J IRAN CHEM SOC (2013) 10:701–708 DOI 10.1007/s13738-012-0203-3
ORIGINAL PAPER
Tumor-targeted drug delivery systems based on supramolecular interactions between iron oxide–carbon nanotubes PAMAM–PEG–PAMAM linear-dendritic copolymers Mohsen Adeli • Masoumeh Ashiri • Beheshteh Khodadadi Chegeni Pezhman Sasanpour
•
Received: 31 July 2012 / Accepted: 30 November 2012 / Published online: 15 January 2013 Ó Iranian Chemical Society 2013
Abstract New hybrid nanostructure-based magnetic drug delivery systems (HNMDDSs) consisting of carbon nanotubes, magnetic iron oxide nanoparticles, and linear-dendritic copolymers linked to anticancer drugs were synthesized and characterized. Polyamidoamine–polyethylene glycol–polyamidoamine (PAMAM–PEG–PAMAM) ABA type linear-dendritic copolymers were used to solubilize and functionalize carbon nanotubes through supramolecular chemistry. There are three key features of HNMDDSs: (a) use of functionalized MWCNTs as a biocompatible platform for the delivery of magnetic iron oxide nanoparticles, therapeutic drugs, and diagnostics, (b) use of PAMAM–PEG–PAMAM linear-dendritic copolymers as water soluble, biocompatible and high functional hybrid materials with a linear polyethylene glycol part which cause a high solubility for MWCNT through supramolecular interactions and dendritic PAMAM parts which cause a high functionality for MWCNT, (c) use of magnetic iron oxide nanoparticles as targeting, imaging, or hyperthermia cancer treatment agents. To prove the efficacy of Electronic supplementary material The online version of this article (doi:10.1007/s13738-012-0203-3) contains supplementary material, which is available to authorized users. M. Adeli M. Ashiri B. Khodadadi Chegeni Department of Chemistry Faculty of Science, Lorestan University, Khoramabad, Iran M. Adeli (&) Department of Chemistry, Sharif University of Technology, Tehran, Iran e-mail:
[email protected];
[email protected] P. Sasanpour Department of Medical Physics and Biomedical Engineering, Faculty of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
synthesized HNMDDSs, they were subjected to the receptor-mediated endocytosis and release inside the cancer cells. Then, it was unambiguously proved that these tumor-targeting HNMDDSs are promising systems for future cancer therapy with low drug doses, thereby forming a solid foundation for further investigation and development. Keywords Linear-dendritic copolymers Carbon nanotubes Anticancer Drug delivery systems Nanostructures
Introduction Efforts to overcome limitations in the progress of the novel cancer therapies such as inefficient distribution, insolubility, killing the health tissues, and the inability to cross cellular barriers that are often appeared in the administration step has been lead to an interest in the nanomaterialbased drug delivery systems, NDDSs. These systems present remarkable opportunities to meet novel cancer therapies challenges and have effectively been used to deliver biologically active agents into living cells for biomedical applications [1, 2]. Use of NDDSs for biomedical applications constitutes a new field called ‘‘nanomedicine’’ which involves a multi-step process from the design, synthesis, in vitro experiments, and initial administration to cross the tissue endothelium barrier and introduction into the interstitial space of tissues, through the cell membrane into organelles of cells and even through the perinuclear membrane into the nucleus of cells. Among diverse classes of NDDSs, those based on carbon nanotubes and magnetic nanoparticles have attracted particular attention as carriers of biologically relevant
