polyethylene glycol and poly(lactic-co-glycolic acid) exhibited a superior release of antineoplastic drug (7-ethyl-10-hydroxycamptothecin) and curcumin. The nanocomposite formulation with hydrophobic coating (dioleoylphosphatidic acid) has shown significant reduction in cell viability of cervical and ovarian cell lines (HeLa, A2780) (Li and Gao 2020). Layer-by-layer deposition of natural polysaccharide chitosan and negatively charged dextran sulfate has been reported using double-emulsion cross-linking technique. Chitosan–paclitaxel was prepared using internal oil in water emulsion. After addition of external water to oil emulsion, dextran sodium and chitosan bound 5-fluorouracil were added and then lyophilized. The dual drug-loaded nanoparticles with particle diameter of about 292 nm were reported to induce significant reduction in cell viability of HepG2 cells (Wang et al. 2020). A bilayer structured vesicle Niosome functionalized with folic acid was found to be effective as a dual drug carrier of curcumin and letrozole. Non-ionic surfactant Span 80 and cholesterol (lipid) to drug ratio optimization resulted in high drug encapsulation. The synergism between both drugs was observed to inhibit the viability of breast cancer cells (MCF-7 and MD-MB-231) leading to downregulation of Bcl2, cyclin D and cyclin E genes and upregulation of p53, Bax, caspase-3 and caspase-9 genes (Akbarzadeh et al. 2020). We have synthesized several zeolites and expanded their applications from traditional petrochemical applications to biomedical applications including drug delivery and diagnostic applications (Jermy et al. 2019; Jermy and Ravinayagam 2019). Curcumin is less-soluble antioxidant and therefore has lower bioavailability that prevents the advantages of curcumin for therapeutics (Karthikeyan et al. 2020). The presence of curcumin along with Pt compound over mesoporous drug delivery system has multiple advantages. The encapsulation of curcumin inside the nanopores is expected to improve the solubility, bioavailability and target specificity. The presence of cisplatin can influence a synergistic effect with curcumin and spinel is expected to be beneficial for imaging. Till now, the combinational effect of curcumin and cisplatin was not explored on spinel-based hierarchical micro/mesoporous materials like mesosilicalite and mesoporous MCM-41.

In the present study, the effect of copper spinel impregnation into mesosilicalite and MCM-41 was explored for dual release of curcumin and cisplatin. The study shows that spinel, curcumin and cisplatin loading varies with pore structures of mesosilicalite and MCM-41. Micro- and meso-pores containing mesosilicalite is more potent as a cytotoxic agent in both cell lines. However, mesoporous MCM-41 is a better candidate due to the wider difference in cytotoxic capability in cancerous and non-cancerous cell lines.

Material and methods

Ludox AS-40 (silica source), tetrapropylammonium bromide (micropore template), cetyltrimethyl ammonium bromide (mesoporous template), copper nitrate, iron nitrate, and anticancer drug (cisplatin) were purchased from Sigma Aldrich. Curcumin was obtained from Molecule on (New Zealand). Q-10 silica with pore diameter of about 18 nm was obtained from Fuji Silysia Chemical Ltd, Japan. Spherical hydrophobic silica was purchased from Superior Silica, USA. All the reagents used in in vitro study were of analytical grade. Cell culture reagents: DMEM (Dulbecco’s modified Eagle medium), heat-inactivated fetal bovine serum (HI-FBS), 100X penicillin streptomycin, and 100X MEM NEAA (MEM non-essential amino acids) were obtained from Gibco, Thermo Fisher Scientific. 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) reagent, cat. M2128 was purchased from Sigma-Aldrich. Hoechst 33342 nuclear stain, cat. 62249, and cleaved-Caspase antibody 3 (c-Caspase 3), cat. 9661, were procured from Thermo Fisher Scientific and Cell Signaling Technology, respectively. Alexa Fluor 594 goat anti-rabbit secondary antibody, cat. R37117 was obtained from Invitrogen, Thermo Fisher Scientific.

Preparation of 30%CuFe 2 O 4 /mesosilicalite and 30%CuFe2O4/MCM-41

Mesosilicalite was prepared by disintegrating silicalite crystals in alkaline medium following the top-down approach. A detailed synthesis procedure for mesosilicalite, MCM-41, SBA-16, and mesobeta are provided in our previous publication (Ravinayagam and Jermy 2017). The copper ferrite-impregnated mesosilicalite and MCM-41 were prepared by dry mixing. Briefly, 0.61 g of copper nitrate trihydrate, 1.01 g of iron nitrate nonahydrate and 1.4 g of predried structured silica were physically mixed for 30 min using mortar pistol. The obtained mixture was calcined at 850 ℃ for 6 h.

Curcumin loading over 30%CuFe 2 O 4 /structured silicas

In the first step, curcumin was loaded on a series of copper spinel-loaded structured silicas. 40 mg of curcumin was dissolved in 10 ml of methanol for 10 min. Then 160 mg of respective spinel-loaded structured silicas (mesosilicalite, MCM-41, SBA-16, Q10 silica, hydrophobic silica, mesobeta, mesoZSM-5) was added and the mixture was sonicated for 2 min. Then the solvent was evaporated using rotary evaporator.

For selected sample like CuFe2O4/mesosilicalite/curcumin and CuFe2O4/MCM-41/curcumin, cisplatin was loaded. In this step, cisplatin (30 mg) was first added in normal saline solution.

(10 ml) and stirred to form a clear solution. Then, CuFe2O4/mesosilicalite/curcumin or CuFe2O4/MCM-41/curcumin (600 mg) was added and stirred overnight under ice cold dark environment. The solution was then filtered, washed and dried. The functionalized cisplatin was estimated using UV–visible spectroscopy at 208 nm.

