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Synthesis of pseudopolyrotaxanes-coated Superparamagnetic Iron Oxide Nanoparticles as new MRI contrast agent
Colloids and Surfaces B: Biointerfaces 103 (2013) 652–657
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Colloids and Surfaces B: Biointerfaces journal homepage: www.elsevier.com/locate/colsurfb
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Synthesis of pseudopolyrotaxanes-coated Superparamagnetic Iron Oxide Nanoparticles as new MRI contrast agent Forouzan Hosseini a , Arash Panahifar b , Mohsen Adeli a,c , Houshang Amiri d,e,f , Alessandro Lascialfari d,e,f , Francesco Orsini d,e , Michael R. Doschak b,g,∗ , Morteza Mahmoudi h,i,∗∗,1 a
Department of Chemistry, Payame Noor University, P.O. Box 19395-3697, Tehran, Iran Faculty of Pharmacy & Pharmaceutical Sciences, University of Alberta, Edmonton, Alberta, Canada c Department of Chemistry, Sharif University of Technology, Tehran, Iran d Dipartimento di Scienze Molecolari Applicate ai Biosistemi, Universita ‘degli Studi di Milano’, 20134 Milan, Italy e CNR-Istituto di Nanoscienze, Centro S3, 41100 Modena, Italy f Dipartimento di Fisica “A. Volta”, Universita ‘di Pavia’, 27100 Pavia, Italy g Department of Biomedical Engineering, Faculty of Medicine, University of Alberta, Edmonton, Alberta, Canada h Department of Nanotechnology, Faculty of Pharmacy, Tehran University of Medical Sciences, Tehran, Iran i Nanotechnology Research Centre, Faculty of Pharmacy, Tehran University of Medical Sciences, Tehran, Iran b
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Article history: Received 30 July 2012 Received in revised form 17 October 2012 Accepted 22 October 2012 Available online 1 November 2012 Keywords: Nanomedicine SPIONs MRI contrast agent Hybrid nanomaterials Polyrotaxanes Supermolecules
a b s t r a c t Superparamagnetic Iron Oxide Nanoparticles (SPIONs) were synthesized and coated with pseudopolyrotaxanes (PPRs) and proposed as a novel hybrid nanostructure for medical imaging and drug delivery. PPRs were prepared by addition of ␣-cyclodextrin rings to functionalized polyethylene glycol (PEG) chain with hydrophobic triazine end-groups. Non-covalent interactions between SPIONs and PPRs led to the assembly of SPIONs@PRs hybrid nanomaterials. Measurements of the 1 H Nuclear Magnetic Resonance (NMR) relaxation times T1 and T2 allowed us to determine the NMR dispersion profiles. Comparison between our SPIONs@PRs hybrid nano-compound and the commercial SPION compound, Endorem®, showed a higher transverse relaxivity for SPIONs@PRs. In vitro MRI experiments showed that our SPIONs@PRs produces better negative contrast compared to Endorem® and can be considered as a novel MRI contrast agent. © 2012 Elsevier B.V. All rights reserved.
1. Introduction Superparamagnetic Iron Oxide Nanoparticles (SPIONs) have been recognized as a powerful tool for various biomedical applications such as targeted drug delivery [1,2], contrast agents for Magnetic Resonance Imaging (MRI) [3–8], and as effector agents capable of eliciting hyperthermia [9], cell/protein separation [10], and tissue repair [11]. To facilitate the contrast of the MRI images, which is crucial issue for precise detection, contrast agents (CAs) are employed [8,12–17]. Although the gadolinium chelates are recognized as the most common compounds used as CAs, their
∗ Corresponding author at: Faculty of Pharmacy & Pharmaceutical Sciences, University of Alberta, Alberta,T6G 2E1, Canada. ∗∗ Corresponding author. Current address: Department of Chemistry, University of Illinois at Urbana-Champaign, 600 South Mathews Avenue, Urbana, IL 61801, United States. E-mail addresses: [email protected] (M.R. Doschak), [email protected], [email protected] (M. Mahmoudi). 1 www.biospion.com 0927-7765/$ – see front matter © 2012 Elsevier B.V. All rights reserved. http://dx.doi.org/10.1016/j.colsurfb.2012.10.035
usage are limited due to the toxicity issues and low targeting capability [3]. Due to their low-toxicity, targeting capability, and multi-tasking potential (e.g. simultaneous capabilities such as drug delivery, hyperthermia, and gene therapy), multifunctional SPIONs are extensively going to be recognized as promising candidate for medical imaging [1,18]. One of the drawbacks of SPIONs as drug carriers is their rapid removal from the body by the reticulo-endothelial system, which ultimately impairs the targeting and delivery of drugs using such an approach. Therefore, in order to increase the performance and safety of the SPIONs for biomedical applications, new coatings have been developed [11,19]. In addition to increasing biocompatibility, non-immunogenicity and stability in biological systems, the following specific goals are targets of the newly developed coating systems: (i) multiple therapeutic compound conjugation on the surface of nanoparticles (NPs); (ii) enhancement of the effective interaction with target cells; (iii) site-specific release of diagnostic and/or therapeutic agents, and (iv) controlled release drug delivery [20]. For instance, the crosslinked poly(ethylene glycol)co-fumarate coating was employed on the surface of SPIONs, in
