Magnetic Mesocellular Foam Functionalized by

Magnetic Mesocellular Foam Functionalized by Curcumin for Potential Multifunctional Therapeutics B. Rabindran Jermy, V. Ravinayagam, S. Akhtar, W. A. Alamoudi, Nada A. Alhamed & A. Baykal Journal of Superconductivity and Novel Magnetism Incorporating Novel Magnetism ISSN 1557-1939 J Supercond Nov Magn DOI 10.1007/s10948-018-4921-3

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ORIGINAL PAPER

Magnetic Mesocellular Foam Functionalized by Curcumin for Potential Multifunctional Therapeutics B. Rabindran Jermy 1 & V. Ravinayagam 2 & S. Akhtar 3 & W. A. Alamoudi 4 & Nada A. Alhamed 5 & A. Baykal 1 Received: 9 August 2018 / Accepted: 22 October 2018 # Springer Science+Business Media, LLC, part of Springer Nature 2018

Abstract The study investigates curcumin/SPIONs hybridized mesocellular foam type silica for potential dual purpose of drug delivery (curcumin) and magnetic resonance imaging. Magnetization capability and curcumin release was assessed for different structured silica such as spherical silica (Q-10), Si-MCM-41, Si-SBA-16, mesocellular foam (MSU-Foam), Si-KIT-6, ULPFDU-12, and silicalite. The phase, textural, and morphological variation was systematically scrutinized using various physico-chemical techniques. Ten weight percent SPIONs loading was found to generate magnetically active SPIONs in the following order: Q-10 (1.44 emu/g) > SBA-16 (0.80 emu/g) > MSU-Foam (0.24 emu/g) > Si-MCM-41 (0.07 emu/g) > Si-KIT-6 (0.07 emu/g) > silicalite (0.08 emu/g), respectively. The iron oxide dispersion, specific surface area, and porosity play a major role in various structured silicas. MSU-Foam with wormhole structure showed highest specific surface area occupation of SPIONs (73%). The presence of interconnected porosity of foam tends to generate external agglomeration of SPIONs (7–18 nm) at the pore surface contributing to expansion of pore sizes from 16.4 to 40.2 nm. The SPIONs over spherical micron-sized silica Q-10 showed the formation of large nanoclusters (10–25 nm). Thirty to 390 μg/ml of curcumin was loaded over silica and SPIONs/silica structured hybrid, and drug release was studied at pH 5.6 for 72 h. SPIONs/MSU-Foam with less magnetization showed the highest cumulative curcumin release (53.2%), while Q-10 spherical silica with high magnetization property showed less cumulative release of curcumin (12%). Keywords Antioxidant . Curcumin . SPIONs . Silica . Drug delivery . Imaging

1 Introduction Antioxidants are known to act against cancers through free radical scavenging abilities. Curcumin is an important known

antioxidant built with polyphenol structure. The beneficial effect of curcumin is limited by the poor bioavailability, structural instability in cell culture (in vitro), and animal experimental study (in vivo). Recently, image-guided drug delivery systems are

Electronic supplementary material The online version of this article (https://doi.org/10.1007/s10948-018-4921-3) contains supplementary material, which is available to authorized users. * B. Rabindran Jermy [email protected]

3

Department of Biophysics Research, Institute for Research and Medical Consultations (IRMC), Imam Abdulrahman Bin Faisal University (IAU), P.O. Box 1982, Dammam 31441, Saudi Arabia

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Department of Neuroscience Research, College of Clinical Pharmacy, Imam Abdulrahman Bin Faisal University, P.O. Box 1982, Dammam 31441, Saudi Arabia

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College of Clinical Pharmacy, Imam Abdulrahman Bin Faisal University, P.O. Box 1982, Dammam 31441, Saudi Arabia

* A. Baykal [email protected] 1

Department of Nano-Medicine Research, Institute for Research and Medical Consultations (IRMC), Imam Abdulrahman Bin Faisal University (IAU), P.O. Box 1982, Dammam 31441, Saudi Arabia

2

Deanship of Scientific Research & Department of Nano-Medicine Research, Institute for Research and Medical Consultations (IRMC), Imam Abdulrahman Bin Faisal University (IAU), P.O. Box 1982, Dammam 31441, Saudi Arabia

Author's personal copy J Supercond Nov Magn

prospected to improve the therapeutic efficiency of such antioxidants. Particularly, nanosilica was the most widely researched support in biomedical application such as targeted oriented drug therapy, diagnostic purpose, stem cell, and bioengineering. The provision to functionalization has led the applications to expand beyond catalysis in fine chemical synthesis to magnetic, optical, battery, and dielectric applications. Encapsulation/loading of insoluble antioxidant such as curcumin over polymeric composites, liposomes, and structured silicas has been shown to improve the biocompatibility, stability, and biodegradability [1]. The drug carrier tends to act as shielding matrices, withheld nonspecific interactions with other biological molecules, and improve the solubility by transforming crystalline nature of curcumin into amorphous state. Our recent study has shown that structured silica such as SBA-16 has great capability to carry acidic type antioxidant such as gallic acid [2]. Though curcumin encapsulated surfactant complexes, hydrogels, and liposomes are reported, their preparation is rather complex for large-scale implementation and offers reduced stability in biological environment [3]. On the other hand, the structured nanosilica particles are rigid due to formidable inorganic framework. Curcumin encapsulated into MCM-41-type mesoporous silica has shown to improve the solubility, and enhance drug release and high cellular delivery [4]. Curcumin functionalized surfactant (cetyltrimethylammonium bromide) over silica-coated nanoparticle is reported for pH responsive in vitro study. However, rapid disintegration of curcumin and cytotoxicity towards normal and cancer cell line was observed at in vitro release pH condition (7.70) [5]. Hexagonal and cubic structured mesoporous silicas have been reported to function as drug delivery agent through in vitro [6] and in vivo studies [7]. In order to reduce the burst release and improve the bioavailability, chitosan-coated curcumin over solid lipid nanoformulation was reported using hot high-speed homogenization and sonication technique [8]. For pH stimuli release of curcumin, xanthan gum-based nanomaterial coated with polyacrylamide-based polymer was reported. The modification of such nanoformulation involves solvent evaporation crosslinking technique under high-speed homogenization condition [9]. However, for effective nanoformulation development, solvent utilization in solution based multi-step protocols, cost, and mode of transport technology has to be taken into consideration. Recent study shows that so far, only 5% of drug reaches the tumors (bioavailability) with nanocarrier. This is equal to the conventional drug (without nanocarrier) efficiency. This is the disadvantage considering the expensive mode of drug delivery compared to conventional drugs. Therefore, due consideration has to be given to the multifunctional uses rather than building prodrug over single nanocarrier support. Recently, the combination of therapeutic compounds with tumor imaging agents was reported to improve the treatment efficacy and limit side effects due to onsite drug delivery [10]. The role of magnetic nanosilica drug carrier is to respond to external magnetic field and thereby assist bioimaging,