Characterization techniques

The phase of spinel-loaded support carriers CuFe2O4/mesosilicalite, CuFe2O4/MCM-41, CuFe2O4/SBA-16, CuFe2O4/hydrophobic silica, CuFe2O4/MesoZSM-5 and CuFe2O4/mesobeta was identified using benchtop XRD (Miniflex 600, Rigaku, Japan). The textural features including BET surface area, pore size and pore volume were measured using nitrogen adsorption technique (ASAP-2020 plus, Micromeritics, USA). The ferrite nanoparticle chemical coordination was analyzed using DRS-UV–visible spectroscopy analysis (JASCO, Japan). Vibrating sample magnetometer (LDJ electronics, 9600) was used to determine the magnetic property of CuFe2O4/mesosilicalite and CuFe2O4/MCM-41. The functional groups of curcumin and cisplatin in our nanoformulation were determined using FT-IR spectroscopy (Perkin Elmer). The morphological variations of spinel ferrite/mesosilicalite/curcumin/cisplatin were investigated using transmission electron microscopy (TEM, JEM2100F, JEOL).

Curcumin release study

In the first step, curcumin release was studied over different copper spinel-loaded structured silicas. The release study was carried out by dissolving 30 mg of curcumin-loaded sample in 50 ml of PBS (pH 5.6). The curcumin release was monitored at 37 °C. At regular time interval, 10 ml of solution was withdrawn and replaced with equal volume of fresh solution. The curcumin release content was identified at specific wavelength of 428 nm. CuFe2O4/mesosilicalite/curcumin/cisplatin and CuFe2O4/MCM-41/curcumin/cisplatin were chosen for cisplatin release. The cisplatin release was measured at 208 nm using UV–visible spectroscopy.

Cell culture

We used human mammary adenocarcinoma (MCF7)), human cervical cancer (HeLa), colorectal cancer (HCT116), and the non-cancerous human foreskin fibroblasts (HFF) cell lines to assess the cytotoxic effect of our compounds. Cells were cultured in a DMEM culture medium containing 10% HI-FBS, 1% penicillin streptomycin, and 1% MEM NEAA. Cells were maintained in a humified setting at 37 °C with 5% CO2. For cell viability assay, cells were seeded in a 96-well plate with a density of 20,000 cells/well. For immunofluorescent staining, 50,000 cells/well were plated on eight-well chamber slides. On the following day, cells were switched to the starve culture medium that contains 0.5% HI-FBS. On the next day, cells were treated with our nanocomposites as described in the following section.

Cell treatment

MCF7 and HFF cells were treated with the subsequent conditions for 48 h: CuFe2O4/mesosilicalite, curcumin, cisplatin, curcumin/cisplatin, CuFe2O4/mesosilicalite/curcumin, CuFe2O4/mesosilicalite/curcumin/cisplatin and CuFe2O4/MCM-41/curcumin/cisplatin. Treatment concentrations of CuFe2O4/mesosilicalite, CuFe2O4/mesosilicalite/curcumin, CuFe2O4/mesosilicalite/curcumin/cisplatin, and CuFe2O4/MCM-41/curcumin/cisplatin nanocomposites were: 0.025, 0.05, 0.1, and 0.5 mg/ml. Based on the drug-loading experiments, simple calculations were followed to reflect the actual quantity of curcumin and cisplatin that was adsorbed on CuFe2O4/mesosilicalite and CuFe2O4/MCM-41 nanoparticles. According to the loading experiments, 1 mg of CuFe2O4 nanoparticles contains 0.25 mg and 0.045 mg of curcumin and cisplatin, respectively. Thus, if CuFe2O4/mesosilicalite concentration was 0.5 mg/ml, there is 0.125 mg/ml of adsorbed curcumin and 0.0225 mg/ml of functionalized cisplatin. Therefore, the treatment concentrations of curcumin were: 0.00625, 0.0125, 0.025 and 0.125 mg/ml and the treatment concentrations of cisplatin were: 0.001125, 0.00225, 0.0045 and 0.0225 mg/ml.

Cell viability (MTT) and EC50

To assess the cytotoxicity of our compounds, we used 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT), a cell viability assay. It measures the cell viability by assessing the ability of mitochondria to convert yellow MTT solution into purple formazan insoluble crystals. Following Mosmann (1983) protocol, 5 mg/ml of MTT powder was dissolved in PBS, and 0.5 mg/ml of MTT working solution was prepared. Cells were washed with PBS and followed by the addition of 100 µl MTT working solution. All the experimental conditions were run in triplicates (technical repeats) with five biological repeats (n=5). The 96-well plate was incubated for 3 h at 37 °C. An MTT negative control (background control) was included in the experimental setting by adding MTT working solution to wells that contain no cells. After the incubation time, 0.04 N HCl isopropyl alcohol was added to solubilize the formazan crystals. The difference in color intensity was measured by SYNERGY-neo2 BioTek ELISA reader at 570 nm. The technical triplicate readings of each condition were averaged, and the absorbance from MTT negative control was deducted from these readings. An initial reading was measured before MTT addition to exclude background interference. The initial reading was subtracted from the final reading. Then, the treatment groups were analyzed by comparing them to the control (untreated cells). Cell viability was calculated using the following equation:

$$\% {\text{ Cell viability }} = \times { 1}00.$$

Data from the cell viability assay were used to calculate the half-maximal effective concentration (EC50) using Prism 9 software (GraphPad, La Jolla, CA). Concentration values were transformed to logarithmic data. Then, a sigmoidal curve was selected to fit the data and generate the calculated log EC50, EC50, and R2 values for each condition.

Immunofluorescent staining

As mentioned above, cells were plated in an 8-well chamber slide at a concentration of 50,000 cells/well. Cells were then treated for 48 h with the following conditions: CuFe2O4/mesosilicalite/curcumin, CuFe2O4/mesosilicalite/curcumin/cisplatin, and CuFe2O4/MCM-41/curcumin/cisplatin at a concentration of 0.5 mg/ml. Cells were fixed and stained with the apoptotic marker cleaved Caspase 3 (c-Caspase 3) antibody (1:200, Cell Signaling Technology) and incubated at 4 °C overnight. After PBS washing, Alexa Fluor 594-conjugated secondary antibody (Invitrogen, Thermo Fisher Scientific) was added to the cells at a final concentration of 1:1000 for 1 h at room temperature. Cells were then washed and stained with the nuclear stain Hoechst 33,342 (Thermo Fisher Scientific) at a concentration of 2 µg/ml and incubated at room temperature for 20 min. After staining, immunofluorescent images were taken using a confocal fluorescent microscope—Zeiss LSM 700. Bright-field images were captured using an inverted microscope—Nikon Eclipse TS100. Although both light and fluorescent pictures were taken from the same sample, they were not taken from the same field of view.