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order to reduce the fast drug release from the surface of nanoparticles [19]. The results confirmed a 21% reduction of the burst release of Tamoxifen citrate, an estrogen receptor antagonist, loaded on the crosslinked coating of SPIONs compared with non-crosslinked NPs [19]. Amiri et al. [21] reported similar results on the reduction of burst effect of various drugs (e.g. Tamoxifen and Doxorubicin) by application of crosslinked poly(ethylene glycol)-co-fumarate coating on the surface of colloidal nanocrystal clusters of SPIONs. Polyrotaxanes (PRs) are highly functional supramolecules consisting of several rings bound to one or more axes, in which the dissociation of rings from the axis is often hindered by bulky groups, the so-called stoppers, at both ends of the axis [22–30]. It is notable that PRs without stoppers are called pseudopolyrotaxanes (PPRs). These rings can slide or rotate around the axis which gives them an incredible capability to be used in multivalent drug delivery where multiple ligands conjugated to the drug carrier interact with multiple receptors. They also offer a large number of hydroxyl groups available for conjugation with drugs. Due to these unique properties, PRs and PPRs have attracted enormous interest as carriers in drug delivery [31,32] and gene delivery [33] fields. Recently, it has been found that non-covalent interactions between PRs and metal NPs or quantum dots lead to core–shell architectures, due to the conversion of the conformation of PRs from extended to circular shape [34]. In this study, PPRs consisting of polyethylene glycol (PEG) axis and ␣-cyclodextrin rings were used as new shells for SPIONs in order to create new biocompatible SPIONs@PRs hybrid nanomaterials with enhanced functionality. ␣-Cyclodextrin rings are FDA approved and PEG is an inert polymer, therefore PPRs consisting of them are biocompatible coating. Carbohydrate backbone of the PRs shell has the following advantages: (i) improving the stability of the SPIONs in the biological medium, (ii) increasing the SPIONs’ interactions and consequently faster transfer through the cell membrane, (iii) increasing the SPIONs functionality and biocompatibility to deliver different therapeutic agents. In conclusion, due to their biocompatible and highly functional shell, the synthesized SPIONs@PRs hybrid nanomaterials are proposed as an excellent candidate for a wide variety of biomedical applications such as imaging and targeted drug delivery. 2. Materials and methods 2.1. Materials glycol (MW = 1000), cyanuric chloride Polyethylene (1,3,5-trichloro-2,4,6-triazine), sodium hydroxide, iron salts, dichloromethane, diethyl ether and ␣-cyclodextrin were purchased from Merck. The morphology of the particles was investigated by Transmission Electron Microscopy (TEM) (ZEISS, EM-10C, Germany) operating at 100 kV. To prepare samples, a drop of suspension was placed on a copper grid and air-dried. Fourier Transform Infrared (FTIR) spectra were recorded on KBr pellets using an ABB Bomem MB-100 FTIR spectrophotometer. High-resolution surface imaging studies were performed using atomic force microscopy (AFM) to estimate surface morphology and particle size distribution. Samples were imaged with the aid of Dualscope/Rasterscope C26, DME, Denmark, using DS 95-50-E scanner with vertical z-axis resolution of 0.1 nm.
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and sodium hydroxide (0.64 g, 16 × 10−3 mol, in 5 ml water) was added drop wise to a solution of cyanuric chloride (13 g, 7 × 10−2 mol, in 150 ml dichloromethane) and stirred at 4 ◦ C for 1 h and then refluxed for additional 6 h. The mixture was then filtered and solvent was evaporated. The obtained solid compound was dissolved in diethyl ether. The solution was filtered and precipitated in an ice bath. The precipitate was then dissolved in dichloromethane, filtered and solvent was evaporated to obtain the final product as a colorless viscose compound. 2.2.2. Preparation of pseudopolyrotaxane Functionalized polyethylene glycol was used to prepare pseudopolyrotaxane, as previously reported [34,37,38]. Briefly, a solution of functionalized PEG (1 g, 0.76 mmol in 2 ml water) was added to a saturated aqueous solution of ␣-CD (3.75 g, 3.85 mmol in 2 ml water) and the mixture was stirred for 3 h at room temperature. The white precipitate that appeared was separated by filtration, washed with distilled water, and dried by vacuum oven to obtain the final product as white powder. 2.2.3. Preparation of SPIONs coated by pseudopolyrotaxanes (SPIONs@PPRs) Iron salts were dissolved in deionized (DI) water containing 1 M HCl, where the mole fraction of Fe2+ to Fe3+ was adjusted to 2:1, respectively; after which the two prepared solutions were blended together at room temperature. Previously deoxygenated DI water with argon was used for reactions. The precipitation started by drop wise addition of iron salt solutions to NaOH solution containing pseudopolyrotaxane under neutral atmosphere (i.e. argon gas) and reaction was allowed to proceed for 30 min. In order to control mass transfer, which may allow particles to combine and build larger polycrystalline particles, turbulent flow was created by putting the reaction flask in an ultrasonic bath and changing the homogenization rates during the first 2 min of the reaction. The synthesized particles were collected by centrifugation at 6000 rpm for 10 min. The obtained ferrofluid was dispersed in DI water and kept at 4 ◦ C for future usage. 2.3. MRI in vitro experiments To measure MRI contrast efficiency, 1 H Nuclear Magnetic Resonance (NMR) technique was employed to measure the longitudinal r1 and transverse r2 relaxivities of compounds in a wide range of frequencies covering most of the clinical scanners (i.e. 8.5, 21, and 63 MHz corresponding to about 0.2, 0.5, and 1.5 T, respectively). For 10 kHz to 10 MHz, the NMR data were collected using a Smartracer Stelar relaxometer (Stelar, Mede, Italy) using the Fast-Field-Cycling technique, while for the frequencies higher than 10 MHz a Stelar Spinmaster spectrometer was used. Standard Carr-Purcell-Meiboom-Gill-like and saturation recovery pulse sequences were applied to determine spin–lattice T1 and spin–spin T2 nuclear relaxation times at room temperature. MRI experiments were performed at 8.5 MHz (0.2 T) using an Artoscan scanner by Esaote SpA (Esaote, Genova, Italy). High resolution spin echo sequence was employed with the following imaging parameters: TR/TE/NEX = 500 ms/26 ms/1, FOV = 180 × 180, matrix = 256 × 192, where TR is the repetition time, TE the echo time, NEX the number of averages (excitations), and FOV the field of view.
