Surface Of Iron Oxide Nanoparticles Research Articles

Engineering magnetic-molecular sequential targeting nanoparticles for anti-cancer therapy.

Nanoparticle drug delivery to tumors via the enhanced permeability and retention (EPR) effect is usually limited by the step of blood circulation and extravasation. Only less than 10% of the administered dose would eventually reach the tumor tissue. To enhance the drug delivery efficiency, we report the approach of magnetic plus molecular dual targeting nanoparticles to combine tumor targeting, drug delivery, and in situ imaging together. The surface of superparamagnetic iron oxide nanoparticles (SPIONs) was coated with biocompatible poly(ethylene glycol)-poly(lactic acid) and then anchored with folic acid (FA). Despite the presence of FA, the hydrodynamic size of SPIONs was less than 100 nm. Increasing the surface FA density sacrificed the aqueous stability of SPIONs, but 20% FA did not induce noticeable particle aggregation. The existence of 20% FA maintained the superparamagnetic property of SPIONs with a saturation magnetization level at ca. 30 emu g-1. The drug release profile was not significantly different between SPIONs with (20%) and without FA. However, the presence of FA dramatically increased the intracellular uptake of SPIONs when using the MCF-7 breast cancer cell line. These results highlighted the role of surface ligand optimization in the design of desired magnetic-molecular dual tumor-targeting nanoparticles.

Dendrimer-Based Multivalent Vancomycin Nanoplatform for Targeting the Drug-Resistant Bacterial Surface

Vancomycin represents the preferred ligand for bacteria-targeting nanosystems. However, it is inefficient for emerging vancomycin-resistant species because of its poor affinity to the reprogrammed cell wall structure. This study demonstrates the use of a multivalent strategy as an effective way for overcoming such an affinity limitation in bacteria targeting. We designed a series of fifth generation (G5) poly(amidoamine) (PAMAM) dendrimers tethered with vancomycin at the C-terminus at different valencies. We performed surface plasmon resonance (SPR) studies to determine their binding avidity to two cell wall models, each made with either a vancomycin-susceptible (D)-Ala-(D)-Ala or vancomycin-resistant (D)-Ala-(D)-Lac cell wall precursor. These conjugates showed remarkable enhancement in avidity in the cell wall models tested, including the vancomycin-resistant model, which had an increase in avidity of four to five orders of magnitude greater than free vancomycin. The tight adsorption of the conjugate to the model surface corresponded with its ability to bind vancomycin-susceptible Staphylococcus aureus bacterial cells in vitro as imaged by confocal fluorescent microscopy. This vancomycin platform was then used to fabricate the surface of iron oxide nanoparticles by coating them with the dendrimer conjugates, and the resulting dendrimer-covered magnetic nanoparticles were demonstrated to rapidly sequester bacterial cells. In summary, this article investigates the biophysical basis of the tight, multivalent association of dendrimer-based vancomycin conjugates to the bacterial cell wall, and proposes a potential new use of this nanoplatform in targeting Gram-positive bacteria.

Temperature-Sensitive Polymer-Coated Magnetic Nanoparticles as a Potential Drug Delivery System for Targeted Therapy of Thyroid Cancer

The objective of this work was to develop and investigate temperature-sensitive poly(N-isopropylacrylamide-acrylamide-allylamine)-coated iron oxide magnetic nanoparticles (TPMNPs) as possible targeted drug carriers for treatments of advanced thyroid cancer (ATC). These nanoparticles were prepared by free radical polymerization of monomers on the surface of silane-coupled iron oxide nanoparticles. In vitro studies demonstrated that TPMNPs were cytocompatible and effectively taken up by cancer cells in a dose-dependent manner. An external magnetic field significantly increased nanoparticle uptake, especially when cells were exposed to physiological flow conditions. Drug loading and release studies using doxorubicin confirmed the temperature-responsive release of drugs from nanoparticles. In addition, doxorubicin-loaded nanoparticles significantly killed ATC cells when compared to free doxorubicin. The in vitro results indicate that TPMNPs have potential as targeted and controlled drug carriers for thyroid cancer treatment.