Statistics

The cell viability assay was performed in five independent experiments (n=5). Statistical analysis was performed using Prism 9 software (GraphPad, La Jolla, CA). The analysis was performed using one-way ANOVA with Dunnett’s post hoc test. Error bars ± S.E.M. * p < 0.05; ** p < 0.01; *** p < 0.001; **** p < 0.0001 versus control. In case there was no indication of significance, it means that results were non-significant. The data analysis of drug delivery was done using Prism 8 software and SPSS software version 20.0.

Results and discussion

The X-ray diffraction patterns of meso- and micro-phases of two supports were identified at low and high angle of MCM-41 and mesosilicalite (Fig. 1). The XRD pattern of CuFe2O4 impregnated over different structured nanocarriers is shown in Additional file 1: Fig. S1. Conventional MCM-41 showed a typical hexagonal peaks at low angle corresponding to the plane (100), (110) and (200). Mesosilicalite showed the presence of MCM-41 and high silica zeolite peaks at 2 theta value of 7.9° and 8.7° corresponding to plane (101) and (200), respectively. In the higher angle (20–60°), a broad peak of MCM-41 indicates the presence of amorphous framework bound to hexagonal phase. Mesosilicalite showed the typical characteristics peaks of MFI structure with corresponding to (321), (113), (501), (422) and (313) plane. In case of spinel impregnated MCM-41 and mesosilicalite, the presence of cubic phase of copper spinel appears with intense peak at 35.6° corresponding to (103) plane. A trace of α-Fe2O3 appears along with a less intense peak corresponding to CuO at 38.7°.

Fig. 1
figure 1

X-ray diffraction pattern of a MCM-41, b CuFe2O4/MCM-41, c mesosilicalite and d CuFe2O4/mesosilicalite

The characteristics of textural surface, pore volume and average pore size of (a) MCM-41, (b) CuFe2O4/MCM-41, (c) mesosilicalite and (d) CuFe2O4/mesosilicalite are shown in Fig. 2. The surface area and pore size distribution of CuFe2O4 impregnated over different structured materials are shown in Additional file 1: Figs. S2 and S3. Before, spinel ferrite impregnation, MCM-41 showed a typical type IV isotherm indicating the presence of uniform pore size distributions (3.7 nm) with high surface area of 914 m2/g and pore volume of 0.85 cc/g (Additional file 1: Table S1). In case of pure hexagonal mesopores of MCM-41, surprisingly, impregnation of spinel, only slightly reduced the surface area to 885 m2/g, while pore volume reduced to 0.52 cc/g. In case of mesosilicalite, which contains micro- and mesopores, the initial surface area of 804 m2/g reduced significantly after impregnation to 74 m2/g. An increase in dual pore sizes from 3.0 nm to 5.9 nm indicates the pore-filling effect and formation of external pores in the hierarchical micro- and meso-pores after spinel ferrite loading. Pore volume reduction from 0.6 cc/g to 0.1 cc/g reflects the pore-filling effect. Overall, the result shows unique deposition of spinel occurs over two supports. The textural characteristics vary depending on the structure of different shaped materials (Additional file 1: Table S1).

Fig. 2
figure 2

Nitrogen adsorption isotherm pattern of a MCM-41, b CuFe2O4/MCM-41, c mesosilicalite and d CuFe2O4/mesosilicalite

The rearrangement of curcumin and cisplatin over CuFe2O4/mesosilicalite was analyzed using TEM, FTIR and diffuse reflectance spectra analysis (Fig. 3A–F). The morphological feature of mesosilicalite/Pt without curcumin coating and after coating sample CuFe2O4/mesosilicalite/curcumin/cisplatin was analyzed using transmission electron microscope at different scale bar of 100 nm, 50 nm and 10 nm (Fig. 3A–D). In case of mesosilicalite/Pt sample, the presence of micro- and meso-phase is clearly seen. The presence of discontinuity as white dots indicates the nanozeolitic microphase, while continued pore channels shows the hexagonal mesopore ordering (Fig. 3A). After curcumin coating, the images shows the presence of curcumin at the external surface of MCM-41 (Fig. 3B and C). Further magnification to 10 nm, a uniformly layered hexagonal pore channels can be clearly seen to coexist with curcumin (Fig. 3D). The FT-IR spectra of cisplatin, curcumin, CuFe2O4/mesosilicalite, CuFe2O4/mesosilicalite/curcumin and CuFe2O4/mesosilicalite/curcumin/cisplatin are shown in Fig. 3E(a-e). Drug cisplatin showed a characteristic functional group related to NH group of platinum complex between 400 and 1800 cm−1. A symmetric and asymmetric bending of NH2 group was clearly observed between 1300 and 1600 cm−1, while plane bending of cisplatin can be seen at about 800 cm−1 (Fig. 3Ea). In case of curcumin, the presence of carbonyl (C=O), carbon–carbon double bond (C=C), and methylene (CH2) bending peaks are observed between 1625 and 1450 cm−1. Both symmetric and asymmetric vibrations corresponding to ether bond (C–O–C) are observed between 1300 and 1000 cm-1 (Bhandari et al. 2016) (Fig. 3Eb). A peak corresponding to enolic OH group of curcumin appears clearly at about 960 cm−1. In case of CuFe2O4/mesosilicalite, a zeolitic peak indicating hybrid formation between mesoporous and microporous zeolite appears at about 550 cm−1 (Fig. 3Ec). After curcumin coating (curcumin loading step 1), the sample CuFe2O4/mesosilicalite/curcumin showed no distinct peaks of curcumin. However, a significant reduction in hydroxyl group of enol indicates an effective interaction inside the mesosilicalite pores and curcumin (Fig. 3Ed). Unexpectedly, the CuFe2O4/mesosilicalite/curcumin/cisplatin (cisplatin loading step 2) sample, the loading of cisplatin showed the peaks of curcumin. It indicates that during cisplatin functionalization step, curcumin present inside the pores of mesosilicalite diffuses out and present at the external surface of mesosilicalite (Fig. 3Ee). In addition, a peak at about 1023 cm−1 indicates the C–O–C stretching of C6H5–O–CH3 group (Mohan et al. 2012). Also, the presence of cisplatin peaks reveals an effective functionalization of drug at external surface of mesosilicalite. Figure 3Fa–g shows the diffuse reflectance UV–visible spectra of curcumin, cisplatin, MCM-41, CuFe2O4/MCM-41, CuFe2O4/mesosilicalite, CuFe2O4/MCM-41/curcumin/cisplatin and CuFe2O4/mesosilicalite/curcumin/cisplatin. Curcumin and cisplatin revealed broad absorption between 200 and 600 nm (Fig. 3Fa and b). The support SiMCM-41 showed the absorption bands at about 210 and 260 nm, indicating the framework coordinated siliceous species (Fig. 3Fc). In case of CuFe2O4/MCM-41 and CuFe2O4/mesosilicalite, the spectra showed a weak absorption below 230 nm and a strong and broad absorption between 240 and 800 nm (Fig. 3Fd and e). The peaks of CuFe2O4/MCM-41 and CuFe2O4/mesosilicalite correlate with cubic spinel exhibits tetrahedral (215 nm) and octahedral (440–700 nm) crystalline coordination sites (Najmoddin et al. 2014). The presence of such peak absorption indicates the dispersion and integrated spinel ferrites over both supports. Importantly, in case of mesosilicalite support, an enhanced intense broad peak shows the presence of higher crystalline mixed phase of oxides due to octahedral coordinated spinel species compared to the MCM-41 support. This can be attributed mainly due to presence of micropores, which tends to accommodate spinel species at the external surface of mesosilicalite. After loading of curcumin and cisplatin, the absorption maximum increases significantly over both CuFe2O4/mesosilicalite and CuFe2O4/MCM-41 nanocomposites. However, in case with CuFe2O4/mesosilicalite/curcumin, a two distinct band absorptions at about 400 nm and 500 nm clearly indicates the distributed curcumin and Pt species (Fig. 3Ff). However, with CuFe2O4/MCM-41/curcumin, a broadness of absorption peak indicates cohabitation of curcumin and Pt species over MCM-41 (Fig. 3Fg). Such increase in homogenous expansion behavior clearly indicates the composite formation over mesoporous MCM-41 support than with mesosilicalite. As detected in XRD and DRS-UV analysis (Figs. 1 and  3F), though the active spinel metal components were not observed in TEM analysis, the migration of curcumin can be clearly observed as a surface coating at the external surface of mesosilicalite.