2.2. Methods 3. Results and discussion 2.2.1. Functionalization of polyethylene glycol Polyethylene glycol with triazine end-groups at both terminals was synthesized according to established procedures [35,36]. Briefly, a solution of polyethylene glycol (PEG) (9 g, 9 × 10−3 mol)
Due to the long lengths, strand-type topology, small diameters, high functionality, biocompatibility, and their ability to wrap around NPs, pseudopolyrotaxanes were used to modify the
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Fig. 1. (a) Incorporation of hydrophobic molecules on the functional end-groups of PEG improves non-covalent interactions between cavity of ␣-cyclodextrin molecules and PEG axis and therefore production of pseudopolyrotaxanes in a short time. (b) Pseudopolyrotaxanes with a large number of hydroxyl functional groups in their backbone interact with the hydroxyl functional groups onto the surface of SPIONs and accumulate them, leading to SPIONs@PRs hybrid nanomaterials. This strategy leads to larger metal nanoparticles with polyrotaxane shell.
physicochemical and biological properties necessary for obtaining a higher efficacy in the biomedical applications of magnetic NPs. Harada and Kamachi [39] tested different molecular weights of PEG for synthesis of pseudopolyrotaxanes with ␣-cyclodextrins and they found out the optimal molecular weight to be 1000. PEG was functionalized through nucleophilic substitution of chlorines of cyanuric chloride with its end hydroxyl functional groups and was used as an axis for the preparation of PPRs. Functionalization of PEG using the reactive and hydrophobic triazine molecule not only favors the interactions between PEG and cavity of ␣-cyclodextrins (leading to PPRs in a short time), but also creates reactive sites on the focal points of PPRs to interact with SPIONs non-covalently. SPIONs@PRs hybrid nanomaterials (Fig. 1) are able to deliver a large dose of therapeutic agents such as anti-tumor drugs because of their high potential to become functionalized. They can also take advantage of enhanced permeability and retention (EPR) effect due to vascular leakage in tumors and be targeted toward tumors ligands, thus allowing them to accumulate delivered anticancer drugs in tumor sites and consequently decreasing the side effects of
anticancer drugs [23,26–29,40]. PEG is a well-known hydrophilic polymer that has been used widely for solubilizing drugs and nanoparticles to prolong their plasma half-life. This systemic circulation retention allows for passive drug accumulation in tumors via EPR effect. SPIONs@PRs hybrid nanomaterials were characterized using different spectroscopy and microscopy methods. Fig. 2 shows the TEM and AFM images of the coated SPIONs presenting formation of spherical core@shell hybrid nanostructure. Based on the TEM images, the average size of iron oxide nanoparticles is in the order of 100 nm. Due to its low contrast, PPRs shell cannot be seen in TEM images. Since AFM images show an average size of around 250 nm for SPIONs@PRs hybrid nanomaterials, the difference between observed sizes by TEM and AFM images may be assigned to the soft PPRs shell around iron oxide NPs. However, in AFM images the observed thickness for the soft shell is around 50 nm – which is much lower than differences between sizes of SPIONs@PRs hybrid nanomaterials observed by TEM and AFM (150 nm) (see Fig. 3a and b).
Fig. 2. (a) TEM image of SPIONs@PRs hybrid nanomaterials; (b) and (c) AFM images of the SPIONs@PRs hybrid nanomaterials at various magnifications showing the formation of the core–shell structure (the scan areas for (b) and (c) are 5 m × 5 m and 3 m × 3 m, respectively; the vertical scale for (b) and (c) are 100 nm and 90 nm, respectively).
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Fig. 3. (a) Topographic AFM image of three SPIONs@PRs hybrid nanomaterials and (b) their image profile. (c) A SPIONs@PRs hybrid nanomaterial with a 40 nm thickness of soft PPRs assembled around it. (d) AFM image showing layer by layer self-assembly of the PPRs onto the surface of a SPIONs@PRs hybrid nanomaterial.
As the thickness of PPRs is around one nanometer, the shell of SPIONs@PRs hybrid nanomaterials may potentially consist of a large number of PPRs strands assembled onto the surface of SPIONs. Strong interactions between the surface of iron oxide NPs and inner strands lead to a partially crystalline shell (see Fig. 3c and d). Therefore, some parts of the crystalline (rigid) NPs (around 100 nm) observed in the AFM images is assigned to the crystalline PPRs absorbed on the surface of iron oxide NPs. It is noteworthy that aqueous solutions of hybrid SPIONs@PRs were stable for 9 months at room temperature [41]. Fig. 4 shows IR spectra of PPRs, uncoated iron oxide nanoparticles, and coated SPIONs. The IR spectra of iron oxide exhibit strong bands in the low-frequency region (1000–500 cm−1 ) which are characteristics of iron oxide skeleton. This pattern is consistent with the magnetite (Fe3 O4 ) spectrum (band in the range 570–580 cm−1 ) or maghemite (␥-Fe2 O3 ) spectrum (broad band in the range 520–610 cm−1 ) [42,43]. The characteristic band of Fe O at 572 cm−1 revealed the particles consisted of mainly Fe3 O4 . In the IR spectra of SPIONs@PRs hybrid nanomaterials, characteristic peaks of both SPIONs (1337 cm−1 ) and PPRs (1576 cm−1 ) can be clearly seen, even if they are slightly shifted toward lower frequencies. These absorption bands prove the presence of both materials in the hybrid nanomaterials and their shift is due to the strong interactions between SPIONs and PPRs. The bands of hydroxyl functional groups of SPIONs@PRs hybrid nanomaterials are shifted toward higher frequencies compared to values for the individual materials. These frequency shifts prove that the main driving force to attach PPRs to the iron oxide NPs is hydrogen bonding between their functional groups. According to the predetermined results, it is noteworthy to mention that the surface functionalization of the nanoparticles did not induce agglomeration.