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molecules due to their unique properties such as thermal and magnetic and their ability to cross cell membranes and also high surface area per unit weight for high drug loading [3–5]. Variety of NDDSs based on carbon nanotubes have been prepared and tested in vitro and in vivo for delivery of drugs recently [6–9]. Superparamagnetic nanoparticles are also used to characterize lymph node status in patients with carcinoma of breast, lung, prostate, endometrium, and cervix. Their conjugated with antibodies have been used to image cancer cells in vitro and in vivo with MRI [10, 11]. As a result combination the magnetic nanoparticles and carbon nanotubes results in new hybrid materials with interesting magnetic and thermal properties. Significant interests have been generated in preparing multifunctional Fe3O4/CNTs hybrid materials for their exceptional electromagnetic properties in many applications such as medical diagnostics and drug delivery [12]. Recently, the potential application of iron-containing carbon nanotubes for magnetic heating in hyperthermia cancer treatment has been investigated [13]. However, poor water solubility and low functionality are two critical factors that limit biomedical applications of CNTs and CNT/c-Fe2O3NP hybrid nanomaterials [14, 15]. Solubility of CNTs or CNTs/metal nanoparticle hybrid nanomaterials can be improved by polymers through covalent or non-covalent methods. In the covalent method, polymers are grafted onto the surface of CNTs by chemical linkages. This method is very effective because grafted polymer raise the solubility and functionality of CNTs even with a low degree grafting but a disadvantage of this method is to create some defects in the structure of CNTs [16–20]. Non-covalent method is based on supramolecular interactions between CNTs and polymers and includes polymer wrapping or adsorption [21–25]. In this method, structure of CNTs does not damage as much as the covalent method, but its disadvantage is the low functionality of the final product. Herein a new method to improve the functionality and water solubility of CNT/c-Fe2O3NP hybrid nanomaterials without damaging their structure using linear-dendritic copolymers has been reported. Linear-dendritic copolymers are hybrid nanomaterials consisting of linear and dendritic blocks [26–29]. Polyethylene glycol (PEG) is a well-studied and abundantly used polymer not only to synthesis variety of linear-dendritic copolymers but also to improve the processability, water solubility and long blood circulation of CNTs through non-covalent interactions [30]. Hence, supramolecular interactions between linear-dendritic copolymers with a PEG block and CNTs leads to water soluble and high functional hybrid nanomaterials.
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Experimental section Full information considering the used materials, instruments, and synthetic procedures is available on the experimental section of supplementary materials, SM.
Results and discussion Polyethylene glycol was functionalized according to reported procedure in literature [29, 31] and it was used as a core to synthesis PAMAM–PEG–PAMAM ABA type linear-dendritic copolymers. Fe3O4/MWCNTs hybrid materials were synthesized as mentioned above. Noncovalent interactions between Fe3O4-MWCNTs hybrid materials and PAMAM–PEG–PAMAM hybrid nanomaterials were led to high functional and water soluble Fe3O4MWCNTs/PAMAM–PEG–PAMAM hybrid nanomaterials (Fig. 1). Aqueous solutions of hybrid nanomaterials were stable over several weeks at room temperature (Fig. 2). Functionalization and structure of nanomaterials was evaluated using different spectroscopy methods. Comparison of the IR, NMR and Raman spectra and also TGA diagrams of MWCNT, PAMAM–PEG–PAMAM, Fe3O4-MWCNTs/ PAMAM–PEG–PAMAM, Doxorubicin/Fe3O4-MWCNTs/ PAMAM–PEG–PAMAM prove that HNMDDSs are synthesized successfully (supplementary materials). The Raman spectroscopy provides an excellent method to evaluate the functionalization of CNTs. Hence, functionalization of Fe3O4-MWCNTs through non-covalent interactions with linear-dendritic copolymers was investigated by Raman spectroscopy. Figure 3a–e shows the Raman spectra of pristine MWCNTs, acid-treatment MWCNTs, Fe3O4-MWCNTs, Fe3O4-MWCNTs/PAMAM–PEG–PAMAM, and DOX/ Fe3O4-MWCNTs/PAMAM–PEG–PAMAM hybride nanomaterials, respectively. In the Raman spectrum of pristine MWCNTs (Fig. 3a), D- and G-bands are appeared at 1,351 and 1,584 cm-1, respectively, while for acid-treatment MWCNTs (Fig. 3b) results in a substantial increase in the D mode and a decrease in the tangential G mode associated with sp2-hybridized carbons from the graphitic sidewalls. The latter is ascribed to the defects produced during purification process. For Fe3O4-MWCNTs (Fig. 3c) D- and G-bands are appeared at 1,322 and 1,633 cm-1, respectively. Compared with that for MWCNTs, both absorption peaks of the Fe3O4-MWCNTs are weaker and shifted. This may be due to the interaction between MWCNTs and Fe3O4 nanoparticles. However in the Raman spectrum of Fe3O4-MWCNTs/ PAMAM–PEG–PAMAM (Fig. 3d) hybrid material, D- and