magnetic targeting agent to carry drug and delivery. The usage of super paramagnetic iron oxide nanoparticles has more advantages due to FDA-approved particles for clinical use and shows intrinsic magnetic characteristics. In addition, the iron oxide surface nature was flexible for modification involving drug molecules. The magnetic nanosilicas have already been shown to have the potential to develop cancer-based drug on commercial basis. The material has shown positive success in animal study and in clinical trials, phase I/II [11]. Smart polymers were also reported which responds to the external magnetic field as well to pH and temperature changes [12]. Magnetic Fe3O4-based mesoporous silica such as SBA-15 (p6mm) and fiber type of silica was also reported to be effective for drug delivery and adsorption [13]. The release ability of doxorubicin over thermal stimuli copolymer-coated magnetic mesosilica (MMSN@P(NIPAM-co-MAA) with Fe3O4 particle size of about 255 nm was reported to respond well to hyperthermia and showed pH-responsive drug release [14]. Dual imaging (fluorescence-magnetic) diagnostic tool with amine functionalized iron oxide/SBA-16 nanocomposite was found to be a suitable carrier for large protein molecules including antibodies [15]. Curcumin loaded in the SPIONs and coated hyaluronic acid (fluorescent dye) was found to be effective for MRI as well as fluorescent imaging studies [16]. However, designing of magnetic and drug loading in a single entity is cumbersome and challenging considering the SPIONs distributions, toxicity, and biocompatibility. The present study investigates a suitable SPIONs/structured silica nanoformulation to engineer the future multifunctional magnetic silica with deliverable curcumin drug.

2 Experimental The silica specified as CARiACT Q-10 with pore diameter of 18.6 nm was purchased from Fuji Silysia Chemical Ltd., while foam type mesosilica termed as (MSU-F) was obtained from Aldrich. The detailed synthesis procedure for the support SiMCM-41, Si-SBA-16, Si-KIT-6, ULPFDU-12, and silicalite was provided in our earlier published article [2]. For hexagonal SiMCM-41 preparation, sodium meta silicate (21.2 g) was mixed with cationic polymer cetyltrimethylammonium ammonium bromide (9.1 g) in 80 ml of aqueous solution. After vigorous stirring overnight, the alkaline pH of solution mixture was adjusted to 9, hydrothermally treated (140 °C) overnight, filtered, and dried at 120 C for 4 h. The polymeric template was removed by calcination at 550 °C for 6 h at 5 °C/min heating rate. For Si-SBA-16 synthesis, hydrophilic non-ionic template F127 (6 g) was dissolved in acidic media (pH 2), in the presence of tetraethylorthosilicate (29 g) and cosolvent n-butanol (19.2 g). The solution mixture was vigorously stirred in Teflon bottle overnight and then hydrothermally treated for 24 h. The


white precipitate solution was filtered, washed with plenty of de-ionized water, dried at 100 °C overnight, and then calcined at 550 °C for 6 h. For Si-KIT-6, triblock copolymer template Pluronic P123 (12 g) was used in similar acidic media to that of SiSBA-16. The cosolvent n-butanol (12 g) and tetraethylorthosilicate (25.9 g) were then added, and similar protocol for stirring, hydrothermal heating, and calcination to that of SiSBA-16 was followed. For Ultralarge pore FDU-12, pluronic F127 (5 g) was dissolved in 2 M HCl solution (300 ml). After stirring for 1 h, KCl (12.5 g) and xylenes (18.5 g) were added to the above solution mixture and stirred for 24 h. After dissolution, tetraethylorthosilicate (22.5 g) was added and continued stirring for 24 h. The solution was then hydrothermally aged at 100 °C for 24 h, centrifuged, dried at 100 °C overnight, and calcined at 550 °C for 6 h. For silicalite, 11 g of Ludox-AS40 (silica source) was mixed with tetrapropyl ammonium hydroxide (8 g) through vigorous stirring in the presence of alkaline solution. The solution mixture was stirred for 1 h and then hydrothermally heated at 160 °C for 72 h. The solution was then centrifuged, dried at 120 °C for 4 h, and calcined at 550 °C for 6 h.

2.1 SPIONs Loading over Nanocarriers Through Enforced Adsorption Technique Ten weight percent SPIONs loading was established by adding 0.7235 g of iron nitrate nonahydrate in 80 ml of water, followed by stirring until dissolution. Then, 1.0 g of nanocarrier was subsequently added and stirred for 24 h at room temperature. After stirring, the material was dried without filtration at 120 °C for 3 h and the recovered material was further calcined at 500 °C for 2 h.

2.2 Curcumin Adsorption Through Equilibrium Adsorption Technique Curcumin adsorption over different nanocarriers and Feimpregnated nanocarriers was carried out through equilibrium adsorption technique. One gram (1000 mg) of nanocarrier was taken and added in the solution containing 200–1500 μg/ml of curcumin in 10% methanol in phosphate-buffered saline (PBS) mixture and stirred for 24 h. Then, the solution was filtered and dried at room temperature. The percentage adsorption was calculated based on the equation:

Percentage of curcumin adsorptionð%Þ ¼ ðInitial curcumin conc−Final curcumin concÞ =Initial curcumin conc 100

The final curcumin concentration was calculated based on the equation: ¼ ðFinal absorbance value Initial curcumin concÞ =Initial absorbance value The study showed the final concentration of adsorption to be 30–390 μg/ml of curcumin.