To evaluate the MRI contrast efficiency of the SPIONs@PRs hybrid nanomaterials, the nuclear longitudinal r1 and transverse r2 relaxivities were obtained from T1 and T2 nuclear relaxation times measured as a function of Larmor frequency, as [32,33]: ri =
(1/Ti )s − (1/Ti )d C
(1)
where i = 1, 2, C is the iron concentration in the sample (in mM), (1/Ti ) are the nuclear relaxation rates and the suffixes s and d stand for sample and diamagnetic host, respectively. The 1 H NMR dispersion profiles (i.e. the relaxivities as a function of Larmor frequency) for SPIONs@PRs hybrid nanomaterials and a well-known commercial MRI contrast agent called Endorem® (dextran coated SPIONs) are reported in Fig. 4. As Fig. 5a demonstrates, the r1 relaxivity of the SPIONs@PRs hybrid nanomaterials presents the typical behavior of superparamagnetic contrast agents. It is worth to mention that the main mechanisms that induce the nuclear relaxation in SPIONs are as follows [32,33]: (a) for < 1–5 MHz, the Neel relaxation of the particle magnetization, giving a correlation time related to the magnetic anisotropy barrier, and an associated reversal time, N , that follows the Arrhenius law; (b) for > 1–5 MHz, the Curie relaxation, which takes into account the sample magnetization through the (square of) Langevin function weighted by the spectral density function JF (ωD ), where ωD = 1/ D , D being the correlation time related to the diffusion of the water. While the mechanism (a) gives a flattening of r1 () at frequencies < 1–5 MHz, the mechanism (b) is responsible of the maximum in r1 () at higher frequencies i.e. > 1–5 MHz. Generally for the SPIONs, the higher the transverse relaxivity r2 , the better the efficiency as a negative contrast agent. In Fig. 5b we have plotted r2 as a function of Larmor frequency for both SPIONs@PRs hybrid nanomaterials and Endorem® . It can be clearly
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Fig. 4. FTIR spectrum of (a) uncoated SPIONs, (b) SPIONs@PRs and (c) pseudopolyrotaxane.
seen that the SPIONs@PRs hybrid nanomaterials have transverse relaxivity slightly better than that of Endorem® over the entire investigated frequency range. To confirm our NMR findings and to investigate our samples efficiency as MRI contrast agent, we performed in vitro MRI experiments using diluted solutions of our samples. The experiments were performed for the SPIONs@PRs hybrid nanomaterials and Endorem® , at 8.5 MHz, using high resolution spin echo sequence
(a)
(see Fig. 6). We used ImageJ software to select region of interest and measure signal intensity in the images in order to examine the contrast efficiency of different NPs. The results showed that mean signal intensity of our sample and Endorem to be 25.35 ± 7.5 and 40.00 ± 6.0, respectively. This information confirms the previous NMR findings and we can conclude that SPIONs@PRs hybrid nanomaterials present a better contrast (i.e. a darker contrast, corresponding to a lower signal) compared to Endorem® .
(b)
-1
r2(mM s)
r1(mM s)
-1
100
10
SPIONs@PRs hybrid nanomaterials Endorem
SPIONs@PRs hybrid nanomaterials Endorem
0.01
0.1
1
10
Larmor Frequency (MHz)
100
10
100
Larmor Frequency (MHz)
Fig. 5. Longitudinal r1 and transverse r2 relaxivities versus Larmor frequency for both SPIONs@PRs hybrid nanomaterials and Endorem® .
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Fig. 6. MRI images of vials containing SPIONs@PRs hybrid nanomaterials and Endorem® imaged at = 8.5 MHz. For imaging parameters, please refer to the text.
4. Conclusion In this article, we detail the synthesis of novel hybrid nanostructured systems as promising candidates for multi-task biomedical applications, such as medical imaging and drug delivery. Non-covalent interactions, mainly hydrogen bonding, between pseudopolyrotaxanes consisting of polyethylene glycol axis and ␣cyclodextrin rings; and hydroxyl functional groups at the surface of iron oxide NPs led to new core@shell hybrid nanomaterials. These hybrid magnetic NPs can be further functionalized for specific targeting by utilizing hydroxyl groups on the ␣-cyclodextrin rings or by other chemical modifications. The high capacity for functionalization allows for the loading of both therapeutic and diagnostic agents on these NPs. The contrast efficiency of the samples investigated by means of NMR and MRI, resulted in negative contrast better than that of Endorem® , thus allowing us to conclude that the synthesized hybrid nanomaterials could find utility as a promising MRI contrast agent. References [1] M. Mahmoudi, S. Sant, B. Wang, S. Laurent, T. Sen, Adv. Drug Delivery Rev. 63 (2011) 24. [2] M. Mahmoudi, A.S. Milani, P. Stroeve, Int. J. Biomed. Nanosci. Nanotechnol. 1 (2010) 164. [3] M. Mahmoudi, H. Hosseinkhani, M. Hosseinkhani, S. Laurent, A. Simchi, W.S. Journeay, K.D. Subramani, S. Broutry, Chem. Rev. 111 (2011) 253. [4] A. Boni, M. Marinone, C. Innocenti, C. Sangregorio, M. Corti, A. Lascialfari, M. Mariani, F. Orsini, G. Poletti, M.F. Casula, J. Phys. D: Appl. Phys. 41 (2008) 134021. [5] M.F. Casula, P. Floris, C. Innocenti, A. Lascialfari, M. Marinone, M. Corti, R.A. Sperling, W.J. Parak, C. Sangregorio, Chem. Mater. 22 (2010) 1739. [6] M. Corti, A. Lascialfari, M. Marinone, A. Masotti, E. Micotti, F. Orsini, G. Ortaggi, G. Poletti, C. Innocenti, C. Sangregorio, J. Magn. Magn. Mater. 320 (2008) e316.