Fig. 3
figure 3

AD Transmission electron microscope of mesosilicalite/Pt, CuFe2O4/mesosilicalite/curcumin/cisplatin at different scale bar of 100 nm, 50 nm and 10 nm. Figure 3E. FTIR spectra of a cisplatin, b curcumin, c CuFe2O4/mesosilicalite, d CuFe2O4/mesosilicalite/curcumin and e CuFe2O4/mesosilicalite/curcumin/cisplatin. F Diffuse reflectance UV–visible spectra of a cisplatin, b curcumin, c MCM-41, d CuFe2O4/mesosilicalite, e CuFe2O4/MCM-41, f CuFe2O4/mesosilicalite/Cur/Pt and g CuFe2O4/MCM-41/Cur/Pt

The magnetic characteristics and saturation value of CuFe2O4/MCM-41 and CuFe2O4/mesosilicalite nanocomposites were analyzed by vibrating sample magnetometer at room temperature (Additional file 1: Fig. S4a and b). A distribution of cations at different coordination sites of A and B characterize the magnetic property. CuFe2O4/MCM-41 and CuFe2O4/Mesosilicalite showed ferromagnetic property with saturation magnetization value of about 0.9 emu/g. The saturation magnetization value was reported to be related to the magnetic phase concentration. Fe loaded on high surface area MCM-41 was reported to exhibit magnetization of 3.86 emu/g (Kiatphuengporn et al. 2016). In our previous study, spinel impregnation over spherical silica with lower surface area of 178 m2/g was found to exhibit similar ferromagnetism with magnetic value of about 7.6 emu/g (Jermy et al. 2019). Further, it has been reported that superparamagnetic effect was due to anti parallel spins of Fe3+ species in tetrahedral coordination site. In present study, the influence of support has shown to influence the magnetic property. The loading of spinel over mesosilicalite support tends to generate different types of nanoclusters at the pore walls (as evidenced by increased pore diameter from 3.0 to 5.9 nm). The generation of small sized nanoclusters reported to generate super paramagnetic Fe3+ ions, while larger nanoclusters generates ferromagnetic behavior (Cuello et al. 2017). In line with the diffuse reflectance spectra, presence of tetrahedral and octahedral species over high surface area parent mesosilicalite and MCM-41 is proposed to lead the broad hysteresis structure characteristics of ferromagnetism. The observed reduction in saturation magnetization value is mainly attributed due to presence of siloxane layers on copper spinel ferrites.

Nanostructured porous materials as drug delivery system facilitates the targeted drug delivery, reduce the in vivo dosage fluctuation, reduce drug disintegration and side effects of drugs (Ghaferi et al. 2020). In present study, a different structured nanocarriers for drug delivery was evaluated by studying the release trend of curcumin under acidic pH (pH=5.6) condition for 72 h (Fig. 4). CuFe2O4 impregnated samples were based on mesosilicalite (hexagonal micro/mesopore), SBA-16 (cubic), MCM-41 (hexagonal mesopore), Q-10 (large pore), hydrophobic silica, mesobeta (BEA large pore) and mesoZSM-5 (MFI). The percentage cumulative release profile of curcumin over hexagonal shaped silica (MCM-41 and mesosilicalite) was found to be superior and high of about 40–50% followed by cubic shaped SBA-16. CuFe2O4/SBA-16, which contains a 3D pore architecture showed a release of about 25% for 72 h. This indicates the ink shaped pores of SBA-16 (about 3.3 nm) are slightly restricted with spinel ferrite impregnation and showed a sustained release behavior with respect to curcumin. MesoZSM-5 with MFI structure consisting of sinusoidal pores of about 0.56 nm (micropore) and spherical silica with hydrophobic character also showed a release ability at about 20%. Q-10 silica with pore size of about 18 nm and mesobeta with medium pore size of 3 nm showed comparatively a less curcumin release of 10%. The release trend shows the aluminosilicate zeolite based structured silica with medium and large pore shapes profoundly affects and induces slow release of curcumin. For quick release, hexagonal shaped channel pores of MCM-41 and mesosilicalite (micro/meso) can be utilized than cubic shaped pores of SBA-16 and aluminosilicates. Based on the present requirement, cisplatin was loaded on curcumin/CuFe2O4/mesosilicalite and curcumin/CuFe2O4/MCM-41.

