One-step synthesis of hydrophilic functionalized and cytocompatible superparamagnetic iron oxide nanoparticles (SPIONs) based aqueous ferrofluids for biomedical applications
Graphical abstract
Introduction
Nowadays, several magnetic nanostructured materials are constantly being developed/modified for the biomedical applications [[1], [2], [3], [4], [5]]. Recently, superparamagnetic iron oxide nanoparticles (SPIONs – particularly magnetite (Fe3O4)/maghemite (Fe2O3)) have been enormously attracted in different applications such as magnetic targeting [[6], [7], [8]], magnetofection [[9], [10], [11], [12]], magnetic fluid hyperthermia (MFH) [[13], [14], [15], [16], [17]] and magnetic resonance imaging (MRI) [[18], [19], [20], [21], [22]] due to their unique magnetic properties, excellent chemical stability and biodegradability [[23], [24], [25]]. However, for effective utilization of the SPIONs in the biomedical fields, they should possess high magnetization, better cytocompatibility and good water dispersibility/solubility (to be used in the form of ferrofluids) which might be altered during their chemical synthesis.
Till date, thermolysis (i.e., thermal decomposition of the iron precursors at elevated temperature) in the presence of high boiling-point non-polar solvents (for e.g., phenyl/benzyl ether), and organic stabilizers/surfactants (for e.g., oleic acid/oleylamine) is one of the very capable methods for synthesizing high quality SPIONs with enhanced crystallinity/saturation magnetization (Ms) and uniform particle size distribution [26,27]. But, these as-synthesized hydrophobic SPIONs can only be dispersed in the organic solvents (e.g., hexane) to form non-aqueous ferrofluids, which are not straightway useful for their biomedical applications. Therefore, surface of these hydrophobic SPIONs should be modified further to convert them into hydrophilic – either via ligand exchange/bilayer stabilization processes [[28], [29], [30], [31]], or polymeric encapsulation methods [[32], [33], [34], [35], [36]] – to form aqueous ferrofluids (AFFs) for instant utilization. Nevertheless, these surface modification procedures (i) are very complicated/time-consuming, and (ii) might significantly affect the magnetization and/or biocompatibility of the SPIONs. Furthermore, there is also a risk of dissociation of the modified hydrophilic surface coatings/layers which might eventually lead to the aggregation of the SPIONs in the aqueous ferrofluid suspensions (AFFs). Recently, polyols (for e.g., diethylene glycol (DEG), triethylene glycol (TEG), tetraethylene glycol (TTEG)) have been extensively used as the high boiling-point polar solvents/stabilizing agents to directly synthesize the hydrophilic SPIONs based AFFs via thermolysis [37,38]. However, these hydrophilic SPIONs are incapable for further bio-conjugations due to lack of their effective surface functional groups.
To overcome this issue, Qu et al. have lately demonstrated the use of polyamines (for e.g., triethylene tetraamine (TETA)) in thermolysis to directly synthesize hydrophilic amine (-NH2) functionalized SPIONs which could be effortlessly bio-conjugated with the biomolecules such as biotin and streptavidin [39,40]. However, the synthesis of hydrophilic SPIONs using other polyamines (apart from TETA) has not been explored. Moreover, there is need for systematic investigations of the physicochemical/magnetic properties, water solubility/dispersibility and cytocompatibility of these amine functionalized SPIONs for their effective utilizations for the biomedical applications.
Therefore, in this work, we have prepared hydrophilic functionalized SPIONs via one-step thermolysis by using the polyamines such as diethylene triamine (DETA), TETA, tetraethylene pentamine (TTEPA) and pentaethylene hexamine (PEHA) or the mixture of a polyamine (TETA) and polyols (DEG/TEG/TTEG) while varying their ratio, reaction temperature and reaction time. Subsequently, their physicochemical/magnetic properties such as size/morphology, crystalline/surface structure, magnetization and water dispersibility/solubility are systematically investigated. Finally, the cytocompatibility and intracellular uptake of the as-prepared amine-functionalized SPIONs are inspected using the cancer cell lines (MCF-7 and HepG2) to evaluate their potentiality for biomedical applications.