Amino covalent binding approach on iron oxide nanoparticle surface: Toward biological applications

We report on the synthesis and the surface modification of different types of magnetic iron oxide particles by developing an original process based on diazonium salts chemistry. Particles were first coated with amino groups and then subjected to polyethylene glycol (PEG) surface modification. They were subsequently characterized by transmission electron microscopy, infrared spectroscopy, diffraction light scattering and by Zeta potential. To show the efficiency of this surface modification method, the potential cytotoxicity and (pro-)inflammatory effect of the PEG magnetic particles were also analyzed in vitro. This covalently surface modification approach based on diazonium salts chemistry provides individually dispersed, PEG-modified magnetic nanoparticles suitable for biological applications.

Superparamagnetic iron oxide nanoparticles as radiosensitizer via enhanced reactive oxygen species formation

Internalization of citrate-coated and uncoated superparamagnetic iron oxide nanoparticles by human breast cancer (MCF-7) cells was verified by transmission electron microscopy imaging. Cytotoxicity studies employing metabolic and trypan blue assays manifested their excellent biocompatibility. The production of reactive oxygen species in iron oxide nanoparticle loaded MCF-7 cells was explained to originate from both, the release of iron ions and their catalytically active surfaces. Both initiate the Fenton and Haber–Weiss reaction. Additional oxidative stress caused by X-ray irradiation of MCF-7 cells was attributed to the increase of catalytically active iron oxide nanoparticle surfaces.

Monitoring iron oxide nanoparticle surface temperature in an alternating magnetic field using thermoresponsive fluorescent polymers

We report indirect measurements of the surface temperature of iron oxide nanoparticles in an alternating magnetic field (AMF) through the temperature induced change in fluorescence of a thermoresponsive/fluorescent polymer consisting of poly(N-isopropylacrylamide) (pNIPAM) copolymerized with a fluorescent modified acrylamide (FMA) monomer with fluorescent intensity that increases as its surroundings change from hydrophilic to hydrophobic. When the particles are suspended in water and subjected to external heating, the fluorescence is observed to remain constant up to about 35 °C, above which temperature it increases. When the particles dissipate heat internally in an AMF, the fluorescence intensity increases immediately upon application of the AMF, even though the temperature (as measured by an immersed fiber-optic probe) is below 35 °C. The observed increase in fluorescence intensity indicates a change in the microenvironment of the FMA due to the transition of the pNIPAM from hydrophilic to hydrophobic. This in turn suggests that the nanoparticle surface temperature is above 35 °C and therefore higher than the temperature of the surrounding medium.

Polyglycerol‐grafted superparamagnetic iron oxide nanoparticles: highly efficient MRI contrast agent for liver and kidney imaging and potential scaffold for cellular and molecular imaging

Polyglycerol as a water-soluble and biocompatible hyperbranched polymer was covalently grafted on the surface of superparamagnetic iron oxide nanoparticles. With this aim, superparamagnetic magnetite nanoparticles were prepared by coprecipitation in aqueous media, then the surface of nanoparticles was modified to introduce the reactive groups on the surface of nanoparticles. After that, polyglycerol was grafted on the surface of nanoparticles by ring-opening anionic polymerization of glycidol using n-bulyllithium as initiator. The magnetometry, relaxometry and phantom MRI experiments of this highly stable ferrofluid showed its high potential as a negative MRI contrast agent. Calculated r(1) and r(2) relaxivities at different magnetic fields were higher than the values reported for commercially available iron oxide contrast agents. The in vivo MRI studies showed that, after intravenous injection into mice, the particles produced a strong negative contrast in liver and kidneys, which persisted for 80 min (in liver) to 110 min (in kidneys). The negative contrast of the liver and kidneys weakened over the time, suggesting that polyglycerol coating renders the nanoparticles stealth and possibly optimal for renal excretion.

In situ surface functionalization of magnetic nanoparticles with hydrophilic natural amino acids

The surface of magnetic iron oxide nanoparticles has been modified with hydrophilic natural amino acids via an in situ method. A rapid ligand exchange reaction was induced at elevated temperatures to replace the original labile solvent layer with amino acids. The functionalized nanoparticles were quasi-spherical and well separated with an average diameter around 7nm. The resulted products were examined to be highly crystalline and phase-pure Fe3O4. The present of amino acids on the surface of the nanoparticles was verified by Fourier transform infrared spectroscopy and X-ray photoelectron spectroscopy, which indicated successful ligand exchange. Zeta potential and dynamic light scattering measurement suggested that functionalized magnetic nanoparticles were well dispersed in both basic and acidic aqueous solution with small polydispersity. The uncoordinated amine groups are highly reactive and available for either conjugation with biocompatible polymers or attachment of small gold nanocrystals, so as to prepare dual-functional nanocomposite.