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Colloids and Surfaces B: Biointerfaces journal homepage: www.elsevier.com/locate/colsurfb
Short communication
Synthesis of pseudopolyrotaxanes-coated Superparamagnetic Iron Oxide Nanoparticles as new MRI contrast agent Forouzan Hosseini a , Arash Panahifar b , Mohsen Adeli a,c , Houshang Amiri d,e,f , Alessandro Lascialfari d,e,f , Francesco Orsini d,e , Michael R. Doschak b,g,∗ , Morteza Mahmoudi h,i,∗∗,1 a
Department of Chemistry, Payame Noor University, P.O. Box 19395-3697, Tehran, Iran Faculty of Pharmacy & Pharmaceutical Sciences, University of Alberta, Edmonton, Alberta, Canada c Department of Chemistry, Sharif University of Technology, Tehran, Iran d Dipartimento di Scienze Molecolari Applicate ai Biosistemi, Universita ‘degli Studi di Milano’, 20134 Milan, Italy e CNR-Istituto di Nanoscienze, Centro S3, 41100 Modena, Italy f Dipartimento di Fisica “A. Volta”, Universita ‘di Pavia’, 27100 Pavia, Italy g Department of Biomedical Engineering, Faculty of Medicine, University of Alberta, Edmonton, Alberta, Canada h Department of Nanotechnology, Faculty of Pharmacy, Tehran University of Medical Sciences, Tehran, Iran i Nanotechnology Research Centre, Faculty of Pharmacy, Tehran University of Medical Sciences, Tehran, Iran b
a r t i c l e
i n f o
Article history: Received 30 July 2012 Received in revised form 17 October 2012 Accepted 22 October 2012 Available online 1 November 2012 Keywords: Nanomedicine SPIONs MRI contrast agent Hybrid nanomaterials Polyrotaxanes Supermolecules
a b s t r a c t Superparamagnetic Iron Oxide Nanoparticles (SPIONs) were synthesized and coated with pseudopolyrotaxanes (PPRs) and proposed as a novel hybrid nanostructure for medical imaging and drug delivery. PPRs were prepared by addition of ␣-cyclodextrin rings to functionalized polyethylene glycol (PEG) chain with hydrophobic triazine end-groups. Non-covalent interactions between SPIONs and PPRs led to the assembly of SPIONs@PRs hybrid nanomaterials. Measurements of the 1 H Nuclear Magnetic Resonance (NMR) relaxation times T1 and T2 allowed us to determine the NMR dispersion profiles. Comparison between our SPIONs@PRs hybrid nano-compound and the commercial SPION compound, Endorem®, showed a higher transverse relaxivity for SPIONs@PRs. In vitro MRI experiments showed that our SPIONs@PRs produces better negative contrast compared to Endorem® and can be considered as a novel MRI contrast agent. © 2012 Elsevier B.V. All rights reserved.
1. Introduction Superparamagnetic Iron Oxide Nanoparticles (SPIONs) have been recognized as a powerful tool for various biomedical applications such as targeted drug delivery [1,2], contrast agents for Magnetic Resonance Imaging (MRI) [3–8], and as effector agents capable of eliciting hyperthermia [9], cell/protein separation [10], and tissue repair [11]. To facilitate the contrast of the MRI images, which is crucial issue for precise detection, contrast agents (CAs) are employed [8,12–17]. Although the gadolinium chelates are recognized as the most common compounds used as CAs, their
∗ Corresponding author at: Faculty of Pharmacy & Pharmaceutical Sciences, University of Alberta, Alberta,T6G 2E1, Canada. ∗∗ Corresponding author. Current address: Department of Chemistry, University of Illinois at Urbana-Champaign, 600 South Mathews Avenue, Urbana, IL 61801, United States. E-mail addresses: [email protected] (M.R. Doschak), [email protected], [email protected] (M. Mahmoudi). 1 www.biospion.com 0927-7765/$ – see front matter © 2012 Elsevier B.V. All rights reserved. http://dx.doi.org/10.1016/j.colsurfb.2012.10.035
usage are limited due to the toxicity issues and low targeting capability [3]. Due to their low-toxicity, targeting capability, and multi-tasking potential (e.g. simultaneous capabilities such as drug delivery, hyperthermia, and gene therapy), multifunctional SPIONs are extensively going to be recognized as promising candidate for medical imaging [1,18]. One of the drawbacks of SPIONs as drug carriers is their rapid removal from the body by the reticulo-endothelial system, which ultimately impairs the targeting and delivery of drugs using such an approach. Therefore, in order to increase the performance and safety of the SPIONs for biomedical applications, new coatings have been developed [11,19]. In addition to increasing biocompatibility, non-immunogenicity and stability in biological systems, the following specific goals are targets of the newly developed coating systems: (i) multiple therapeutic compound conjugation on the surface of nanoparticles (NPs); (ii) enhancement of the effective interaction with target cells; (iii) site-specific release of diagnostic and/or therapeutic agents, and (iv) controlled release drug delivery [20]. For instance, the crosslinked poly(ethylene glycol)co-fumarate coating was employed on the surface of SPIONs, in
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order to reduce the fast drug release from the surface of nanoparticles [19]. The results confirmed a 21% reduction of the burst release of Tamoxifen citrate, an estrogen receptor antagonist, loaded on the crosslinked coating of SPIONs compared with non-crosslinked NPs [19]. Amiri et al. [21] reported similar results on the reduction of burst effect of various drugs (e.g. Tamoxifen and Doxorubicin) by application of crosslinked poly(ethylene glycol)-co-fumarate coating on the surface of colloidal nanocrystal clusters of SPIONs. Polyrotaxanes (PRs) are highly functional supramolecules consisting of several rings bound to one or more axes, in which the dissociation of rings from the axis is often hindered by bulky groups, the so-called stoppers, at both ends of the axis [22–30]. It is notable that PRs without stoppers are called pseudopolyrotaxanes (PPRs). These rings can slide or rotate around the axis which gives them an incredible capability to be used in multivalent drug delivery where multiple ligands conjugated to the drug carrier interact with multiple receptors. They also offer a large number of hydroxyl groups available for conjugation with drugs. Due to these unique properties, PRs and PPRs have attracted enormous interest as carriers in drug delivery [31,32] and gene delivery [33] fields. Recently, it has been found that non-covalent interactions between PRs and metal NPs or quantum dots lead to core–shell architectures, due to the conversion of the conformation of PRs from extended to circular shape [34]. In this study, PPRs consisting of polyethylene glycol (PEG) axis and ␣-cyclodextrin rings were used as new shells for SPIONs in order to create new biocompatible SPIONs@PRs hybrid nanomaterials with enhanced functionality. ␣-Cyclodextrin rings are FDA approved and PEG is an inert polymer, therefore PPRs consisting of them are biocompatible coating. Carbohydrate backbone of the PRs shell has the following advantages: (i) improving the stability of the SPIONs in the biological medium, (ii) increasing the SPIONs’ interactions and consequently faster transfer through the cell membrane, (iii) increasing the SPIONs functionality and biocompatibility to deliver different therapeutic agents. In conclusion, due to their biocompatible and highly functional shell, the synthesized SPIONs@PRs hybrid nanomaterials are proposed as an excellent candidate for a wide variety of biomedical applications such as imaging and targeted drug delivery. 2. Materials and methods 2.1. Materials glycol (MW = 1000), cyanuric chloride Polyethylene (1,3,5-trichloro-2,4,6-triazine), sodium hydroxide, iron salts, dichloromethane, diethyl ether and ␣-cyclodextrin were purchased from Merck. The morphology of the particles was investigated by Transmission Electron Microscopy (TEM) (ZEISS, EM-10C, Germany) operating at 100 kV. To prepare samples, a drop of suspension was placed on a copper grid and air-dried. Fourier Transform Infrared (FTIR) spectra were recorded on KBr pellets using an ABB Bomem MB-100 FTIR spectrophotometer. High-resolution surface imaging studies were performed using atomic force microscopy (AFM) to estimate surface morphology and particle size distribution. Samples were imaged with the aid of Dualscope/Rasterscope C26, DME, Denmark, using DS 95-50-E scanner with vertical z-axis resolution of 0.1 nm.
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and sodium hydroxide (0.64 g, 16 × 10−3 mol, in 5 ml water) was added drop wise to a solution of cyanuric chloride (13 g, 7 × 10−2 mol, in 150 ml dichloromethane) and stirred at 4 ◦ C for 1 h and then refluxed for additional 6 h. The mixture was then filtered and solvent was evaporated. The obtained solid compound was dissolved in diethyl ether. The solution was filtered and precipitated in an ice bath. The precipitate was then dissolved in dichloromethane, filtered and solvent was evaporated to obtain the final product as a colorless viscose compound. 2.2.2. Preparation of pseudopolyrotaxane Functionalized polyethylene glycol was used to prepare pseudopolyrotaxane, as previously reported [34,37,38]. Briefly, a solution of functionalized PEG (1 g, 0.76 mmol in 2 ml water) was added to a saturated aqueous solution of ␣-CD (3.75 g, 3.85 mmol in 2 ml water) and the mixture was stirred for 3 h at room temperature. The white precipitate that appeared was separated by filtration, washed with distilled water, and dried by vacuum oven to obtain the final product as white powder. 2.2.3. Preparation of SPIONs coated by pseudopolyrotaxanes (SPIONs@PPRs) Iron salts were dissolved in deionized (DI) water containing 1 M HCl, where the mole fraction of Fe2+ to Fe3+ was adjusted to 2:1, respectively; after which the two prepared solutions were blended together at room temperature. Previously deoxygenated DI water with argon was used for reactions. The precipitation started by drop wise addition of iron salt solutions to NaOH solution containing pseudopolyrotaxane under neutral atmosphere (i.e. argon gas) and reaction was allowed to proceed for 30 min. In order to control mass transfer, which may allow particles to combine and build larger polycrystalline particles, turbulent flow was created by putting the reaction flask in an ultrasonic bath and changing the homogenization rates during the first 2 min of the reaction. The synthesized particles were collected by centrifugation at 6000 rpm for 10 min. The obtained ferrofluid was dispersed in DI water and kept at 4 ◦ C for future usage. 2.3. MRI in vitro experiments To measure MRI contrast efficiency, 1 H Nuclear Magnetic Resonance (NMR) technique was employed to measure the longitudinal r1 and transverse r2 relaxivities of compounds in a wide range of frequencies covering most of the clinical scanners (i.e. 8.5, 21, and 63 MHz corresponding to about 0.2, 0.5, and 1.5 T, respectively). For 10 kHz to 10 MHz, the NMR data were collected using a Smartracer Stelar relaxometer (Stelar, Mede, Italy) using the Fast-Field-Cycling technique, while for the frequencies higher than 10 MHz a Stelar Spinmaster spectrometer was used. Standard Carr-Purcell-Meiboom-Gill-like and saturation recovery pulse sequences were applied to determine spin–lattice T1 and spin–spin T2 nuclear relaxation times at room temperature. MRI experiments were performed at 8.5 MHz (0.2 T) using an Artoscan scanner by Esaote SpA (Esaote, Genova, Italy). High resolution spin echo sequence was employed with the following imaging parameters: TR/TE/NEX = 500 ms/26 ms/1, FOV = 180 × 180, matrix = 256 × 192, where TR is the repetition time, TE the echo time, NEX the number of averages (excitations), and FOV the field of view.