2.3 Curcumin Release Study The release study was carried out in PBS solution (pH 5.6) at 37 °C. Specifically, for drug release study, 30 mg of (390 μg/ml curcumin/nanocarrier) sample was taken and dissolved in 50 ml of PBS (pH 5) solution in a conical flask. Then, the temperature was raised to 37 °C and gradually stirred at 50 rpm for the following drug release study. At certain period, 10 ml of solution was withdrawn and replaced with equal volume of fresh PBS solution. Then, the release amount was calculated based on the calibration curve at specified wavelength of 428 nm.

2.4 Characterization The crystalline and amorphous phase of curcumin and SPIONs/structured silica nano was analyzed using Rigaku MiniFlex 600. The textural variations before and after SPIONs loading were measured using an ASAP-2020 plus, accelerated surface area, and porosimetry, Micromeritics, Norcross, GA, USA. The magnetic properties of nanoformulations were analyzed using VSM (LDJ Electronics Inc., Model 9600). The coordination nature of SPIONs over structured silica was measured using diffuse r e f l e c t a n c e s p e c t r o s c o p y ( V- 7 5 0 , J A S C O ) . T h e functionalization between curcumin and porous network of silica was using FT-IR with UATR accessory (PerkinElmer). The average size and the surface morphology of samples were measured using scanning electron microscope (FE-SEM, TESCAN FERA3) and transmission electron microscope (TEM, FEI, Morgagni, Czech Republic).

3 Results and Discussion The X-ray diffraction pattern of curcumin adsorption over different 10 wt% SPIONs/structured silica nanoformulations (curcumin, Q-10 silica, Si-MCM-41, Si-SBA-16, Mesocellular foam, Si-KIT-6, ULPFDU-12, and silicalite) is shown in Fig. 1(a–h). In the case of pure curcumin, various diffraction peaks over the 2-theta range 15–30° are observed indicating characteristic crystalline phase of curcumin (Fig. 1(a)) [9]. Except Q-10 silica, curcumin loading over different SPIONs/ structured silica nanoformulations showed no such crystalline


peaks of curcumin indicating an effective amorphous transition due to intermolecular interaction with porous structured silica matrix. Earlier literature shows that such transformation of crystalline drug to non-crystalline (amorphous) form is attributed to the confinement of drug inside the geometrically constructed nanopores [17]. Cubic cage nanopores of SBA-16 are reported to be effective for such crystalline transformation of drug to nanoform. In the case of carvedilol molecules (CAR), the presence of cage type of 3D nanopores of SBA-16 was reported to thwart the transformation of the CAR molecules into crystalline state by preventing the extension of the crystal lattice inside the 3D nanopores [18]. However, the existence of curcumin peaks over SPIONs/Q-10 nanoformulation clearly indicates the lack of such interactions between curcumin and micron-sized spherical silica (Fig. 1(b)). Over Q-10, the presence of nanosized Fe3O4 species was observed at 2 theta value of 35.4°. In the case of MCM-41, SiSBA-16, MSU-Foam, and SiKIT-6 (Fig. 1(c–f)), the presence of broad peaks with variable intensity corresponding to α-Fe2O4 (33.1°), γ-Fe2O4, and Fe3O4 species (30°, 35.3°, 53.4°, 56.9°, 62.5°) was observed (Fig. 1(c–h)). ULPFDU-12 showed the crystalline deposition of SPIONs (Fig. 1(g)). Over active support MSU-Foam, the presence of weak diffraction peaks of SPIONs corresponds to Fe3O4 of crystalline cubic structure (magnetite). Silicalite showed characteristic diffraction peaks of MFI between 2 theta range 10–70°, which superimpose on iron oxide peaks (Fig. 1(h)). Overall, the diffraction patterns of different nanoformulations show that surface modification of Fe3O4 particles tends to change depending on the nature of structured silica. The textural characteristic changes in the absence and presence of SPIONs were evaluated using N2 adsorption isotherm -Fe2O4 Fe3O4/ -Fe2O4

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2 Theta Fig. 1 X-ray diffraction pattern of curcumin/10 wt% SPIONs loaded over different structured nanocarriers: (a) curcumin, (b) Q-10 silica, (c) SiMCM-41, (d) Si-SBA-16, (e) MSU-Foam, (f) Si-KIT-6, (g) ULPFDU12, and (h) silicalite

technique (Fig. 2). The BET surface area and pore size distributions of different nanocarriers are presented in Table 1. In the case of parent nanocarrier, typical isotherm patterns for each structured silica were observed. MSU-Foam exhibited type IV isotherm due to cellular foam structure. In the case of Si-SBA-16 and Si-KIT-6, H1-type isotherm appears indicating typical cubic cage-type pores. The Si-MCM-41 exhibited reversible type IV isotherm pattern with uniform pore size distribution. In the case of Q-10 silica, after impregnation, non-significant changes were observed with respect to both specific (258 m2/g) and cumulative surface area (274 m2/g), while appreciable pore filling of about 16% (1.22 to 1.02 cm3/ g) along with pore diameter decreases from 18.6 to 15.8 nm was observed (Table 1). Similarly, the surface area of SPIONs/ Si-MCM-41 slightly increases from 923 to 951 m2/g, while 11.2% decrease in cumulative surface area and 19.3% decrease in the pore volume were observed. The pore diameter only slightly varied from 3.1 to 3 nm after SPIONs deposition. In the case of SPIONs/Q10, surface area deposition remains negligibly small, whereas pore volume and pore diameter variation occur significantly. In the case of SPIONs/Si-MCM-41, cumulative surface area and pore volume decrease, while pore diameter remains unaffected. This shows that Fe impregnation over Q10 fills the pore volume and eventually affects pore diameter. In the case of 3D cubic SBA-16, a significant decrease in the textural characteristics was observed. Specifically, a decrease of specific surface area from 980 to 327 m2/g, and cumulative surface area from 591 to 194 m2/g, which is about 67% of SPIONs occupation, was observed after iron oxide impregnation. The cumulative pore volume showed a similar decrease (32%) compared to parent SiSBA16. Reversely, the average pore diameter increases from 3.3 to 4.0 nm. The analysis shows that both surface area and pore volume are being affected and being filled in the 3D pore structure, while enlargement of pore size shows deposition of Fe3O4 around the pore walls that helps to expand the pore size. In the case of MSU-Foam, reversely, a significant change was observed with isotherm and capillary condensation, while pore volume remains mostly unchanged. The pore diameter showed significant variation. The texture of foam type of silica before iron oxide impregnation was of mesoporous type with high surface area of 554 m2/g, with large pore volume of 2.27 cc/g. The average pore size diameter was of 16 nm before impregnation. The isotherm pattern of mesocellular foam (parent form) and after iron oxide impregnation are shown in Fig. 2. The results are presented in Table 1. Before impregnation, the foam showed characteristic type IV isotherm pattern with H1 hysteresis loop indicating welldistributed cells along with windows [19]. After impregnation, a significant textural change with respect to surface area and pore volume was observed. A shift in capillary filling P/P0 range is observed. Specifically, an occupation of about