Fig. 4
figure 4

Drug (curcumin, cisplatin) delivery over CuFe2O4 impregnated on different structured nanoporous materials at pH 5.6

In case of parent cisplatin, a quick release was reported of about 76% within 1 h. However, loading cisplatin on biodegradable polybutylcyanoacrylate polymer shown to significantly reduce such burst release and enhance both in vitro and in vivo studies (Ghaferi et al. 2020). In a similar stance, the free curcumin release was completed (100%) within 24 h. However, using solid lipid nanoparticles as nanocarriers tends to extend the drug release up to 120 h (Gupta et al. 2020). In our present study, the mesosilicalite and MCM-41 were found to promote release of cisplatin for longer duration. For instance, mesosilicalite showed about 88% of cisplatin release for 72 h, while mesopores of MCM-41 showed a release of about 63% for 72 h. This suggests that cisplatin tends to functionalize on the external micropores of mesosilicalite, while MCM-41 is able to accommodate the cisplatin inside the mesopores. The release trend of cisplatin and curcumin with the presence of both nanocarriers clearly shows the functionalization ability and advantageous of mesopores than cisplatin and curcumin alone. For different structured mesoporous nanocarrier, data analysis was done using Prism 8 software and SPSS software version 20.0 (Additional file 1: Tables S2–S5).

The Additional file 1: Table S2 shows the mean and standard deviation of curcumin drug release at pH 5. While reviewing the results, CuFe2O4/MCM-41 showed a high mean score of 40.67, whereas CuFe2O4/Q-10 Silica/Curcumin demonstrated a low mean score of 6.38. The maximum score of curcumin drug release at pH 5.6 was observed in CuFe2O4/MCM-41/Curcumin and CuFe2O4/mesoZSM-5/curcumin, however the minimum curcumin release was observed in CuFe2O4/hydrophobic silica/curcumin. From Additional file 1: Table S3, the results showed that there is significant difference between the groups with respect to curcumin release at pH 5.6 (p < 0.05). As significant difference was found, Scheffe’s post hoc test was calculated to find out the significant difference between two groups at the same time. It is observed that the mean difference in the curcumin release between the groups such as CuFe2O4/MCM-41 and CuFe2O4/mesoZSM-5; CuFe2O4/mesosilicalite and CuFe2O4/mesoZSM-5; CuFe2O4/MCM-41 and CuFe2O4/mesoZSM-5; CuFe2O4/Q-10 silica and CuFe2O4/mesoZSM-5 was observed to be significant (p < 0.05). However, no significant mean difference was observed between the groups such as CuFe2O4/SBA-16 and CuFe2O4/mesoZSM-5; CuFe2O4/Hydrophobic silica and CuFe2O4/mesoZSM-5; CuFe2O4/mesoZSM-5 and CuFe2O4/mesoZSM-5 with respect to the curcumin release (p > 0.05). Notably, CuFe2O4/MCM-41 showed a high mean difference score of curcumin release (40.67) with CuFe2O4/mesoZSM-5 when compared other CuFe2O4/structured silica-based nanoformulations (Additional file 1: Table S4).

Using Pearson correlation, it was inferred that CuFe2O4/MCM-41 has a significant strong and positive correlation with only CuFe2O4/Q-10 silica/curcumin (p < 0.01). The formulation variable CuFe2O4/mesosilicalite/curcumin showed a significant strong and positive correlation with the variables such as CuFe2O4/SBA-16/curcumin, CuFe2O4/MCM-41/curcumin, CuFe2O4/hydrophobic silica/curcumin, CuFe2O4/mesoZSM-5/curcumin, and CuFe2O4/mesobeta/curcumin (p < 0.01). Similarly, CuFe2O4/SBA-16/curcumin described a significant strong and positive correlation with the formulation variables such as CuFe2O4/MCM-41/curcumin, CuFe2O4/hydrophobic silica/curcumin, and CuFe2O4/mesobeta/curcumin (p < 0.01). Further, CuFe2O4/MCM-41/curcumin showed a significant strong and positive correlation with CuFe2O4/hydrophobic silica/curcumin and CuFe2O4/mesobeta/curcumin (p < 0.01). A significantly strong and positive relationship was observed between CuFe2O4/hydrophobic silica/curcumin and CuFe2O4/mesobeta/curcumin (p < 0.01) (Additional file 1: Table S5). On the other hand, CuFe2O4/Q-10 silica/curcumin described a significant moderate and positive correlation with CuFe2O4/mesosilicalite/curcumin, CuFe2O4/SBA-16/curcumin, and CuFe2O4/MCM-41/curcumin (p < 0.05). A significant moderate and positive correlation was also observed between CuFe2O4/mesoZSM-5/curcumin and CuFe2O4/hydrophobic silica/curcumin (p < 0.05) (Additional file 1: Table S5). To test the efficiency of our nanocomposites as potential chemotherapeutic agents, we investigated their effects on the cell viability of MCF7 (human breast cancer), HeLa (human cervical cancer), HCT116 (human colorectal. Cancer) and HFF (human foreskin fibroblast) cell lines. The cell viability assay, MTT, was performed after 48 h of treatment with the following conditions: CuFe2O4/mesosilicalite, curcumin, cisplatin, curcumin/cisplatin, CuFe2O4/mesosilicalite/curcumin, CuFe2O4/mesosilicalite/curcumin/cisplatin, and CuFe2O4/MCM-41/curcumin/cisplatin nanocomposites (Fig. 5). Treatment concentrations of CuFe2O4/mesosilicalite, CuFe2O4/mesosilicalite/curcumin, CuFe2O4/mesosilicalite/curcumin/cisplatin, and CuFe2O4/MCM-41/curcumin/cisplatin nanocomposites were: 0.025, 0.05, 0.1, and 0.5 mg/ml. While treatment concentrations for curcumin were: 0.00625, 0.0125, 0.025 and 0.125 mg/ml and that for the cisplatin group: 0.001125, 0.00225, 0.0045, and 0.0225 mg/ml. As detailed in the Materials and methods section, treatment concentrations of curcumin and cisplatin were adjusted to reflect the actual concentration adsorbed onto the mesosilicalite nanocomposites.