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Fig. 1 The schematic representation of preparation of HNMDDSs. i FeCl3 6H2O, FeSO4 6H2O, 70 °C, ii water, 25 °C, 10 min, iii water, Doxorubicin, 25 °C, 10 min
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Fig. 2 Aqueous solution of a MWCNTs after 1 h and b Fe3O4MWCNTs/PAMAM–PEG–PAMAM after 2 weeks at room temperature
G-bands of Fe3O4-MWCNTs are shifted to the 1,380 and 1,620 cm-1 compared to that of acid-treatment MWCNTs and Fe3O4-MWCNTs respectively, showing that there is a strong interaction between linear-dendritic copolymer and Fe3O4-MWCNTs and they are not just a physical mixture. The Raman spectrum of DOX/Fe3O4-MWCNTs/PAMAM– PEG–PAMAM (Fig. 3e) hybrid nanomaterials is very similar to the Raman spectrum Fe3O4-MWCNTs/PAMAM–PEG–PAMAM but with a little increased intensity and frequency which can be attributed to the presence of DOX on the surface of Fe3O4-MWCNTs. UV–visible spectroscopy was used to demonstrate adsorption of DOX on Fe3O4-MWCNTs surface. DOX was added to a solution of Fe3O4-MWCNTs/PAMAM–PEG– PAMAM until the solution started to precipitation. The resulted mixture was centrifuged and its UV–visible spectrum was recorded. Absorption peak centered at 490 nm is assigned to the DOX molecules loaded onto the surface of CNT. In order to calculate the loading capacity of hybrid nanomaterial UV–visible spectrum of an aqueous solution containing the same amount of DOX, that was added to the Fe3O4-MWCNTs/PAMAM–PEG–PAMAM solution, was recorded and it was compared with the UV–visible spectrum of the supernatant, free DOX, of the prepared drug delivery system. Difference between the intensity of the maximum absorption of DOX in both cases was adjusted with the calibration curve and loading capacity for drug delivery system was calculated about 67 % (Fig. 4). Conformation and morphology of drug delivery systems is one of the most important factors dominating their interactions with biological systems and cell membranes. Therefore morphology and conformation of the synthesized hybrid nanomaterials in solution was investigated. According to dynamic light scattering, DLS, the average diameter of Fe3O4-MWCNTs hybrid nanomaterials in water change from 293 to 207 nm upon interaction with PAMAM–PEG– PAMAM linear-dendritic copolymers (Fig. 5a–d). As it has
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Fig. 3 Raman spectra of a pristine MWCNTs, b acid-treatment MWCNTs, c Fe3O4-MWCNTs, d Fe3O4-MWCNTs/PAMAM–PEG– PAMAM, and e DOX/Fe3O4-MWCNTs/PAMAM–PEG–PAMAM hybrid nanomaterials
been reported by our group, conformation of CNTs changes from extended, linear, to closed, globular, upon interaction with hydrophilic polymers such as glycerol [32]; hence, noncovalent interactions with PAMAM–PEG–PAMAM lineardendritic copolymers should change their conformation toward globular forms and consequently decrease their size in the solution state. Size of DOX/Fe3O4-MWCNTs/PAMAM–PEG–PAMAM drug delivery system in water is smaller than that for Fe3O4-MWCNTs/PAMAM–PEG– PAMAM hybrid nanomaterial, proving that the staking of DOX onto the surface of CNT affects the non-covalent interactions between PAMAM–PEG–PAMAM linear-dendritic copolymer and Fe3O4-MWCNTs. Figure 6 shows the TGA thermograms of PAMAM–PEG– PAMAM linear-dendritic copolymer, Fe3O4-MWCNTs, Fe3O4-MWCNTs/PAMAM–PEG–PAMAM, and DOX/
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Fig. 6 TGA thermograms of a PAMAM–PEG–PAMAM, b Fe3O4MWCNTs, c Fe3O4-MWCNTs/PAMAM–PEG–PAMAM, and d DOX/ Fe3O4-MWCNTs/PAMAM–PEG–PAMAM hybrid nanomaterials Fig. 4 UV–visible spectrum of hybrid nanomaterials
Fig. 5 DLS diagrams for a PAMAM–PEG–PAMAM, b Fe3O4MWCNTs, c Fe3O4-MWCNTs/PAMAM–PEG–PAMAM, and d DOX/ Fe3O4-MWCNTs/PAMAM–PEG–PAMAM hybrid nanomaterials