2.2. Methods 3. Results and discussion 2.2.1. Functionalization of polyethylene glycol Polyethylene glycol with triazine end-groups at both terminals was synthesized according to established procedures [35,36]. Briefly, a solution of polyethylene glycol (PEG) (9 g, 9 × 10−3 mol)
Due to the long lengths, strand-type topology, small diameters, high functionality, biocompatibility, and their ability to wrap around NPs, pseudopolyrotaxanes were used to modify the
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Fig. 1. (a) Incorporation of hydrophobic molecules on the functional end-groups of PEG improves non-covalent interactions between cavity of ␣-cyclodextrin molecules and PEG axis and therefore production of pseudopolyrotaxanes in a short time. (b) Pseudopolyrotaxanes with a large number of hydroxyl functional groups in their backbone interact with the hydroxyl functional groups onto the surface of SPIONs and accumulate them, leading to SPIONs@PRs hybrid nanomaterials. This strategy leads to larger metal nanoparticles with polyrotaxane shell.
physicochemical and biological properties necessary for obtaining a higher efficacy in the biomedical applications of magnetic NPs. Harada and Kamachi [39] tested different molecular weights of PEG for synthesis of pseudopolyrotaxanes with ␣-cyclodextrins and they found out the optimal molecular weight to be 1000. PEG was functionalized through nucleophilic substitution of chlorines of cyanuric chloride with its end hydroxyl functional groups and was used as an axis for the preparation of PPRs. Functionalization of PEG using the reactive and hydrophobic triazine molecule not only favors the interactions between PEG and cavity of ␣-cyclodextrins (leading to PPRs in a short time), but also creates reactive sites on the focal points of PPRs to interact with SPIONs non-covalently. SPIONs@PRs hybrid nanomaterials (Fig. 1) are able to deliver a large dose of therapeutic agents such as anti-tumor drugs because of their high potential to become functionalized. They can also take advantage of enhanced permeability and retention (EPR) effect due to vascular leakage in tumors and be targeted toward tumors ligands, thus allowing them to accumulate delivered anticancer drugs in tumor sites and consequently decreasing the side effects of
anticancer drugs [23,26–29,40]. PEG is a well-known hydrophilic polymer that has been used widely for solubilizing drugs and nanoparticles to prolong their plasma half-life. This systemic circulation retention allows for passive drug accumulation in tumors via EPR effect. SPIONs@PRs hybrid nanomaterials were characterized using different spectroscopy and microscopy methods. Fig. 2 shows the TEM and AFM images of the coated SPIONs presenting formation of spherical core@shell hybrid nanostructure. Based on the TEM images, the average size of iron oxide nanoparticles is in the order of 100 nm. Due to its low contrast, PPRs shell cannot be seen in TEM images. Since AFM images show an average size of around 250 nm for SPIONs@PRs hybrid nanomaterials, the difference between observed sizes by TEM and AFM images may be assigned to the soft PPRs shell around iron oxide NPs. However, in AFM images the observed thickness for the soft shell is around 50 nm – which is much lower than differences between sizes of SPIONs@PRs hybrid nanomaterials observed by TEM and AFM (150 nm) (see Fig. 3a and b).
Fig. 2. (a) TEM image of SPIONs@PRs hybrid nanomaterials; (b) and (c) AFM images of the SPIONs@PRs hybrid nanomaterials at various magnifications showing the formation of the core–shell structure (the scan areas for (b) and (c) are 5 m × 5 m and 3 m × 3 m, respectively; the vertical scale for (b) and (c) are 100 nm and 90 nm, respectively).
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Fig. 3. (a) Topographic AFM image of three SPIONs@PRs hybrid nanomaterials and (b) their image profile. (c) A SPIONs@PRs hybrid nanomaterial with a 40 nm thickness of soft PPRs assembled around it. (d) AFM image showing layer by layer self-assembly of the PPRs onto the surface of a SPIONs@PRs hybrid nanomaterial.
As the thickness of PPRs is around one nanometer, the shell of SPIONs@PRs hybrid nanomaterials may potentially consist of a large number of PPRs strands assembled onto the surface of SPIONs. Strong interactions between the surface of iron oxide NPs and inner strands lead to a partially crystalline shell (see Fig. 3c and d). Therefore, some parts of the crystalline (rigid) NPs (around 100 nm) observed in the AFM images is assigned to the crystalline PPRs absorbed on the surface of iron oxide NPs. It is noteworthy that aqueous solutions of hybrid SPIONs@PRs were stable for 9 months at room temperature [41]. Fig. 4 shows IR spectra of PPRs, uncoated iron oxide nanoparticles, and coated SPIONs. The IR spectra of iron oxide exhibit strong bands in the low-frequency region (1000–500 cm−1 ) which are characteristics of iron oxide skeleton. This pattern is consistent with the magnetite (Fe3 O4 ) spectrum (band in the range 570–580 cm−1 ) or maghemite (␥-Fe2 O3 ) spectrum (broad band in the range 520–610 cm−1 ) [42,43]. The characteristic band of Fe O at 572 cm−1 revealed the particles consisted of mainly Fe3 O4 . In the IR spectra of SPIONs@PRs hybrid nanomaterials, characteristic peaks of both SPIONs (1337 cm−1 ) and PPRs (1576 cm−1 ) can be clearly seen, even if they are slightly shifted toward lower frequencies. These absorption bands prove the presence of both materials in the hybrid nanomaterials and their shift is due to the strong interactions between SPIONs and PPRs. The bands of hydroxyl functional groups of SPIONs@PRs hybrid nanomaterials are shifted toward higher frequencies compared to values for the individual materials. These frequency shifts prove that the main driving force to attach PPRs to the iron oxide NPs is hydrogen bonding between their functional groups. According to the predetermined results, it is noteworthy to mention that the surface functionalization of the nanoparticles did not induce agglomeration.