Section snippets
Materials
Iron (III) acetylacetonate (Fe(acac)3), potassium hexacyanoferrate (C6N6FeK3), and potassium thiocyanate (KSCN) are purchased from Sigma-Aldrich. Diethylene glycol (DEG), diethylene triamine (DETA), triethylene glycol (TEG), triethylene tetraamine (TETA), tetraethylene glycol (TTEG), tetraethylene pentamine (TEPA), pentaethylene hexamine (PEHA), ethanol and ethyl acetate are obtained from Fisher Scientific. Fetal bovine serum (FBS), phosphate buffer saline (PBS) and Dulbecco's modified eagle
Effects of polyamines
Initially, the SPIONs are synthesized via thermolysis in the presence of different polyamines such as DETA, TETA, TTEPA, and PEHA at their corresponding refluxing/reaction temperature for 1 h to obtain the samples - S1, S2, S3 and S4, respectively (refer Table 1).
Fig. 1(i–iv) show the respective TEM images of S1–S4 samples and the average particle sizes of these samples are determined (using Image J software) as 6.1 ± 0.9, 7.0 ± 1.4, 7.2 ± 2.5, and 9.7 ± 3.2 nm, respectively. It can be seen
Conclusions
In summary, we report the synthesis of hydrophilic functionalized SPIONs via one-step thermolysis of iron (III) acetylacetonate by using the polyamines or mixture of polyamines and polyols. However, the as-prepared polyamines (DETA/TETA/TTEPA/PEHA) coated SPIONs (i.e. S1–S4) demonstrated lower Ms. values ranging from 31.8–48.5 emu/g. The magnetization values of the SPIONs are gradually improved from 51.9 to 57.8 emu/g by the addition of increased amount of TEG to TETA from 4:1 to 1:1 v/v ratio
Acknowledgments
The financial supports obtained from the following funding agencies are highly acknowledged: (i) Nanomission (Grant No. SR/NM/NS-1141/2015 (G)), Department of Science and Technology (DST), New Delhi, India and (ii) Shiv Nadar University, Uttar Pradesh, India.
References (72)
- et al.
Ferrofluids of magnetic multicore nanoparticles for biomedical applications
J. Magn. Magn. Mater.
(2009) - et al.
Magnetic nanoparticles and targeted drug delivering
Pharmacol. Res.
(2010) - et al.
Comprehensive cytotoxicity studies of superparamagnetic iron oxide nanoparticles
Biochem. Biophys. Rep.
(2018) - et al.
Iron oxide-loaded nanotheranostics: major obstacles to in vivo studies and clinical translation
J. Control. Release
(2015) - et al.
Magnetically enhanced nucleic acid delivery. Ten years of magnetofection-Progress and prospects
Adv. Drug Deliv. Rev.
(2011) - et al.
Systematic investigations on heating effects of carboxyl-amine functionalized superparamagnetic iron oxide nanoparticles (SPIONs) based ferrofluids for in vitro cancer hyperthermia therapy
J. Mol. Liq.
(2018) - et al.
Systematic magnetic fluid hyperthermia studies of carboxyl functionalized hydrophilic superparamagnetic iron oxide nanoparticles based ferrofluids
J. Colloid Interface Sci.
(2018) - et al.
Multifunctional poly (lactide‑co‑glycolide) nanoparticles for luminescence/magnetic resonance imaging and photodynamic therapy
Int. J. Pharm.
(2012) - et al.
Recent advances in superparamagnetic iron oxide nanoparticles (SPIONs) for in vitro and in vivo cancer nanotheranostics
Int. J. Pharm.
(2015) - et al.