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observed. In the case of pore shape retainment, 57.3% of pore filling was observed. The pore diameter of cellular foam increases from 16.4 to 40.2 nm. Significantly, the pore diameter

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Q-10 (1D) 10 wt% SPIONs/Q-10 Si-MCM-41 (2D) 10 wt% SPIONs Si-MCM-41 Si-SBA-16 (3D) 10 wt% SPIONs/Si-SBA-16 MSU-Foam (3D) 10 wt% SPIONs/MSU-Foam ULPFDU-12 (3D) 10 wt% SPIONs/ULPFDU-12 Si-KIT-6 (3D) 10 wt% SPIONs/Si-KIT-6

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showed significant alteration after iron oxide impregnation. Compared to parent MSU, the pore diameter increases from 16.4 to 40.2 nm. Such pattern shows external agglomeration of SPIONs at the pore surface contributing to expansion in the pore sizes. The cage type of mesoporous with Fm3m structure (ULPFDU-12) showed typical broad hysteresis indicating interrelated large pores with small-sized window type of pores. In this type of material, an abrupt loss in the textural property was observed. With 10 wt% SPIONs impregnation, about 91% surface occupation was observed, where decrease in surface area occurs from 270 to 9 m2/g. The pore volume reduced significantly of about 94% from 0.33 to 0.02 cc/g. With respect to pore size distribution, like cellular foam type, pore size expansion occurred with impregnation from 4.7 to 13.1 cc/g. The cubic structure of Si-KIT-6 with Ia3d symmetry showed 77% of textural filling with 676 m2/g specific surface area and 71% with 616 m2/g cumulative surface area occupation with SPIONs impregnation. Unlike Si-SBA-16, the pore volume of KIT-6 was enough to accommodate the impregnated iron oxide particles. As observed with Si-SBA-16 and MSU-Foam type of silicas, the external pore agglomeration was not observed. The impregnation led to the pore volume occupation of 78% that reduces from 1.23 to 0.96 cc/g. In addition, KIT-6 pore diameter only marginally reduces from 5.7 to 5.6 nm. This study shows that Si-MCM-41 showed more pore filling, followed by cubic type Si-SBA-16, while Q-10 and MSU-Foam type showed external deposition of SPIONs, while pore volume remains largely unfilled. Figure 3 shows the magnetic property of 10 wt% SPIONs loaded over different nanocarrier: Q-10, Si-MCM-41, SiSBA-16, MSU-foam, Si-KIT-6, and Q-10, respectively.

Among the different nanocarriers, magnetically active support order was determined as SPIONs/Q-10 > SPIONs/SBA-16 > SPIONs/MSU-Foam > SPIONs/Si-MCM-41 > SPIONs/ SiKIT-6. The study showed that Q-10 followed by Si-SBA-16 and MSU-Foam was active, while SiMCM-41 and silicalite were not active. In the case of SPIONs/Si-KIT-6, though the pore structure was like that of Si-SBA-16, it did not show positive magnetization for the dual application of magnetically driven drug delivery approach. The presence of narrow hysteresis loop showed the superparamagnetic behavior of SPIONs/Q-10, SPIONs/Si-SBA-16, and SPIONs/MSUFoam, respectively. It has been reported that such paramagnetic Fe3+ ions are formed through incorporation at the pore walls of support [20]. In the case of silicalite, despite large iron oxide particle deposition, it showed weaker magnetization. Therefore, the study showed that three samples namely SPIONs/Q-10, SPIONs/Si-SBA-16, and SPIONs/MSUFoam have the reasonable intrinsic magnetization capability that can be utilized in addition to drug delivery. Figure 4 shows the Drs-UV-visible spectra for SPIONs loaded on structured silica samples. The technique is used to characterize the coordination environment of Fe3+ species. The analysis shows that despite loading similar amount of SPIONs, the coordinative dispersion of nanoparticle varies depending on the structural integrity of silicas such as spherical Q-10, hexagonal SiMCM-41, cubic type of pores of Si-SBA-16, Si-KIT-6, ULPFDU-12, MSU-Foam, and silicalite. The presence of three types of bands with varying degree of intensity at about 250 nm, 370 nm, and 500 nm was observed for analyzed samples. The characteristic absorption band between 200 and 300 nm shows the dispersed Fe3+ cation in tetrahedral coordination due to dπpπ charge transfer (Fe-O). The band appearance between 300 and 450 nm shows the formation of small oligomeric nanocluster, while Fe3O4 larger clusters are indicated through the presence of broad band between 450 and 600 nm [21]. In 1

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In case of SPIONs/ULPFDU-12, the presence of broad peaks shows characteristics of variable SPIONs deposition occurs at the external surface area (Fig. 4(f)). However, structural irregularity with respect to specific surface area and pore volume (Table 1) shows the deteriorating impact of SPIONs impregnation inside the mesopores leading to disintegration of overall structural parameters (Table 1). The SPIONs over silicalite (MFI structure) showed no strong absorption bands corresponding to tetrahedral or octahedral coordination (Fig. 4(g)). The FT-IR spectra of parent silica (Q-10) and SPIONs/ silica (Q-10) sample showed no significant details between 400 and 1800/cm (Fig. 5(a, b)). Curcumin showed a variety of vibrational peaks due to the presence of different functional groups [24]. The vibration of free hydroxyl groups was observed with distinct peak at 3507/cm, while carbonyl and carbon-carbon double bond were observed at 1625, 1603, and 1505/cm, respectively. Methylene (CH2) bending vibrations and several peaks corresponding to –C–O–C– symmetric and asymmetric vibrations are observed between 1000 and 1460/cm (Fig. 5(c)). A distinct peak at 962/cm of curcumin corresponds to the enolic hydroxyl group (>C=C (OH)–). In the case of curcumin/Q-10 silica, a significant reduction occurs corresponding to the peaks of curcumin (Fig. 5(d)). In the case of curcumin/SPIONs/silica hybrid composite, the peak corresponding to such in-plane bending of OH group of enol decreases considerably over MSU-Foam than Q-10 silica and SiSBA-16 indicating effective interaction between wormhole porous structure of foam and curcumin through keto enol functional group (Fig. 5(e–g)). The observed functionalization trend is in line with Fe 3 O 4 nanoparticle for curcumin functionalization. In case of curcumin, the presence of distinct peak at 3504/cm shows the hydroxyl functional group (figure not shown). Compared to Q-10 and SiSBA-16, the peak corresponding to carbon-carbon double bond and carbonyl group (a) (b)