Fe3O4-MWCNTs/PAMAM–PEG–PAMAM hybrid nanomaterials in the range of 25–700 °C. For Fe3O4-MWCNTs there is no significant weight loss up to 400 °C. However, at the same temperature, Fe3O4-MWCNTs/PAMAM–PEG–PAMAM, and DOX/Fe3O4-MWCNTs/PAMAM–PEG–PAMAM hybrid nanomaterials lose significant weight which is ascribed to the presence of the corresponding PAMAM– PEG–PAMAM and DOX onto the surface of MWCNTs. The TGA thermogram of Fe3O4-MWCNTs (Fig. 6a) shows weight loss in three stages at 120, 274–332, and 400–600 °C which are attributed to the evaporation of physically adsorbed water (1 %), loss of functional groups of Fe3O4 nanoparticles (about 6 %) and the gradual decomposition of carbon nanotubes (7 %), respectively. The weight loss of the PAMAM–
PEG–PAMAM (TGA thermogram in Fig. 6b) occurs in several stages at 100–120 °C which is attributed to the physically adsorbed water (6 %), 208–296 °C in which the dendrons in linear-dendritic copolymer were decomposed (26 %) and 328–400 °C is attributed to decomposition of PEG block (18 %). TGA plot of Fe3O4-MWCNTs/PAMAM–PEG–PAMAM (Fig. 6c) shows weight loss in three discrete stages. The first weight loss, about 6 %, between 119 and 251 °C corresponds to decomposition of dendron blocks. The second weight loss between 252 and 396 °C represents the removal of functional groups of Fe3O4 nanoparticles (10 %) and the decomposition of PEG block (4.3 %). The third weight loss between 423 and 500 °C about 32 %, is attributed to the decomposition of carbon nanotubes. These results suggest that the slope of weight loss of Fe3O4MWCNTs/PAMAM–PEG–PAMAM hybrid materials is lower than that of PAMAM–PEG–PAMAM which is ascribed to the presence of the c- Fe3O4-MWCNTs. The TGA thermogram of DOX/Fe3O4-MWCNTs/PAMAM– PEG–PAMAM hybrid nanomaterials (Fig. 6d) shows three weight loss stages. The first weight loss, about 4 %, between 150 and 235 °C corresponds to decomposition of dendron blocks. The second weight loss between 273 and 404 °C represents the removal of functional groups of Fe3O4 nanoparticles (8 %) and the decomposition of PEG block (3 %). The third weight loss between 452 and 512 °C about 27 %, is attributed to the decomposition of carbon nanotubes. The weight loss for Fe3O4-MWCNTs/PAMAM–PEG–PAMAM is occurred in higher temperature than that of Fe3O4-MWCNTs and PAMAM–PEG–PAMAM individually. It can be concluded that non-covalent interactions between Fe3O4-MWCNTs, DOX, and PAMAM–PEG–PAMAM increased their thermal stability. The zeta potential of Fe3O4-MWCNTs changes from -38.6 to ?23.6 mV after interacting with PAMAM–PEG–
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PAMAM linear-dendritic copolymer showing functionalization of carbon nanotubes with the amino functional groups of linear-dendritic copolymer. This surface charge increased to ?34.1 for DOX/Fe3O4-MWCNTs/PAMAM– PEG–PAMAM because of the adsorption of DOX containing N–H functional groups on Fe3O4-MWCNTs/PAMAM–PEG–PAMAM (Table 1). Hybrid nanostructure-based magnetic drug delivery systems can be targeted to tumors or the target tissues using a magnetic field. As above-mentioned the main reason to introduce magnetic nanoparticles in the synthesized drug delivery systems was to target them to tumors using a magnetic field (Fig. 7). All synthesized hybrid nanomaterials were magnetically active so that they easily response to a magnetic field. To prove the efficiency of Fe3O4 nano particles to target HNMDDSs to tumors, interaction of an external magnetic field with magnetic fluid (blood containing HNMDDSs) was numerically simulated by multiphysics modeling. In the model, Maxwell’s equation has been used for magnetic field and dynamic flow is governed with Navier–stokes equation. Effect of magnetic field on
Table 1 Zeta potential values for PAMAM–PEG–PAMAM, Fe3O4MWCNTs, Fe3O4-MWCNTs/PAMAM–PEG–PAMAM, and DOX/ Fe3O4-MWCNTs/PAMAM–PEG–PAMAM Sample
Zeta potential(mV)
PAMAM–PEG–PAMAM
?22
Fe3O4-MWCNTs
-38.6
Fe3O4-MWCNTs/PAMAM–PEG–PAMAM
?23.6
DOX/Fe3O4-MWCNTs/PAMAM–PEG–PAMAM
?34.1
Fig. 7 HNMDDSs are sensitive to magnetic field. Fe3O4-MWCNTs response to a magnet and it can be drawn through the wall of a sampler easily