To evaluate the MRI contrast efficiency of the SPIONs@PRs hybrid nanomaterials, the nuclear longitudinal r1 and transverse r2 relaxivities were obtained from T1 and T2 nuclear relaxation times measured as a function of Larmor frequency, as [32,33]: ri =
(1/Ti )s − (1/Ti )d C
(1)
where i = 1, 2, C is the iron concentration in the sample (in mM), (1/Ti ) are the nuclear relaxation rates and the suffixes s and d stand for sample and diamagnetic host, respectively. The 1 H NMR dispersion profiles (i.e. the relaxivities as a function of Larmor frequency) for SPIONs@PRs hybrid nanomaterials and a well-known commercial MRI contrast agent called Endorem® (dextran coated SPIONs) are reported in Fig. 4. As Fig. 5a demonstrates, the r1 relaxivity of the SPIONs@PRs hybrid nanomaterials presents the typical behavior of superparamagnetic contrast agents. It is worth to mention that the main mechanisms that induce the nuclear relaxation in SPIONs are as follows [32,33]: (a) for < 1–5 MHz, the Neel relaxation of the particle magnetization, giving a correlation time related to the magnetic anisotropy barrier, and an associated reversal time, N , that follows the Arrhenius law; (b) for > 1–5 MHz, the Curie relaxation, which takes into account the sample magnetization through the (square of) Langevin function weighted by the spectral density function JF (ωD ), where ωD = 1/ D , D being the correlation time related to the diffusion of the water. While the mechanism (a) gives a flattening of r1 () at frequencies < 1–5 MHz, the mechanism (b) is responsible of the maximum in r1 () at higher frequencies i.e. > 1–5 MHz. Generally for the SPIONs, the higher the transverse relaxivity r2 , the better the efficiency as a negative contrast agent. In Fig. 5b we have plotted r2 as a function of Larmor frequency for both SPIONs@PRs hybrid nanomaterials and Endorem® . It can be clearly
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Fig. 4. FTIR spectrum of (a) uncoated SPIONs, (b) SPIONs@PRs and (c) pseudopolyrotaxane.
seen that the SPIONs@PRs hybrid nanomaterials have transverse relaxivity slightly better than that of Endorem® over the entire investigated frequency range. To confirm our NMR findings and to investigate our samples efficiency as MRI contrast agent, we performed in vitro MRI experiments using diluted solutions of our samples. The experiments were performed for the SPIONs@PRs hybrid nanomaterials and Endorem® , at 8.5 MHz, using high resolution spin echo sequence
(a)
(see Fig. 6). We used ImageJ software to select region of interest and measure signal intensity in the images in order to examine the contrast efficiency of different NPs. The results showed that mean signal intensity of our sample and Endorem to be 25.35 ± 7.5 and 40.00 ± 6.0, respectively. This information confirms the previous NMR findings and we can conclude that SPIONs@PRs hybrid nanomaterials present a better contrast (i.e. a darker contrast, corresponding to a lower signal) compared to Endorem® .
(b)
-1
r2(mM s)
r1(mM s)
-1
100
10
SPIONs@PRs hybrid nanomaterials Endorem
SPIONs@PRs hybrid nanomaterials Endorem
0.01
0.1
1
10
Larmor Frequency (MHz)
100
10
100
Larmor Frequency (MHz)
Fig. 5. Longitudinal r1 and transverse r2 relaxivities versus Larmor frequency for both SPIONs@PRs hybrid nanomaterials and Endorem® .
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Fig. 6. MRI images of vials containing SPIONs@PRs hybrid nanomaterials and Endorem® imaged at = 8.5 MHz. For imaging parameters, please refer to the text.
4. Conclusion In this article, we detail the synthesis of novel hybrid nanostructured systems as promising candidates for multi-task biomedical applications, such as medical imaging and drug delivery. Non-covalent interactions, mainly hydrogen bonding, between pseudopolyrotaxanes consisting of polyethylene glycol axis and ␣cyclodextrin rings; and hydroxyl functional groups at the surface of iron oxide NPs led to new core@shell hybrid nanomaterials. These hybrid magnetic NPs can be further functionalized for specific targeting by utilizing hydroxyl groups on the ␣-cyclodextrin rings or by other chemical modifications. The high capacity for functionalization allows for the loading of both therapeutic and diagnostic agents on these NPs. The contrast efficiency of the samples investigated by means of NMR and MRI, resulted in negative contrast better than that of Endorem® , thus allowing us to conclude that the synthesized hybrid nanomaterials could find utility as a promising MRI contrast agent. References [1] M. Mahmoudi, S. Sant, B. Wang, S. Laurent, T. Sen, Adv. Drug Delivery Rev. 63 (2011) 24. [2] M. Mahmoudi, A.S. Milani, P. Stroeve, Int. J. Biomed. Nanosci. Nanotechnol. 1 (2010) 164. [3] M. Mahmoudi, H. Hosseinkhani, M. Hosseinkhani, S. Laurent, A. Simchi, W.S. Journeay, K.D. Subramani, S. Broutry, Chem. Rev. 111 (2011) 253. [4] A. Boni, M. Marinone, C. Innocenti, C. Sangregorio, M. Corti, A. Lascialfari, M. Mariani, F. Orsini, G. Poletti, M.F. Casula, J. Phys. D: Appl. Phys. 41 (2008) 134021. [5] M.F. Casula, P. Floris, C. Innocenti, A. Lascialfari, M. Marinone, M. Corti, R.A. Sperling, W.J. Parak, C. Sangregorio, Chem. Mater. 22 (2010) 1739. [6] M. Corti, A. Lascialfari, M. Marinone, A. Masotti, E. Micotti, F. Orsini, G. Ortaggi, G. Poletti, C. Innocenti, C. Sangregorio, J. Magn. Magn. Mater. 320 (2008) e316.
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