-C-O-C- (1000-1300)

Transmit ta nce

the case of Q-10 silica sample, in addition to tetrahedral coordination, a broad peak appears and extends up to 600 nm (Fig. 4(a)). Particularly, an intense peak absorption band is observed at about 520 nm that shows formation of large nanoclusters. Therefore, large microsphere silicas of Q-10 silica have been shown to assist formation of octahedral species due to extra framework iron oxide species than isolated tetrahedral iron oxide species. The formation of such octahedral coordinated species is reported to occur due to nanoclusters [22]. In the case of hexagonal pore channels Si-MCM-41 containing SPIONs, the presence of intense tetrahedral species at about 280 nm shows that fine dispersion of iron oxides incorporated into the framework through Si-O-Fe linkage (Fig. 4(b)) [23]. The formation of small nanoclusters to smaller extent was also observed with less intense absorption band at 460 nm. Overall, SPIONs/Si-MCM-41 shows formation of finely dispersed SPIONs nanoparticles. Such decreased absorption at longer wavelength shows the systematic deposition and stabilization of SPIONs inside the mesopores leading to reduced mobility of such nanospecies after calcination [21]. In case of SPIONs/SiSBA-16, in addition to tetrahedral species, a significant proportional of extra framework species occurs at about 530 nm (Fig. 4(c)). The less intense tetrahedral absorption band between 200 and 300 nm shows that distribution of particles is not fine compared to that of Si-MCM-41 support but rather agglomerated type like that of Q-10 silica. The main reason for such agglomeration over cubic Im3m pores of SBA16 could be attributed to restricted pore entrance size that are relatively smaller than primary mesopore, thus limiting the intraparticle mass transfer. SPIONs/mesocellular foam showed three types of absorption bands (Fig. 4(d)). The foam-like pore structure of mesocellular silica induced an absorption peak at 250 nm indicating the presence of tetrahedral SPIONs. Comparatively, an intense absorption peak at 370 nm for foam silica showed the presence of small nanoclusters to larger extent, while visible absorption peak at 520 nm shows existence of some large nanoclusters. Overall, the presence of small-sized agglomerated octahedral species was found to be higher than Si-MCM41, while large type of nanoclusters is lesser than that found in SBA-16 cage type of pores and spherical silica. SPIONs/ SiKIT-6 with cubic Ia3d pores showed a prominent isolated tetrahedral and small nanocluster (Fig. 4(e)) compared to cage type of Im3m structure, which showed external agglomerated octahedral species. Importantly, the large pore volume (1.23 cc/g) of Ia3d cage type of pores of Si-KIT-6 is expected to show the difference with respect to pore filling ability compared to Si-SBA-16 counterpart with Im3m structure (0.49 cc/ g) (Table 1). In addition, the presence of large pore size distributions of Si-KIT-6 showed a non-significant change in pore diameter from 5.7 to 5.6 nm, while Si-SBA-16 showed an increase in pore size from 3.3 to 4.0 nm indicating pore expanding due to SPIONs around the thick pore walls of SiSBA-16.

(c) (d)

1025 962 C=C (OH)-

1455-CH 1625 1603 1505 2 C=O C=C C=C

(e) (f) (g)

1028

1800

1600

1400

1200

1000

800

600

400

Wave number (cm-1 )

Fig. 5 FTIR spectra of (a) Q-10 silica, (b) SPIONs/Q-10, (c) curcumin, (d) curcumin/Q-10, (e) curcumin/SPIONs/Q-10, (f) curcumin/SPIONs/ mesocellular foam, and (g) curcumin/SPIONs/SiSBA-16, respectively


at 1603/cm over MSU-Foam reduced significantly indicating effective interaction of curcumin with SPIONs hybridized Foam. In addition, surface functionalization of curcumin is assigned by the peak at 1023/cm for C–O–C stretching of C6H5–O–CH3 group [25]. In the case of MSU-Foam and SiSBA-16, the curcumin functionalization that leads to broadening of such peak indicates effective functionalization at the structured nanopores (Fig. 5(f, g)). Figures 6 and 7 show the SEM micrographs based on comparative surface morphological features of 10 wt% SPIONs loaded over magnetically active nanocarrier: (a) Q-10 silica, (b) SPIONs/Q-10, (c) SiSBA-16, (d) SPIONs/SiSBA-16, (e) mesocellular foam, and (f) SPIONs/mesocellular foam, respectively. The magnification was set to an appropriate value in order to capture the representative features of the specimens in each case. The Q10 silica shows the presence of spherical shaped microspheres with estimated average size of 100-μm sizes. In the case of SPIONs/Q-10, the regularity of the spheres was affected by non-crystalline Fe3O4 loaded through enforced impregnation technique followed by calcination (Fig. 6(a, b)). The deposition of nanoclusters was clearly seen at higher scale bar 50 μm compared to parent Q-10 silica (Fig. 7(a, b)). A similar irregularly shaped microsphere morphology but with less average sized spheres (~ 4 μm) was observed in the case of SiSBA-16 and SPIONs/SiSBA-16 (Fig. 6(c, d)). In the case of MSU-Foam, the lower scale bar