Fig. 5
figure 5

Cytotoxic effects on several cancerous and control cell lines. Cell viability using MTT assay on A MCF7, B HeLa, C HCT116, and B HFF cell lines. Cells were treated with the following conditions for 48 h: CuFe2O4/mesosilicalite (group A), curcumin (group B), cisplatin (group C), curcumin/cisplatin (group D), CuFe2O4/mesosilicalite/curcumin (group E), CuFe2O4/mesosilicalite/curcumin/cisplatin (group F), and CuFe2O4/MCM-41/curcumin/cisplatin (group G). For groups A, E, F, and G treatment concentrations were as follows: 0.025, 0.05, 0.1, and 0.5 mg/ml. We used drug-loading experiments to calculate the concentration of adsorbed curcumin and cisplatin. Therefore, treatment concentrations of curcumin (group B) were: 0.00625, 0.0125, 0.025, and 0.125 mg/ml. Treatment concentrations of cisplatin (group C) were: 0.001125, 0.00225, 0.0045, 0.0225 mg/ml. n=5 independent experiments. Dashed line represents untreated cells control. Error bars ± S.E.M. Statistical analysis is shown in Additional file 1: Table S5

Our results were analyzed by comparing data from the treated cells with the control group (untreated cells) (Additional file 1: Table S6). Cells treated with CuFe2O4/mesosilicalite nanocomposites had no effect on either MCF7, HeLa, HCT116, or HFF cells suggesting that the CuFe2O4/mesosilicalite nanocarrier did not interfere with cell viability. Pure curcumin reduced cell viability only at the highest concentration in MCF7; however, it minimally reduced the cell viability in HFF cell lines. As anticipated, pure cisplatin resulted in a reduction in cell viability in both MCF7 and HFF cell lines. Cells treated with free curcumin and cisplatin resulted in a combined effect and a greater cytotoxicity than the either one of them. Furthermore, cells that were treated with our nanocomposites CuFe2O4/mesosilicalite/curcumin, CuFe2O4/mesosilicalite/curcumin/cisplatin, and CuFe2O4/MCM-41/curcumin/cisplatin all resulted in a significant reduction in cell viability in a dose-dependent manner with CuFe2O4/MCM-41/curcumin/cisplatin having the highest effect (Fig. 5).

Upon close investigation at the third dose of treatment in MCF7 cells, the pure curcumin reduced cell viability to 80.71%, while the nanocomposites that were coated with curcumin either with or without cisplatin significantly reduced the cell viability to 20.98% (group D in Fig. 5A), and 8.96% (group E in Fig. 5A). In HeLa cells, the pure curcumin reduced cell viability to 63.07%, while the nanocomposites that were coated with curcumin without cisplatin significantly reduced the cell viability to 56.13%. In HCT116, cell viability was 65.64% and 59.5% in free curcumin and CuFe2O4/mesosilicalite/curcumin, respectively. In contrast, using the same dose on the non-cancerous cell line HFF, the pure curcumin reduced cell viability to 84.12%, whereas the nanocomposites that were coated with curcumin did not result in a significant reduction in cell viability (72.88%; group D in Fig. 5B); whereas HFF treated with nanocomposites that were coated with curcumin and functionalized with cisplatin resulted in a significant reduction in cell viability of 12.93% (group E in Fig. 5B). Interestingly, the CuFe2O4/MCM-41/curcumin/cisplatin nanocomposite (group F in Fig. 5) resulted in a significant reduction of cell viability of 24.44% in MCF7, 5.9% in HeLa, 36% in HCT116, and an insignificant reduction in viability of 75.53% in HFF. Using a drug combination of cisplatin and curcumin nanocomposites will increase the cumulative cytotoxic effects of both compounds, solve the problem of cisplatin drug resistance in tumors, and increase the bioavailability of curcumin. The CuFe2O4/mesosilicalite/curcumin/cisplatin nanocomposite had a stronger effect even at lower concentrations on all cell lines. However, using the MCM-41/mesosilicalite in our cisplatin/curcumin nanocomposite had a significant effect on MCF7, HeLa, and HCT116, while having a minimal effect on HFF. Our results suggest that using MCM-41 with our cisplatin/curcumin drug combination has the potential of affecting cancerous cells while sparing normal ones.

To calculate the EC50 of treatment conditions, we used the data from Fig. 5 to calculate the EC50 (Fig. 6). Treatment with cisplatin resulted in an EC50 of 4.425, 6.48, 6.73, and 3.763 µg/ml in MCF7, HeLa, HCT116, and HFF, respectively. Coating the CuFe2O4/mesosilicalite with curcumin resulted in an EC50 of 80.2 µg/ml in MCF7; 102.1 µg/ml in HeLa; 117.6 µg/ml in HCT116; and 141.0 µg/ml in HFF. Moreover, functionalizing the CuFe2O4/Mesosilicalite with curcumin and cisplatin resulted in an EC50 of 81.23 µg/ml in MCF7; 47.55 µg/ml in HeLa; 48.96 µg/ml in HCT116; and 76.83 µg/ml in HFF. However, functionalizing curcumin and cisplatin onto CuFe2O4/MCM-41 nanocomposite resulted in an EC50 of 72.51 µg/ml in MCF7; 58.6 µg/ml in HeLa; 62.58 µg/ml in HCT116; and 154.2 µg/ml in HFF. These results show that while using the mesosilicalite resulted in a similar EC50, using the MCM-41 support resulted in a 1 to 1.5 fold difference in EC50 values between HFF and the other cell lines. When comparing between our nanocomposites, our results show that both CuFe2O4/mesosilicalite/curcumin/cisplatin and CuFe2O4/MCM-41/curcumin/cisplatin nanocomposites are potential novel chemotherapeutic options. However, our results show that CuFe2O4/MCM-41/Curcumin/Cisplatin is a better candidate due to the wider difference in EC50 (a 1–1.5 fold change) between cancerous and non-cancerous cell line.