Copper (II) removal by pectin–iron oxide magnetic nanocomposite adsorbent

This study describes an effective copper removal method using pectin-coated iron oxide magnetic nanocomposite as an adsorbent. The nanocomposite adsorbent was synthesized with the iron salt co-precipitation method followed by direct encapsulation with pectin coating without cross linking with calcium ions. Scanning electron microscopy (SEM) images showed pectin–iron oxide magnetic nanocomposite (PIOMN) adsorbent was spherical in shape and 77±5nm in diameter. Fourier transform infrared spectroscopy (FTIR) spectra provided the evidence that pectin was successfully coated on the surface of iron oxide nanoparticle. The interaction between copper ions and pectin on PIOMN surface was elucidated from energy dispersive analysis system of X-ray (EDAX) spectra. The amount of adsorbed Cu(II) by PIOMN adsorbent increased with increasing pH, followed by decreased pH value after copper uptake, attesting to the ion exchange and electrostatic force mechanism during the adsorption process. Sorption kinetic data were well fitted with a pseudo second-order model, and sorption isotherms were described by both Langmuir and Freundlich equation with maximum adsorption capacity of 48.99mg/g. Furthermore, the adsorbents can be regenerated using 0.01M EDTA, remaining 93.70% of its original capacity after the first regeneration cycle, and still reaching 58.66% of the original capacity after the fifth cycle.

PEGylated Versus Non-PEGylated γ Fe2O3@Alendronate Nanoparticles

Thanks to their magnetic properties, superparamagnetic iron oxide nanoparticles are considered as a good delivery vehicle after grafting a therapeutical drug on their surface. For additional “stealth” characteristics, PEGylation of surfaces is necessary. The presence of PEG chains divert nanoparticles from their preferred target, the liver macrophages and increased the particle time circulation. In this work, PEG chain is added to an anticancer drug Alendronate. This molecule is grafted on iron oxide nanoparticle surface in one step surface functionalization method. The in vitro cytotoxic efficiency of γ-Fe2O3- Alendronate-PEG nanocrystals is compared with that of free Alendronate, Alendronate-PEG and γ-Fe2O3- Alendronate nanocrystals.

The interplay of catechol ligands with nanoparticulate iron oxides

The unique properties exhibited by nanoscale materials, coupled with the multitude of chemical surface derivatisation possibilities, enable the rational design of multifunctional nanoscopic devices. Such functional devices offer exciting new opportunities in medical research and much effort is currently invested in the area of "nanomedicine", including: multimodal imaging diagnostic tools, platforms for drug delivery and vectorisation, polyvalent, multicomponent vaccines, and composite devices for "theranostics". Here we will review the surface derivatisation of nanoparticulate oxides of iron and iron@iron-oxide core-shells. They are attractive candidates for MRI-active therapeutic platforms, being potentially less toxic than lanthanide-based materials, and amenable to functionalisation with ligands. However successful grafting of groups onto the surface of iron-based nanoparticles, thus adding functionality whilst preserving their inherent properties, is one of the most difficult challenges for creating truly useful nanodevices from them. Functionalised catechol-derived ligands have enjoyed success as agents for the masking of superparamagnetic iron-oxide particles, often so as to render them biocompatible with medium to long-term colloidal stability in the complex chemical environments of biological milieux. In this perspective, the opportunities and limitations of functionalising the surfaces of iron-oxide nanoparticles, using coatings containing a catechol-derived anchor, are analysed and discussed, including recent advances using dopamine-terminated stabilising ligands. If light-driven ligand to metal charge transfer (LMCT) processes, and pH-dependent ligand desorption, leading to nanoparticle degradation under physiologically relevant conditions can be suppressed, colloidal stability of samples can be maintained and toxicity ascribed to degradation products avoided. Modulation of the redox behaviour of iron catecholate systems through the introduction of an electron-withdrawing substituent to the aromatic π-system of the catechol is a promising approach towards achieving these goals.