shows the presence of irregular agglomerated silica forms that are observed (Fig. 7(c, d)). Compared to MSU-Foam (Fig. 6(e, f)), SPIONs/mesocellular foam clearly shows the porous morphological characteristics changes with agglomerated nanosphere structures at lower scale bar of 3 μm (Fig. 7(e, f)). The sample morphology and structure were further analyzed by TEM. Figure 8 shows the TEM images of 10 wt% SPIONs loaded over different nanocarrier (a) SiSBA-16, (b) Si-MCM-41, (c) Q-10 silica, (d) MSU-Foam, and (e) Silicate, respectively. The TEM analysis shows that SPIONs deposition is unique and depends on the support nature, where the dispersion and agglomeration vary based on the nanocarrier pore architecture. For instance, with three-dimensional cage type of SBA-16 pores, the presence of agglomerated forms of SPIONs as nanoclusters was observed along the pore channels (Fig. 8(a)), while in hexagonal Si-MCM-41 support, the SPIONs are finely dispersed (Fig. 8(b)). The cage type of porous layer of SBA-16 appears to be homogeneous with a constant thickness, and particles were found connected to the layers. In the case of microsphere Q10 silica, MSU-Foam and silicalite, external agglomeration of SPIONs with varying degree was observed (Fig. 8(c–e)). The average size measurement of SPIONs with standard deviation for each sample was calculated. There were two sets of nanoparticles that were observed in each case (Fig. 8(f)). The average size of the first set of particles was in the range of 3–21 nm and the second of

(a) Q-10 silica

(c) SiSBA-16

(e) Mesocellular Foam

(b) Fe/Q-10 silica

(d) Fe/SiSBA-16

(f) Fe/Mesocellular Foam

Fig. 6 SEM micrographs based on comparative surface morphological features of 10 wt% SPIONs loaded over magnetically active nanocarrier: (a) Q-10 silica, (b) SPIONs/Q-10, (c) SiSBA-16, (d) SPIONs/SiSBA-16, (e) mesocellular foam, and (f) SPIONs/mesocellular foam, respectively


13–58 nm. The order of SPIONs particle size was found to be in the following order: silicalite > Q-10 > Si-SBA-16 > MSUFoam > Si-MCM-41. Specifically, average SPIONs particle size of the Fe/Si-SBA-16 measured from TEM images was found to be 21.0 ± 1.1 and 9.0 ± 0.3. In support Si-MCM-41, finely dispersed SPIONs in the range of 3–13 nm was observed. Among the support, silicalite showed larger particles in the range of 21–58 nm followed by Q10 silica, which showed of 10–25 nm. Table 2 shows the adsorption capacity over absence and SPIONs loaded on different nanocarrier supports in solution containing 30 and 60 μg/ml of curcumin in 10% methanolphosphate-buffered saline (pH 7) mixture for 24 h. The adsorption was measured based on the Beer-Lambert’s law. The results show that loading of curcumin over SPIONs impregnated structured silica is not affected but rather improved slightly than parent nanocarriers. Thirty and 60 μg/ml of curcumin solution were treated with nanocarriers and SPIONs/structured silica hybrids. The study showed that curcumin adsorption of 89.1% and 90.0% occurs over SiSBA-16. In the case of SPIONs/SiSBA-16 nanoformulation, similar adsorption capacity with slight improvement occurs (94.1% and 97.3% for 30 and 60 μg/ml of curcumin solution). In the case of Q-10 silica, Si-MCM-41, and silicalite nanocarrier, similar trend of curcumin adsorption was observed (Table 2). The pictorial representation of curcumin

adsorption over SiSBA-16 nanocarrier and SPIONs/SiSBA16 was shown at different concentrations ranging from 30 to 390 μg/ml curcumin/nanocarrier in methanol-phosphatebuffered saline (PBS) mixture stirred for 24 h (Fig. S1). The equilibrium adsorption study shows that a systematic yellow color variation from light yellow to dark yellow occurs over nanocarrier SiSBA-16 (Fig. S1a–e), while the clear filtrate shows effective adsorption due to large available surface area and accommodatable pore volume (Table 1). In the case of SPIONs/SiSBA-16, similar effective adsorption was observed with increased curcumin loadings. The filtered solution showed no visible brown coloration indicating no apparent diffusion of adsorbed SPIONs nanoparticles from solid to solution phase. Notably, the solid sample coloration after ambient temperature drying showed transformation of color from dark brown to yellow-brown indicating increased curcumin adsorption (Fig. S1f–j). The curcumin release profile over nanocarriers and SPIONs loaded on different nanocarrier supports in PBS solution (pH 5) was studied for 72 h (Fig. 9). The study shows that curcumin delivery rate is affected by the pore architecture and SPIONs loading over the structured silica. Impressively, curcumin/SPIONs/MSU-Foam nanocomposite showed highest cumulative release (53% in 72 h) than curcumin/ MSU-Foam (43.6% for 72 h). The release profile shows that the steadiness of curcumin in foam is rather boosted and is not

(a) Q-10 silica

(c) SiSBA-16

(e) Mesocellular Foam

(b) Fe/Q-10 silica

(d) Fe/SiSBA-16

(f) Fe/Mesocellular Foam

Fig. 7 Magnified SEM micrographs based on comparative surface morphological features of 10 wt% SPIONs loaded over magnetically active nanocarrier: (a) Q-10 silica, (b) SPIONs/Q-10, (c) SiSBA-16, (d) SPIONs/SiSBA-16, (e) mesocellular foam, and (f) SPIONs/mesocellular foam


affected by iron oxide impregnation. The relative ease of curcumin release with respect to SPIONs/MSU-Foam nanocomposite shows that presence of pores with largest average pore size (16.4 nm) distribution can accommodate SPIONs well and provide release access for curcumin through flexible hydrogen bonding cleavage. Followingly, SPIONs/SBA-16 with cubic cage narrow pores (3.3 nm) showed lower but steady cumulative release comparable to parent SiSBA-16 over the period of 72 h (18.6%), which shows formation of diffusion restriction in cubic type mesopores for curcumin after addition of SPIONs. Followingly, SiMCM-41 with hexagonal pore structure showed highest curcumin release ability. SiMCM-41 without SPIONs showed high curcumin release of about 40% at 72 h. In this hexagonal nanotype system, an initial high burst release was observed. For instance, a high curcumin release of about 54% was observed between 15 and 30 min, which then stabilizes at about 40% through the course of study time. However, after SPIONs addition, about 20% Fig. 8 TEM images and average size of SPIONs. (a) SPIONs/SiSBA-16, (b) SPIONs/Si-MCM41, (c) SPIONs/Q-10, (d) SPIONs/MSU-foam, (e) SPIONs/ silicate, and (f) average size measurement with standard deviation for each specimen. Ten or more than ten particles were taken for size estimation and shown in the form of average size. Two range of particles were found; one small sized (blue bars) and second large sized (green bars). All scale bars correspond to 100 nm