Fig. 6
figure 6

EC50 analysis. Data from the cell viability assay (Fig. 5) were used to extrapolate EC50 of the following conditions: cisplatin, CuFe2O4/mesosilicalite/curcumin, CuFe2O4/mesosilicalite/curcumin/cisplatin, and CuFe2O4/MCM-41/curcumin/cisplatin. A, B Represent data from MCF7, C, D from HeLa, E, F from HCT116, and G, H from HFF cell lines. A, C, E, G) are the cell viability curves against Log concentration of each condition. B, D, F, H Represent the Log EC50, EC50, and R2 values of each group

We further explored the apoptotic effects of treating cells with CuFe2O4/mesosilicalite/curcumin, CuFe2O4/mesosilicalite/curcumin/cisplatin, and CuFe2O4/MCM-41/curcumin/cisplatin nanocomposites. Cells were viewed under light and fluorescent microscopes (Fig. 7). For the latter, cells were stained with the apoptotic marker cleaved-Caspase 3 (c-Caspase 3), and Hoechst, which is a nuclear marker. Our images clearly showed cells stained with c-Caspase 3 (magenta), which is the activated form of the protein, after treatment with our nanocomposites for 48 h. These results suggest that our nanocomposites significantly reduce cell viability by activating apoptosis.

Fig. 7
figure 7

taken from the same field). For the immunofluorescence images, cells were stained with cleaved-Caspase 3 (magenta) and Hoechst (blue)

Apoptotic effect of different treatment conditions on MCF7 and HFF. Cells were treated with: CuFe2O4/mesosilicalite/curcumin, CuFe2O4/mesosilicalite/curcumin/cisplatin, and CuFe2O4/MCM-41/curcumin/cisplatin at a concentration of 0.5 mg/ml for 48 h. Left column is light microscopy images, while right column is fluorescence microscopy images (not

Here, we explored merging two compounds that have potential benefits, but suffer from several side effects: curcumin and cisplatin. Curcumin has been extensively investigated as a chemotherapeutic agent in breast cancer, hepatocellular carcinoma, pancreatic cancer, gastric cancer, osteoclastoma, and bladder cancer (Syng-Ai et al. 2004; Zhu and Bu 2017; Li et al. 2017; Cao et al. 2015; Zhang et al. 2018). It has been found to activate JNK pathway, induce the generation of reactive oxygen species (ROS), and subsequently apoptosis (Syng-Ai et al. 2004; Zhu and Bu 2017). However, curcumin has some problems that hinder its full potential such as low solubility, low bioavailability, and rapid elimination from the body (Anand et al. 2007). Research is being conducted to increase the bioavailability of curcumin. On the other hand, cisplatin is a well-established chemotherapeutic drug. Unfortunately, it is fraught with several issues such as drug resistance and systemic toxicity (Dasari and Tchounwou 2014). The mechanism of action of cisplatin is by activating the JNK pathway and inducing oxidative stress, DNA damage, and apoptosis. However, cisplatin will also result in increased levels of Glutathione S transferase (GST), resulting in a reduction in ROS, and resistance to cisplatin. Therefore, a combination treatment of cisplatin and curcumin, which increases ROS, might augment the cytotoxic effect and prevent cisplatin-related drug resistance (Townsend and Tew 2003).Curcumin was shown to have a synergistic effect with cisplatin and enhance the cytotoxic effect in non-small cell lung cancer and laryngeal squamous cancer cell lines (Abdul Satar et al. 2021; Gökçe Kütük et al. 2019). A combinational drug mixtures of curcumin (B) and cisplatin (C) with varying concentrations (20.7025 µM, 41.405 µM, 82.8099 µM, 414.0495 µM) of were taken and studied on different cell lines such as MCF-7, HeLa, HCT116 cancer cells and HFF normal cells (Additional file 1: Table S5 and Fig. 5A–D). Combinational drug without nanocarrier decreases the cell viability of the MCF-7, He La, HCT116 cells and also HFF normal cells. Curcumin and cisplatin combinational drug clearly show a synergistic effect. Cisplatin has toxicity on normal cells. On the other hand, loading of combinational drugs on nanocomposite also showed cytotoxicity effects on cancer cells except HFF cells. The results show that the prepared nanoformulation containing curcumin with cisplatin reduce the toxicity in normal cells. Potential therapeutic approach of using curcumin may enhance the effects of cisplatin by targeting the cancer cells. The presence of high surface area CuFe2O4/MCM-41 nanocarrier helps to synergistic action of dual drugs and maintaining a sustained release of drugs could assist selectively targeting cancer cells.

In addition, loading of such dual combinational drugs on a biodegradable polymer based on polycaprolactone, linked with Pt using amine based polymer and PEG shell exhibited a synergistic effect (combination index = 0.4–0.8) with dual delivery in one nanocarrier against multidrug resistant cancer. The use of polymeric nanocarrier improves the transport of curcumin and cisplatin in to the cells by endocytosis (Scarano et al. 2015). Our results show that a simple coating of curcumin and functionalization of cisplatin into hexagonal pore structural framework of silica had a significant effect on the cytotoxic effectiveness of nanocomposites on various cancer cells.

We previously tested cisplatin-functionalized cubic spinel CuFe2O4 loaded on monodispersed spherical hydrophilic silica (HYPS) nanoparticles on MCF7 breast cancer cells (Jermy et al. 2019). In our current work, we investigated two nanoformulations using the hexagonally shaped silica: (a) the mesosilicalite with zeolite (strong) framework, and (b) the MCM-41 with amorphous (weak) framework. Both of which were coated with curcumin and functionalized with cisplatin. While the EC50 of our previous spherical shaped silica nanoformulation was equal to 180.89 µg/ml (Jermy et al. 2019), our current hexagonal shaped silica nanocomposites were 81.23 µg/ml (mesosilicalite) and 72.51 µg/ml (MCM-41).

The present study clearly indicates that changing the structural framework from spherical to hexagonally shaped silica increased the chemotherapeutic efficiency and reduced the EC50 values. The improved effectiveness is most likely attributed to the increased loading capacity in the hexagonally shaped nanocomposites as indicated in the drug release studies (Fig. 4).