Carboxyl–polyethylene glycol–phosphoric acid: a ligand for highly stabilized iron oxide nanoparticles

A new and simple synthetic strategy allows the direct introduction of phosphoric acid anchoring group and carboxyl functional group into polyethylene glycol (PEG), leading to strong binding to iron oxide nanoparticle surfaces through bidentate or tridentate Fe–O–P coordination bonds, and providing functionality for further conjugation of targeting ligands. The carboxyl–PEG–phosphoric-acid-stabilized nanoparticles exhibited extremely high stability in various harsh aqueous environments. The in vivo magnetic resonance imaging (MRI) results showed that the nanoparticles exhibited a long blood circulation time and accumulated in lymph nodes, which indicates that the stabilized Fe3O4 nanoparticles are highly stable in the blood stream and are of exceptionally small hydrodynamic diameter. A promising, rapid, easy synthetic procedure, and a successful in vivo MRI application demonstrate the potential of these functionalized nanoparticles as ideal candidates for biomedical applications.

PH-Titratable Superparamagnetic Iron Oxide for Improved Nanoparticle Accumulation in Acidic Tumor Microenvironments

A wide variety of nanoparticle platforms are being developed for the diagnosis and treatment of malignancy. While many of these are passively targeted or rely on receptor-ligand interactions, metabolically directed nanoparticles provide a complementary approach. It is known that both primary and secondary events in tumorigenesis alter the metabolic profile of developing and metastatic cancers. One highly conserved metabolic phenotype is a state of up-regulated glycolysis and reduced use of oxidative phosphorylation, even when oxygen tension is not limiting. This metabolic shift, termed the Warburg effect, creates a "hostile" tumor microenvironment with increased levels of lactic acid and low extracellular pH. In order to exploit this phenomenon and improve the delivery of nanoparticle platforms to a wide variety of tumors, a pH-responsive iron oxide nanoparticle was designed. Specifically, glycol chitosan (GC), a water-soluble polymer with pH-titratable charge, was conjugated to the surface of superparamagnetic iron oxide nanoparticles (SPIO) to generate a T(2)*-weighted MR contrast agent that responds to alterations in its surrounding pH. Compared to control nanoparticles that lack pH sensitivity, these GC-SPIO nanoparticles demonstrated potent pH-dependent cellular association and MR contrast in vitro. In murine tumor models, GC-SPIO also generated robust T(2)*-weighted contrast, which correlated with increased delivery of the agent to the tumor site, measured quantitatively by inductively coupled plasma mass spectrometry. Importantly, the increased delivery of GC-SPIO nanoparticles cannot be solely attributed to the commonly observed enhanced permeability and retention effect since these nanoparticles have similar physical properties and blood circulation times as control agents.

Phosphonate-Anchored Monolayers for Antibody Binding to Magnetic Nanoparticles

Targeted delivery of magnetic iron oxide nanoparticles (IONPs) to a specific tissue can be achieved by conjugation with particular biological ligands on an appropriately functionalized IONP surface. To take best advantage of the unique magnetic properties of IONPs and to maximize their blood half-life, thin, strongly bonded, functionalized coatings are required. The work reported herein demonstrates the successful application of phosphonate-anchored self-assembled monolayers (SAMs) as ultrathin coatings for such particles. It also describes a new chemical approach to the anchoring of antibodies on the surface of SAM-coated IONPs (using nucleophilic aromatic substitution). This anchoring strategy results in stable, nonhydrolyzable, covalent attachment and allows the reactivity of the particles toward antibody binding to be activated in situ, such that prior to the activation the modified surface is stable for long-term storage. While the SAMs do not have the well-packed crystallinity of other such monolayers, their structure was studied using smooth model substrates based on an iron oxide layer on a double-side polished silicon wafer. In this way, atomic force microscopy, ellipsometry, and contact angle goniometry (tools that could not be applied to the nanoparticles' surfaces) could contribute to the determination of their monomolecular thickness and uniformity. Finally, the successful conjugation of IgG antibodies to the SAM-coated IONPs such that the antibodies retain their biological activity is verified by their complexation to a secondary fluorescent antibody.