Synthesis of magnetite nanoparticles via a solvent-free thermal decomposition route
J. Magn. Magn. Mater.
(2009)
Key synthesis of magnetic Janus nanoparticles using a modified facile method
Particuology
One-pot synthesis of water-soluble superparamagnetic iron oxide nanoparticles and their MRI contrast effects in the mouse brains
Mater. Sci. Eng. C
Synthesis, magnetic and electrical characteristics of poly(2‑thiophen‑3‑yl‑malonic acid)/Fe3O4 nanocomposite
J. Alloys Compd.
Studies of magnetite nanoparticles synthesized by thermal decomposition of iron (III) acetylacetonate in tri(ethylene glycol)
J. Magn. Magn. Mater.
Synthesis of iron oxide nanoparticles under oxidizing environment and their stabilization in aqueous and non-aqueous media
J. Magn. Magn. Mater.
Effect of sugar alcohol on colloidal stabilization of magnetic nanoparticles for hyperthermia and drug delivery applications
J. Alloys Compd.
Monodisperse sodium oleate coated magnetite high susceptibility nanoparticles for hyperthermia applications
J. Magn. Magn. Mater.
PVA and PEG functionalised LSMO nanoparticles for magnetic fluid hyperthermia application
Mater. Charact.
Superparamagnetic iron oxide nanoparticles coated with different polymers and their MRI contrast effects in the mouse brains
Appl. Surf. Sci.
Enhanced colloidal stability of polymer coated La0.7Sr0.3MnO3 nanoparticles in physiological media for hyperthermia application
Colloids Surf. B: Biointerfaces
In vitro hyperthermia with improved colloidal stability and enhanced SAR of magnetic core/shell nanostructures
Mater. Sci. Eng. C
Applications of magnetic nanoparticles in biomedicine
J. Phys. D. Appl. Phys.
Application of magnetic nanoparticles to gene delivery
Int. J. Mol. Sci.
Synthesis, characterization, applications, and challenges of iron oxide nanoparticles
Nanotechnol. Sci. Appl.
Rethinking cancer nanotheranostics
Nat. Rev. Mater.
Magnetofection: a reproducible method for gene delivery to melanoma cells
Biomed. Res. Int.
Functional nanostructures for effective delivery of small interfering RNA therapeutics
Theranostics
One-pot synthesis of PDMAEMA-bound iron oxide nanoparticles for magnetofection
J. Mater. Chem. B
Fundamentals and advances in magnetic hyperthermia
Appl. Phys. Rev.
Magnetic fluid hyperthermia: advances, challenges, and opportunity
Int. J. Hyperth.
Advances in magnetic nanoparticles for biomedical applications
Adv. Healthc. Mater.
Facile synthesis of water-stable magnetite nanoparticles for clinical MRI and magnetic hyperthermia applications
Nanomedicine
High-performance nanostructured MR contrast probes
Nanoscale
Induced clustered nanoconfinement of superparamagnetic iron oxide in biodegradable nanoparticles enhances transverse relaxivity for targeted theranostics
Magn. Reson. Med.
Inorganic nanoparticles for MRI contrast agents
Adv. Mater.
Synthesis, functionalization, and Design of Magnetic Nanoparticles for Theranostic applications
Adv. Healthc. Mater.
Cited by (27)
Superparamaetic iron oxide nanoparticles target BxPC-3 cells and silence MUC4 for theranostics of pancreatic cancer
2023, Biochimica et Biophysica Acta - General SubjectsAn overview of biomedical applications of oxide materials
2023, Oxides for Medical ApplicationsSynthesis and characterization of ferrite nanostructures for specific biomedical applications
2023, Applications of Nanostructured FerritesSurface engineered palmitoyl-mesoporous silica nanoparticles with supported lipid bilayer coatings for high-capacity loading and prolonged release of dexamethasone: A factorial design approach
2022, Journal of Drug Delivery Science and TechnologyCitation Excerpt :Even after ultra-sonication, these particles were not be well dispersed [62,63]. However, increasing the palmitoyl chloride ratio reduced particle sizes of MSN-PALM9 and MSN-PALM13 to around 100 nm, which may be explained by further reacting palmitoylated secondary amines to palmitoyl chloride reagent to obtain MSNs covered with palmitoyl chains preventing particle aggregation after ultra-sonication [62,64]. This finding was supported by the fact that MSN-PALM9 and MSN-PALM13 had PDI values less than 0.3 (Table 1).
Theranostic silk sericin/SPION nanoparticles for targeted delivery of ROR1 siRNA: Synthesis, characterization, diagnosis and anticancer effect on triple-negative breast cancer
2022, International Journal of Biological Macromolecules