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the ferrofluid is applied inside Navier–Stokes through volume force field. Systems of equations are solved using Finite element method with COMSOL Multiphysics software. Figure 3a SM shows the geometry and mesh structure of numerical simulation. Structure consists of an external magnet which is used for magnetic field source. Two layers have been considered for vessel and skin structure. Ferrofluid is flowing in vessel structure. Boundary condition used for fluid injection inside the vessel is applied on left boundary of vessel and consists of sinusoidal pulse shape, describing heart beat. The procedure to obtain velocity of blood has been illustrated in flow chart as shown in Fig. 3b SM. Effect of magnetic nanoparticles inside fluid is imported to the model through their VSM curves (Fig. 8). The prepared Fe3O4MWCNTs (7-1) exhibited the superparamagnetic behavior without magnetic hysteresis. The saturation of magnetization of Fe3O4-MWCNTs was 3 emu/g at 4841 Oe. The saturation of magnetization of Fe3O4-MWCNTs/PAMAM–PEG–PAMAM(7-2) and DOX/Fe3O4-MWCNTs/ PAMAM–PEG–PAMAM(7-3) were little smaller than that of Fe3O4-MWCNTs, but both had similar properties that were close to the superparamagnetic behavior, indicating that the magnetic properties of Fe3O4-MWCNTs did not lose by the non-covalent interaction of DOX and PAMAM– PEG–PAMAM on their surfaces. With this unique property, DOX/cFe3O4-MWCNTs/PAMAM–PEG–PAMAM were hybrid nanomaterial that can be used as a promising material in many fields such as cancer diagnosis and therapy. Since changing the velocity of blood from the ‘‘x’’ direction, along the blood vessel, to the ‘‘y’’ direction, perpendicular to blood vessel, show the affectivity of magnetic nanoparticles to increase the diffusion of blood from blood vessel to tissues or tumors, the velocity of blood containing hybrid nanomaterials in the presence and
Fig. 8 VSM curves of (1) Fe3O4-MWCNTs (2) Fe3O4-MWCNTs/ PAMAM–PEG–PAMAM, (3) DOX/Fe3O4-MWCNTs/PAMAM– PEG–PAMAM
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Fig. 9 Velocity of fluid in ‘‘y’’ direction (perpendicular to vessel) for a Fe3O4-MWCNTs, b Fe3O4-MWCNTs/PAMAM–PEG–PAMAM, c DOX/Fe3O4 MWCNTs/PAMAM–PEG–PAMAM in the magnetic
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field and d DOX/Fe3O4-MWCNTs/PAMAM–PEG–PAMAM in the absence of the magnetic field
Fig. 10 The MTT assay results for PAMAM–PEG–PAMAM, Fe3O4-MWCNTs, Fe3O4MWCNTs/PAMAM–PEG– PAMAM, DOX/Fe3O4MWCNTs/PAMAM–PEG– PAMAM hybrid nanomaterials
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absence of a magnetic field was calculated. Results showed that there is a considerable difference between velocity of blood in the ‘‘y’’ direction in the presence (Fig. 9a–c) and absence (Fig. 9d) of a magnetic field. When blood was containing magnetic HNMDDSs, impacting of the blood to the vessel wall increased more than ten times upon switching the magnetic field on. However, there was not a sensible difference between the y-velocity of the blood in the presence of Fe3O4-MWCNTs (Fig. 9a) and Fe3O4MWCNTs/PAMAM–PEG–PAMAM (Fig. 9b) and DOX/ Fe3O4-MWCNTs/PAMAM–PEG–PAMAM (Fig. 9c), confirming that assembling of linear-dendritic copolymers and doxorubicin on Fe3O4-MWCNTs do not quench their response to a magnetic field and targeting the drugs. In order to examine the potential application of HNMDDSs in nanomedicine and to understand their limitation and capability as nano-excipients in biological systems in vitro cytotoxicity tests were conducted on mouse tissue connective fibroblast adhesive cell line (L929) (Fig. 10). Interestingly in low concentrations the toxicity of HNMDDSs is much higher than other systems and even free DOX. This result shows that carbon nanotube has a critical role in transferring HNMDDSs, and therefore loaded DOX, from the cell membrane. On the other hand the toxicity results show that despite the functionalization of carbon nanotubes by different objects, they still are toxic against normal fibroblasts cells.
Conclusion Hybrid nanostructure-based magnetic drug delivery systems with a hybrid properties of individual moieties are promising systems to deliver anticancer drugs to tumors. They are able to load anticancer drugs and kill cancer cells efficiently even in low concentrations.
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