Dendronized iron oxide nanoparticles for multimodal imaging

The synthesis of small-size dendrons and their grafting at the surface of iron oxide nanoparticles were achieved with the double objective to obtain a good colloidal stability with a mean hydrodynamic diameter smaller than 100 nm and to ensure the possibility of tuning the organic coating characteristics including morphology, functionalities, physico-chemical properties, grafting of fluorescent or targeting molecules. Magnetic resonance and fluorescence imaging are then demonstrated to be simultaneously possible using such versatile superparamagnetic iron oxide nanocrystals covered by a dendritic shell displaying either carboxylate or ammonium groups at their periphery which could be further labelled with a fluorescent dye. The grafting conditions of these functionalized dendrons at the surface of SPIO NPs synthesized by co-precipitation have been optimized as a function of the nature of the peripheral functional group. The colloidal stability has been investigated in water and osmolar media, and in vitro and in vivo MRI and optical imaging measurements have been performed showing encouraging biodistribution.

Preparation of highly dispersible and tumor-accumulative, iron oxide nanoparticles: Multi-point anchoring of PEG- b-poly(4-vinylbenzylphosphonate) improves performance significantly

This paper describes the preparation of iron oxide nanoparticles, surface of which was coated with extremely high immobilization stability and relatively higher density of poly(ethylene glycol) (PEG), which are referred to as PEG protected iron oxide nanoparticles (PEG-PIONs). The PEG-PIONs were obtained through alkali coprecipitation of iron salts in the presence of the PEG-poly(4-vinylbenzylphosphonate) block copolymer (PEG- b-PVBP). In this system, PEG- b-PVBP served as a surface coating that was bound to the iron oxide surface via multipoint anchoring of the phosphonate groups in the PVBP segment of PEG- b-PVBP. The binding of PEG- b-PVBP onto the iron oxide nanoparticle surface and the subsequent formation of a PEG brush layer were proved by FT-IR, zeta potential, and thermogravimetric measurements. The surface PEG-chain density of the PEG-PIONs varied depending on the [PEG- b-PVBP]/[iron salts] feed-weight ratio in the coprecipitation reaction. PEG-PIONs prepared at an optimal feed-weight ratio in this study showed a high surface PEG-chain surface density (≈0.8 chains nm −2) and small hydrodynamic diameter (<50 nm). Furthermore, these PEG-PIONs could be dispersed in phosphate-buffered saline (PBS) that contains 10% serum without any change in their hydrodynamic diameters over a period of one week, indicating that PEG-PIONs would provide high dispersion stability under in vivo physiological conditions as well as excellent anti-biofouling properties. In fact we have confirmed the prolong blood circulation time and facilitate tumor accumulation (more than 15% ID g −1 tumor) of PEG-PIONs without the aid of any target ligand in mouse tumor models. The majority of the PEG-PIONs accumulated in the tumor by 96 h after administration, whereas those in normal tissues were smoothly eliminated by 96 h, proving the enhancement of tumor selectivity in the PEG-PION localization. The results obtained here strongly suggest that originally synthesized PEG- b-PVBP, having multipoint anchoring character by the phosphonate groups, is rational design for improvement in nanoparticle as in vivo application. Two major points, viz., extremely stable anchoring character and dense PEG chains tethered on the nanoparticle surface, worked simultaneously to become PEG-PIONs as an ideal biomedical devices intact for prolonged periods in harsh biological environments.

In-vitro cytotoxicity and cell uptake study of gelatin-coated magnetic iron oxide nanoparticles

The aim of this study was to modify the surfaces of magnetic iron oxide nanoparticles (IOPs) with gelatin in order to reduce cytotoxicity and enhance cellular uptake. The gelatin-coated IOPs were characterized in terms of their functionalization, size, surface charge, morphology and crystalline structure using Fourier transform infrared (FT-IR) spectroscopy, thermogravimetric analysis (TGA), dynamic light scattering (DLS), transmission electron microscopy (BIO-TEM) and x-ray diffraction (XRD) analysis. The cytotoxicity of the gelatin-coated IOPs to human fibroblasts was assessed using an MTT-assay and was compared with uncoated IOPs. Similarly, the cellular uptake of the coated and uncoated IOPs was visualized using BIO-TEM and quantified using inductively coupled plasma spectroscopy (ICPS). As shown by the Fourier emission scanning electron microscopy (FE-SEM) and viability test, the massive uptake of uncoated IOPs lead to reduced viability. However, gelatin coating lead to increased viability and slow uptake without any visible distortion to the cell morphology.

