Doxorubicin loaded large-pore mesoporous hydroxyapatite coated superparamagnetic Fe3O4 nanoparticles for cancer treatment
Graphical abstract
Introduction
Nowadays, nanoscience is considered as one of the most important research and development fields in modern science. Due to the advent of new and improved technology during the recent years, research on nanotechnology, in particular, engineered nanomaterials, has received considerable attention. Engineered nanomaterials such as carbon nanotubes, quantum dots, and magnetic nanoparticles are among the most promising materials being used as essential platforms for targeted drug delivery, imaging and monitoring of therapeutic efficacy (Singh and Lillard, 2009, Xie et al., 2010).
Engineered nanomaterials can be designed and synthesized with very specific properties via certain chemical or physical processes putting them at the leading edge of the rapidly developing nanosciences. Magnetic nanoparticles (MNPs) are an important class of engineered nanomaterials that can be manipulated by external magnetic fields. Depending on the size and subsequent change in magnetic properties, the magnetic nanoparticles are useful for a wide range of applications ranging from drug localization and magnetic hyperthermia to gene transfection and enhancement of medical images (Shubayev et al., 2009).
The synthesis of nanosized magnetic materials is currently the subject of intense study due to their potential applications in areas of biology, medicine, pharmacy and diagnostics. MNPs have been synthesized with a number of different compositions and phases, including pure metals (Fe, Co and Ni), metal oxides, ferrites and metal alloys (Mahmoudi et al., 2011, Faraji et al., 2010). Inorganic nanoparticles, especially magnetic iron oxides, have gained attention because of their unique properties, such as ease of handling, biocompatibility and suitable surface chemistry and potential applications in various fields, such as magnetically assisted drug delivery (Sun et al., 2008, Neuberger et al., 2005), magnetic resonance imaging (MRI) contrast agents (Yallapu et al., 2011), hyperthermia (Kumar and Mohammad, 2011) and tissue engineering (Bock et al., 2010).
Most of these applications require the nanoparticles to be chemically stable, uniform in size, and well dispersed in liquid media (Laurent et al., 2008). To achieve these aims, MNPs can be coated, surface modified or combined with different materials such as polymeric coatings (Poly ethylene glycol–PEG) (Veiseh et al., 2010), dextran (Veiseh et al., 2010) and oleic acid (Tomitaka et al., 2012) to prevent nanoparticles agglomeration (due to their superparamagnetic properties and as a result of their high surface energy) and avoid oxidation. There are other types of coatings like inorganic materials such as silica (Pankhurst et al., 2003), bioglass (Wu et al., 2011) and hydroxyapatite (Tran and Webster, 2011) which are inert and even bioactive. These inorganic materials unlike polymeric ones are stable and also nontoxic which characteristics are useful for biomedical application such as drug delivery (Son et al., 2007)
For a proper and efficient drug delivery, the coating material should have places for drug molecules adsorption. Mesoporous materials which have unique tunable pore size, higher surface area and relatively large pore volume can offer these places (Wang, 2009). Accordingly, in recent years, mesoporous materials have been widely employed for drug delivery and controlled-release systems. The basic imperfection of these platforms would be the small size of their pores which do not have ability to adsorb large amount of drugs or drugs with large molecular sizes (Rosenholm et al., 2011). To modify this defect, mesoporous hydroxyapatite was synthesized with large pores (about 12 nm) by a rapid, low cost, wet chemistry method as a coating for magnetic nanoparticles with the application in targeted drug delivery.
Although mesoporous materials are one of the best candidates to incorporate high doses of drugs into the mesoporous and release them at a controlled rate, most of them are based on silica or doped-silica materials which suffer from several limitations such as the poor bioactivity and biodegradability. In addition, the overuse of silica may exhibit a significant degree of toxicity such as silicosis, chronic bronchitis even pulmonary cancer (Faraji and Wipf, 2009). Therefore, currently many researches are going on to obtain more biocompatible mesoporous materials for drug delivery and controlled release systems.