decrease in the release ability was observed for SiMCM-41. Similarly, SPIONs loaded over SiKIT-6 showed a burst release of 42% for 15 min, which then steadied at about 22%. In the case of ULPFDU-12, an initial high release of curcumin was observed (37% at 15 min), which then significantly reduces to 12% during steady state. Such release trend was mainly attributed due to the dispersion of drug at the external surface and pore entrance of the 3D channels [13]. The large type of microspheres (Q10 and SPIONs/Q10), which exhibited high magnetization value, showed the lowest curcumin release of about 12.1% in 72 h. Overall, the drug release study shows that MSU-Foam can be a potential nanocarrier for dual functional therapeutics. The percentage cumulative release effect of curcumin versus magnetization (M/emu/g) of different mesostructured silicas at 72 h is shown in Scheme 1. Magnetization release effect was compared at a constant loading of 10 wt% SPIONs. The study shows an inverse relation between magnetization and curcumin

Author's personal copy J Supercond Nov Magn Table 2 Adsorption of curcumin over different structured nanocarriers and SPIONs/ structured silica hybrid in solution containing 30 and 60 μg/ml of curcumin in 10% methanolphosphate-buffered saline (pH 7) mixture for 24 h

Nanocarrier

Metal content (wt%)

Role

Initial concentration (μg/ml)

Final concentration (μg/ml)

Adsorption (%)

Q-10 SPIONs/Q-10

– 10

Single Dual

30 30

3.18 0.64

89.4 97.8

Q-10 SPIONs/Q-10

– 10

Single Dual

60 60

1.70 1.30

97.2 97.8

Si-SBA-16

–

Single

30

3.25

89.1

SPIONs/Si-SBA-16 Si-SBA-16

10 –

Dual Single

30 60

1.76 6.00

94.1 90.0

SPIONs/Si-SBA-16 Si-MCM-41

10 –

Dual Single

60 30

1.64 2.29

97.3 92.4

SPIONs/Si-MCM-41

10

Dual

30

1.75

94.2

Si-MCM-41 SPIONs/Si-MCM-41

– 10

Single Dual

60 60

2.20 2.18

96.3 96.4

Silicalite SPIONs/silicalite

– 10

Single Dual

30 30

6.80 3.25

78.0 89.2

Silicalite

–

Single

60

2.50

95.8

SPIONs/silicalite

10

Dual

60

2.00

96.6

The percentage adsorption was calculated based on the equation Percentage of curcumin adsorption (%) = (Initial curcumin conc − Final curcumin conc)/Initial curcumin conc × 100 The final curcumin concentration was calculated based on the equation = (Final absorbance value × Initial curcumin conc)/Initial absorbance value

70

70

Cumulative Release (%)

SPIONs/MSU-Foam

MSU-Foam

SiSBA-16

SPIONs/SiSBA-16

60

60

50

50

40

40

30

30

20

20

10

10

SPIONs/SiKIT-6

SiKIT-6

ULPFDU-12

SPIONs/ULPFDU-12

0

0 0

20

40

60

0

80

70

20

40

60

80

70 SPIONs/Q10 silica

Q10 silica

SiMCM-41

SPIONs/SiMCM-41

60

60

50

50

40

40

30

30

20

20

10

10

0

Silicalite

SPIONs/Silicalite

0 0

20

40

60

80

0

10

20

30

40

50

60

70

80

Time (h) Fig. 9 Curcumin release profile over absence and SPIONs loaded on different nanocarrier supports (powdered form): Q-10 silica, Si-SBA-16, mesocellular foam, Si-MCM-41, Si-KIT-6, ULPFDU-12, and silicalite in PBS solution (pH 5) for 72 h


Scheme 1 Curcumin cumulative release (%) versus magnetization (emu/g) over SPIONs/structured silicas

release. MSU-Foam with magnetization value of 0.24 emu/g showed the highest cumulative percentage release of curcumin (52.3%), while Q-10 spherical silica with high magnetization value of 1.44 emu/g showed the lowest curcumin release of 12.1% at 72 h. The X-ray diffraction analysis as shown in Fig. 1(a–h) shows that except silicalite, the loaded SPIONs and curcumin were effectively transformed into amorphous form. The textural characterization (Fig. 2 and Table 1) shows that impregnation of SPIONs over different structured silica has unique textural changes and affects the structural integrity of each silica. The spherical Q-10 silica and hexagonal Si-MCM41 showed very less textural changes with respect to specific and cumulative surface area over iron oxide impregnation. Both the type of silica showed marginal pore filling. Contrastingly, the cubic 3D Si-SBA-16 with Im3m symmetry and MSUFoam showed significant decreases with respect to surface area and as well as pore volume after impregnation. The average pore diameter measurement shows an enlargement after SPIONs impregnation, which signals external deposition of SPIONs around the pore walls, thereby assisting additional expanded pores. However, in the case of ULPFDU-12, a significant loss in the textural changes (both surface area and pore volume) occurs with SPIONs loadings (Table 1) signaling limited SPIONs loading ability for potential dual applications. The characterization of magnetic property shows that Q-10 microsphere silica showed high magnetic property, followed by SiSBA-16 and mesocellular foam (Fig. 3). The diffuse reflectance study shows that octahedral coordinated species corresponding to small and large nanoclusters are required to induce magnetic property (Fig. 4). A well-dispersed SPIONs in hexagonal structure and SPIONs present inside the mesopores of