Iron oxide nanoparticle coating of organic polymer‐based monolithic columns for phosphopeptide enrichment

A new monolithic capillary column with an iron oxide nanoparticle coating has been developed for selective and efficient enrichment of phosphopeptides. Iron oxide nanoparticles were prepared by a co-precipitation method and stabilized by citrate ions. A stable coating of nanoparticles was obtained via multivalent electrostatic interactions of citrate ions on the surface of iron oxide nanoparticles with a quaternary amine functionalized poly(glycidyl methacrylate-co-ethylene dimethacrylate) monolith. A high dynamic binding capacity of 86 μmol/mL column volume was measured with an adenosine-5'-triphosphate. Performance of the monolithic column was demonstrated with the efficient and selective enrichment of phosphopeptides from peptide mixtures of α-casein and β-casein digests and their MALDI/MS characterization in off-line mode.

Self-limiting Deposition of N-(3-Trimethoxysilylpropyl)ethylenediaminetriacetic Acid for the Production of Aqueous-stable Iron Oxide Nanoparticles

Abstract This paper presents a novel self-limiting deposition of a carboxysilane functional group to the surface of maghemite iron oxide nanoparticles (IOP). Self-limited deposition of N-(3-trimethoxysilylpropyl)ethylenediaminetriacetic acid on iron oxide is achieved by rapid injection of the basic silane into acid-stabilized iron oxide. The instant pH shift from 2.3 to 11 through neutral promotes silane deposition on the iron oxide surface but is rapid enough to prevent aggregation and free condensation. Carboxysilane iron oxide particles (CSIOP) are rendered aqueous stable in all pH &amp;gt;5.95. Silane coating is characterized by FTIR, TEM, and DLS.

99mTc-Bisphosphonate-Iron Oxide Nanoparticle Conjugates for Dual-Modality Biomedical Imaging

The combination of radionuclide-based imaging modalities such as single photon emission computed tomography (SPECT) and positron emission tomography (PET) with magnetic resonance imaging (MRI) is likely to become the next generation of clinical scanners. Hence, there is a growing interest in the development of SPECT- and PET-MRI agents. To this end, we report a new class of dual-modality imaging agents based on the conjugation of radiolabeled bisphosphonates (BP) directly to the surface of superparamagnetic iron oxide (SPIO) nanoparticles. We demonstrate the high potential of BP-iron oxide conjugation using (⁹⁹m)Tc-dipicolylamine(DPA)-alendronate, a BP-SPECT agent, and Endorem/Feridex, a liver MRI contrast agent based on SPIO. The labeling of SPIOs with (⁹⁹m)Tc-DPA-alendronate can be performed in one step at room temperature if the SPIO is not coated with an organic polymer. Heating is needed if the nanoparticles are coated, as long as the coating is weakly bound as in the case of dextran in Endorem. The size of the radiolabeled Endorem (⁹⁹m)Tc-DPA-ale-Endorem) was characterized by TEM (5 nm, Fe₃O₄ core) and DLS (106 ± 60 nm, Fe₃O₄ core + dextran). EDX, Dittmer-Lester, and radiolabeling studies demonstrate that the BP is bound to the nanoparticles and that it binds to the Fe₃O₄ cores of Endorem, and not its dextran coating. The bimodal imaging capabilities and excellent stability of these nanoparticles were confirmed using MRI and nanoSPECT-CT imaging, showing that (⁹⁹m)Tc and Endorem co-localize in the liver and spleen In Vivo, as expected for particles of the composition and size of (⁹⁹m)Tc-DPA-ale-Endorem. To the best of our knowledge, this is the first example of radiolabeling SPIOs with BP conjugates and the first example of radiolabeling SPIO nanoparticles directly onto the surface of the iron oxide core, and not its coating. This work lays down the basis for a new generation of SPECT/PET-MR imaging agents in which the BP group could be used to attach functionality to provide targeting, stealth/stability, and radionuclides to Fe₃O₄ nanoparticles using very simple methodology readily amenable to GMP.