Hydroxyapatite [Ca10(PO4)6(OH)2 or HA] has long been known for its excellent biocompatibility, unique mechanical properties, bioactivity, and excellent ability to form chemical bond with living bone tissue (Vallet-Regí and Ruiz-Hernández, 2011). Because of its nontoxic and non-inflammatory properties, HA with various morphologies and surface properties has also been investigated as carriers for the delivery of a variety of pharmaceutical molecules (Matsumoto et al., 2004) and even for ocular implants (Kundu et al., 2004). But the low surface area may limit their further application in many conditions (Ng et al., 2010). Therefore, many efforts have been made to overcome these drawbacks including synthesis of different morphologies of HA materials. Among them, synthesis of mesoporous HA has attracted much more attention because of its ability to overcome these drawbacks to a certain extent along with its good biocompatibility and bioactivity properties with respect to bone cells and tissues.
It is also possible to increase the advantages of this remarkable framework by appropriate combinations of different types of functional nano-structured materials. Super paramagnetic iron oxide nanoparticles (SPIONs) can offer multiple opportunities to improve the efficacy of these multifunctional nano-structured systems. There are numerous reports in which SPIONs have been used to increase the accumulation of a therapeutic agent in target tissues with local strong magnetic fields (Veiseh et al., 2010). As a hyperthermic agent, SPIONs can provide an additional strategy for treatment of malignant tissues (Laurent et al., 2011). SPIONs can be also used as a tracer due to their ability for easy detection by optical microscopy or electron microscopy.
In the present study, a series of novel multifunctional composite nanoparticles were developed for the first time by the assembly of three functionalities: super paramagnetic Fe3O4 nano particles for providing the magnetic properties, mesoporous HA coating with cavities for drug adsorption, and doxorubicin (DOX) as the main therapeutic agent. From synthetic point of view, to the best of our knowledge, this is the first study that demonstrates synthesis of magnetic mesoporous HA.
The loading and release profile of DOX were accomplished by these novel nano-carriers in different pH values. It is expected that such a study would provide and promote the therapeutic efficiency through increasing concentration of DOX in tumor cells, providing longer residence time of drug in the targeted tissue, and reducing denaturation and toxicity of DOX. Moreover, this new platform has the potential of hyperthermic effect due to existence of SPIONs inside the nanocomposites.
Section snippets
Materials
Ferric chloride hexahydrate (FeCl3·6H2O), ferrous chloride tetrahydrate (FeCl2·4H2O), ethanol and aqueous ammonia (25% (v/v) aqueous solution), Potassium di-hydrogenphosphate (KH2PO4) were purchased from Merck, Germany. Calcium acetate (Ca(C2H3OO)2) with molecular weight of 158.17 g/mol and F127 Triblock copolymer with chemical formula EO99PO65EO99 and molecular weight of 12,600 g/mol used as a surfactant were obtained from Panreac QUIMCA Company and Sigma Aldrich, respectively. Sucrose used in
Chemical structure characteristics of samples
Fig. 1 shows the wide angle XRD pattern of mesoporous HA and mesoporous HAcoated Fe3O4 nanoparticles.
The peaks detected for mesoporous HA and mesoporous HA coated Fe3O4 nanoparticles were similar to those of JCPDS card No. 00-009-0432 Hydroxyapatite and JCPDS card No.79-0417 for mesoporous HA coated Fe3O4 nanoparticles, respectively indicating formation of both HA and Fe3O4. As it has been shown in Fig. 1, the site of characteristic peaks of mesoporous HA demonstrated in Fig. 1A are also
Discussion
HA with excellent properties such as biocompatibility, bioactivity, non-mutagenicity, non-toxicity, diverse morphologies and surface properties has been known as an effective delivery system for several drugs and biological molecules (Kalita et al., 2007). Creating more pores in the structure of this platform can make it much more useful for delivery aims. The use of SPIONs particularly in conjugation with other delivery platforms is another interesting strategy that has been widely studied for
Conclusion
Large-pore mesoporous HA coated superparamagnetic nanoparticles with pore sizes of around 12 nm were successfully synthesized. The mesoporous coating was synthesized using a very simple method which is wet chemistry route. The washing method was used for extracting surfactant instead of calcination which ensures no change in physical and chemical properties of mesoporous HA and magnetite due to lack of heat. Owing to large pores, these nanoparticles can be a very noteworthy carrier for a
Conflicts of interest
The authors declare that there are no conflicts of interest.
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