PEG mediated shape-selective synthesis of cubic Fe3O4 nanoparticles for cancer therapeutics
Graphical abstract
Introduction
The development of nanomaterials with controlled size and shape continues to cumulate widespread attention because of their exclusive physico-chemical properties, which make them distinct from their atomic as well as bulk counterparts [1], [2]. Although a large variety of nanomaterials are being used in biomedical applications, the magnetic nanoparticles (MNPs) seem to hold the utmost potential of achievement. They are already established in clinical use as contrast agent for magnetic resonance imaging (MRI) [3]. In addition to this, MNPs have found potential applications in magnetic drug targeting and non-invasive hyperthermia therapy [4]. Among the abundant array of MNPs, superparamagnetic iron oxide (Fe3O4) nanoparticles have turned up as delicate therapeutic vehicle for these applications [5], [6], [7], [8], [9], [10]. The applicability of Fe3O4 nanoparticles depends upon their size, size distribution, surface functionality, aqueous colloidal stability and biocompatibility [11], [12], [13], [14]. These characteristics are highly dependent on the method of preparation, type of precursors and coating agents. Numerous methods such as co-precipitation, thermal decomposition, microemulsion and hydrothermal synthesis etc. are extensively employed for preparation of Fe3O4 nanoparticles of well-defined sizes, shapes and other physical properties [15], [16], [17], [18], [19]. Among these, thermal decomposition of organometallic precursors of iron in presence of surfactants in high boiling solvent is highly favoured for the preparation of Fe3O4 MNPs with high crystallinity and uniform particle size distribution [16], [20]. Further, this method is also used for preparation of different shaped Fe3O4 particles by adjusting reaction parameters such as surfactant/precursor ratio, heating rate, reaction time and use of co-surfactants etc [20], [21], [22], [23]. The particle anisotropy (associated with both shape and surface morphology) strongly influences the transverse relaxivity as well as heating efficacy of MNPs [24]. However, thermal decomposition method mainly yields organic-soluble hydrophobic MNPs, which needs to be functionalized with suitable bioactive ligands for their water-solubility and biocompatibility [18], [21]. Therefore, the surface modification of Fe3O4 MNPs with desired functionality is crucial for biomedical applications. Further, the functional moieties provide sites for binding of therapeutic molecules such as anticancer drugs or antibodies.
Amongst the others, poly(ethylene glycol) (PEG) has been found to be a favourable coating agent due to its biocompatible and hydrophilic nature [16], [25], [26]. In addition, non-immunogenic properties and resistance to plasma protein deposition make it as a unique surface modifying agent. This PEGylation makes them improved nanocarriers for therapeutic applications by providing protein resistance characteristics and increased blood circulation time [27], [28]. For instance, Ruiz et al. [29] reported that the residence time in blood was doubled for Fe3O4 MNPs modified with PEG as compared to their bare counterpart and consequently particle accumulation in liver and spleen was reduced. However, they employed multistep coating procedure for developing water-dispersible magnetite nanoparticles (obtained via thermal decomposition of an iron coordination complex). Thus, the development of cost effective methods for the preparation of PEG coated uniform sized Fe3O4 MNPs would be of extreme importance. Herein, we report a facile strategy for one-pot synthesis of water-dispersible, PEGylated Fe3O4 cubic magnetic nanoparticles (PCMN) by thermal decomposition of iron (III) acetylacetonate in presence of carboxyl terminated PEG-diacid using PEG as a solvent. The presence of the free carboxyl group on the surface of PCMN provides aqueous colloidal stability, non-toxicity and protein resistance properties to them. These PCMN have high affinity for electrostatic binding of positively charged anticancer drug, DOX. It has been observed that DOX in conjugation with PCMN retained good therapeutic efficacy and showed substantial cellular internalization in WEHI-164 cells. In addition, these nanoparticles possess superparamagnetic behaviour and excellent heating efficacy under external AC magnetic field.
Section snippets
Materials
Iron (III) acetylacetonate (97%), poly(ethylene glycol) (PEG, Mn = 600), PEG diacid (poly(ethylene glycol) bis(carboxymethyl) ether, Mn = 600), doxorubicin hydrochloride (DOX, 98%), and bovine serum albumin (BSA) were purchased from Sigma Aldrich, USA. Sodium acetate, ferrous ammonium sulphate and 1, 10-phenanthroline monohydrate were procured from SRL Pvt. Ltd., India. NIH 3T3 and WEHI-164 cells were obtained from National Centre for Cell Science (NCCS), India. Dulbecco's Modified Eagle Medium
Results and discussion
PEG and PEG-diacid mixture play multiple roles in the formation of highly crystalline Fe3O4 nanoparticles. They not only serve as solvent and complexing agents for the iron but also stabilize the resulting nanoparticles. Our synthesis protocol does not involve multiple steps and use of surfactants such as oleic acid, oleylamine, 1,2-dodecanediol and 1,2-hexadecanediol etc. which are commonly used in thermal decomposition method [17], [31], [32], [33]. Moreover, the PEGylation of nanoparticles
Conclusions
We have demonstrated a simple and one-pot synthesis method for preparation of water-dispersible, negatively charged PEGylated cubic shaped Fe3O4 nanoparticles. The free carboxyl groups present on the surface of PCMN provide colloidal stability, biocompatibility and protein resistance characteristics to the particles. Thus, these particles can be readily usable for various biomedical applications without subsequent surface modifications. The negatively charged PCMN showed good binding affinity
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