SiKIT-6 tend to be magnetically non-active (Fig. 3). The FTIR spectroscopy analysis shows that curcumin functionalization over magnetically active support Q-10 silica and SiSBA-16 occurs majorly inside the structured nanopores, while mesocellular foam indicates the presence of certain proportion of curcumin at the external surface (Fig. 5). SEM (Figs. 6 and 7) and TEM images of SPIONs over different supports (Fig. 8) show the presence of different types of particle size distributions depending on the structural features of nanopores. DRSUV analysis shows the presence of extra framework species on Q-10, SBA-16 support. While SEM image shows the uniform characteristics between Q-10 and SBA-16, i.e., microspheres. Both supports have unique characteristics built through microspheres though with different particle sizes. The presence of such microspheres might eventually help the SPIONs to be deposited, as extra framework species outside the external surfaces and therefore becomes magnetically active. Reversely, in the case of Si-MCM-41 and Si-KIT-6, nanocarrier, the presence of nanopores with large pore volume (Table 1) helps the SPIONs to be dispersed well throughout the 1D pore channels (as evidenced from TEM image), leading to magnetically inactive species. The formation of finely dispersed SPIONs nanoparticles is confirmed through TEM analysis (Fig. 8), which showed that the nanoparticles are well dispersed in the range of 3–13 nm. In the case of SPIONs/silicalite, extremely largesized iron oxide particles are agglomerated but are not magnetically active, which shows that such support might form other form of Fe oxide that are not magnetically active. The equilibrium adsorption study shows a systematic color variation of SiSBA-16 from yellow to dark yellow, while brown to yellowish brown are observed over SPIONs/SiSBA-16 (Fig. S1).


MSU-Foam exhibited the highest cumulative release followed by SiMCM-41, SiKIT-6, SiSBA-16, ULPFDU-12, and Q-10, respectively (Fig. 9). The BET surface area analysis of foam type silica shows an increased pore size distribution from 16.4 to 40.2 nm after SPIONs impregnation (Fig. 2 and Table 1). DRS-UV analysis (Fig. 3) and FTIR (Fig. 4) confirm the presence of octahedral SPIONs as nanoclusters with effective functionalization between curcumin and wormhole structure of foam leading to high cumulative release (Scheme 1). Conversely, in the case of SiSBA-16, less cumulative release was observed with SPIONs addition. The textural characterization shows that gradual surface area and pore filling occurs over cubic cage pores without any abrupt pore size variations (Fig. 2 and Table 1). The DRS-UV and TEM analysis (Figs. 4 and 8) confirms the presence of octahedral species at the external surface as nanoclusters. However, sustained cumulative release trend over MSU-Foam shows pore diffusional release of curcumin. Such entrapped curcumin in interconnected foam type of pores are critical to diffuse through the pores for sustained release over the tested drug release period of 72 h. In the case of hexagonal Si-MCM-41, the presence of high surface area and pore size distribution can accommodate SPIONs well as dispersed fine oxides majorly in tetrahedral coordination (Fig. 4), which are supported by TEM analysis that shows visible fine dispersion of oxides in segregated form (3–13 nm) incorporated well into the framework rather than desired agglomeration. Subsequently, the curcumin drug release also reduced with SPIONs loading that compete with curcumin. In case of silicalite nanocarrier, an enhancement in the release trend was observed over SPIONs/silicalite (Fig. 9). The cubic cage type of SiKIT-6 (Ia3d symmetry) with the presence of large surface area and pore volume showed different accommodation phenomena. The iron oxides are deposited mostly inside the pore volume of SiKIT-6. The magnetization analysis showed the presence of non-magnetically active species over SiKIT-6 (Fig. 3). In line with Drs-UV spectroscopy, though the cluster formation occurs which are indicated by the octahedral coordinated SPIONs (Fig. 4), the absence of magnetic active species shows that the deposition might occur well inside the cubic pores of KIT-6. This indicates that despite close textural relation with SBA-16, the deposition of SPIONs at the internal or external surface determines the magnetization property, which in turn depends on the unique structural ordering of respective silica. The pore size distribution of Si-SBA-16 shows the presence of 3D cage type of mesopores in the range of 5 nm (Table 1) in Im3m symmetry. The generation of pores using pluronic F127 is reported to produce thicker pore walls due to long PO chains of F127, which might help the SPIONs to deposit significant proportional of extra framework species as nanoclusters. Overall, the study shows that nanocarrier textural features are very important to tune the iron oxide nanoparticle deposition, which in turn decide the dual response for imaging and therapeutics.

4 Conclusion The present study investigates the curcumin/SPIONs hybridized silica for potential multifunctional therapeutics. The magnetic Fe3O4 was deposited on nanostructures through enforced impregnation methodology followed by curcumin functionalization through equilibrium adsorption. SPIONs loading over different nanocarriers was found to generate magnetically active SPIONs in the following order: Q-10 (1.44 emu/g) > SBA-16 (0.80 emu/g) > MSU-Foam (0.24 emu/g) > Si-MCM-41 (0.07 emu/g) > Si-KIT-6 (0.07 emu/g) > silicalite (0.08 emu/g), respectively. Textural analysis showed that magnetically active species formation depends on the specific surface area occupation, and nanocluster formation. MSU-Foam with wormhole structure tends to generate nanoclusters (7–18 nm) around the pore walls (as evidenced from SEM and TEM analysis), effective functionalization of curcumin through keto enol functional group (FT-IR) leading to high cumulative curcumin release (53.2%). Hexagonal SiMCM-41 with hexagonal pore structure showed fine dispersion of iron oxides with non-significant magnetization. After iron oxide impregnation over SiMCM-41, about 20% decrease was observed in the curcumin release. Micronsized spherical silica Q-10 and SiSBA-16 showed super paramagnetic property but lower percentage cumulative curcumin release (≤ 20%). ULPFDU-12, KIT-6, and silicalite are found to be magnetically inactive with release capacity of 15.7%, 23.3%, and 21.1%, respectively. Overall, the study showed an inverse relation between magnetization and cumulative release capacity of curcumin. Acknowledgements The assistance of Ms. Hanan Aldossary, Institute for Research and Medical Consultations (IRMC), IAU, is highly appreciated. The authors acknowledge IRMC, IAU for providing sample characterization facilities. Ms. Nada A. Alhamed would like to thank IRMC, IAU for giving the opportunity to work under the scheme of volunteer program. Funding Information The authors B.R. Jermy and V. Ravinayagam was supported by a grant from Deanship of Scientific Research (2016-099IRMC and 2017-111-DSR), Imam Abdulrahman Bin Faisal University (IAU).

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