CuFe2O4/mesosilicalite/curcumin/cisplatin, and CuFe2O4/MCM-41/curcumin/cisplatin nanocomposites utilize the benefits of curcumin and cisplatin. This combination resulted in novel nanocomposites that significantly reduced cell viability of the MCF7 breast cancer cell line by activating the apoptotic pathway as indicated by c-caspase 3. Our results show that both CuFe2O4/mesosilicalite/curcumin/cisplatin and CuFe2O4/MCM-41/curcumin/cisplatin nanocomposites are potential novel chemotherapeutic options. However, CuFe2O4/MCM-41/curcumin/cisplatin nanocomposites offer an added advantage of a wider gap in cytotoxicity between cancerous and non-cancerous cell lines (Scheme 1).

Scheme 1:
scheme 1

Spinel ferrite/mesosilicalite and MCM-41 nanocomposite for curcumin–cisplatin bound nanotherapeutic effect against MCF-7, HeLa and HCT 116 cancer cell lines

Conclusions

Synergistic action of curcumin and cisplatin on structured magnetically active hexagonal nanocarriers was studied for targeted combinational therapeutics. Mesoporous MCM-41 and mesosilicalite with micro/mesopores were developed and impregnated with copper spinel ferrite. The textural characteristics have been analyzed with various physico-chemical techniques. A significant difference in curcumin release was observed among the different CuFe2O4/structured silica-based nanoformulations. Also, those CuFe2O4/MCM-41 structured silica-based nanoformulations showed a significant positive relationship with each other. CuFe2O4/mesosilicalite followed by CuFe2O4/MCM-41 with high curcumin release ability was further functionalized with cisplatin. The effects of our nanocomposite on cell viability of MCF7 and HFF cell lines were tested. Treatment with either CuFe2O4/mesosilicalite/curcumin/cisplatin or CuFe2O4/MCM-41/curcumin/cisplatin nanocomposites resulted in a significant reduction in cell viability that was greater than treatment with either curcumin or cisplatin. Furthermore, cells treated with our two nanocomposites had a higher number of c-Caspase 3-positive cells than the untreated control. These results suggest that the reduction in cell viability is triggered by activating the apoptotic signaling pathway. The EC50 for CuFe2O4/mesosilicalite/curcumin/cisplatin was 81.23 µg/ml in MCF7; 47.55 µg/ml in HeLa; 48.96 µg/ml in HCT116 and 76.83 µg/ml in HFF. The EC50 for CuFe2O4/MCM-41/curcumin/cisplatin was 72.51 µg/ml in MCF7; 58.6 µg/ml in HeLa; 62.58 µg/ml in HCT116; and 154.2 µg/ml in HFF. Our results show that both nanocomposites can be further explored as potential novel chemotherapeutic options. CuFe2O4/MCM-41/curcumin/cisplatin nanocomposites offer the added advantage of a wider gap in cytotoxicity between cancerous and non-cancerous cell lines.

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The data obtained in this study are provided in this manuscript and in supplementary file. Further additional data can be provided by corresponding authors upon request.

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Acknowledgements

Rabindran Jermy would like to acknowledge the advanced state of art facilities provided by Institute for Research and Medical Consultations (IRMC), Imam Abdulrahman Bin Faisal University, Dammam, Saudi Arabia. The authors would like to acknowledge Ms. Dorothy Joy H. Huelar for her assistance in the in vitro studies. Technical assistance of Ms. Janaica Yu Logan is acknowledged.

Funding

Rabindran Jermy would like to acknowledge the funding from Deanship of Scientific Research (DSR), Imam Abdulrahman Bin Faisal University with grant number 2018-025-IRMC.

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Conception and design: BRJ, VR. Data acquisition: BRJ, DA. Investigation, analysis and interpretation: DA, WAA, VR. Software, microscope and validation: RMP, HD, investigation: NA, AAA, TMA. Drafting article: VR, DA, BRJ. Final approval of article: BRJ, VR. All authors read and approved the final manuscript.

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Correspondence to B. Rabindran Jermy or Vijaya Ravinayagam.

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Supplementary Information

Additional file 1: Figure S1.

X-ray diffraction pattern of CuFe2O4 impregnated on different structured mesoporous materials. Figure S2. Nitrogen adsorption-desorption isotherm of CuFe2O4 impregnated on different structured mesoporous materials (a) CuFe2O4/Q-10 silica, (b) CuFe2O4/SBA-16, (c) CuFe2O4/Hydrophobic silica, (d) CuFe2O4/MesoZSM-5, (e) CuFe2O4/Mesobeta. Figure S3. Pore size distributions of CuFe2O4 impregnated on different structured mesoporous materials (a) CuFe2O4/Q-10 silica, (b) CuFe2O4/SBA-16, (c) CuFe2O4/Hydrophobic silica, (d) CuFe2O4/MesoZSM-5, (e) CuFe2O4/Mesobeta. Figure S4. Vibrating sample magnetometer analysis of (a) CuFe2O4/MCM-41 and (b) CuFe2O4/Mesosilicalite. Table S1. Textural characteristics of 30% CuFe2O4 impregnated on different mesostructured materials. Table S2. Descriptive statistics of curcumin release over different CuFe2O4/structured silica based nanoformulations. Table S3. Curcumin release over different CuFe2O4/structured silica based nanoformulations (One way ANOVA). Table S4. Post hoc tests for mean difference in curcumin release among different CuFe2O4/structured silica based nanoformulations. Table S5. Pearson correlation of curcumin release over different CuFe2O4/structured silica based nanoformulations. Table S6. Statistical analysis of the cell viability assay performed on (A) MCF7, (B) HeLa, (C) HCT116, and (D) HFF cell lines. Analysis of drug treated was performed compared to cell control (without treatment) using 2way ANOVA with Dunnett’s post hoc test. *p < 0.05; **p < 0.01; ***p < 0.001; ****p < 0.0001; ns not significant.

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Jermy, B.R., Almohazey, D., Alamoudi, W.A. et al. Synergistic action of curcumin and cisplatin on spinel ferrite/hierarchical MCM-41 nanocomposite against MCF-7, HeLa and HCT 116 cancer cell line. Cancer Nano 12, 33 (2021). https://doi.org/10.1186/s12645-021-00106-7

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Keywords

  • Multifunctional
  • Curcumin
  • Coating, cisplatin
  • MCM-41
  • Nanotherapeutics