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1.  Enhanced pulsed magneto-motive ultrasound imaging using superparamagnetic nanoclusters 
Nanotechnology  2010;22(4):045502.
Recently, pulsed magneto-motive ultrasound (pMMUS) imaging augmented with ultra-small magnetic nanoparticles has been introduced as a tool capable of imaging events at molecular and cellular levels. The sensitivity of a pMMUS system depends on several parameters, including the size, geometry and magnetic properties of the nanoparticles. Under the same magnetic field, larger magnetic nanostructures experience a stronger magnetic force and produce larger displacement, thus improving the sensitivity and signal-to-noise ratio (SNR) of pMMUS imaging. Unfortunately, large magnetic iron-oxide nanoparticles are typically ferromagnetic and thus are very difficult to stabilize against colloidal aggregation. In the current study we demonstrate improvement of pMMUS image quality by using large size superparamagnetic nanoclusters characterized by strong magnetization per particle. Water-soluble magnetic nanoclusters of two sizes (15 and 55 nm average size) were synthesized from 3 nm iron precursors in the presence of citrate capping ligand. The size distribution of synthesized nanoclusters and individual nanoparticles was characterized using dynamic light scattering (DLS) analysis and transmission electron microscopy (TEM). Tissue mimicking phantoms containing single nanoparticles and two sizes of nanoclusters were imaged using a custom-built pMMUS imaging system. While the magnetic properties of citrate-coated nanoclusters are identical to those of superparamagnetic nanoparticles, the magneto-motive signal detected from nanoclusters is larger, i.e. the same magnetic field produced larger magnetically induced displacement. Therefore, our study demonstrates that clusters of superparamagnetic nanoparticles result in pMMUS images with higher contrast and SNR.
doi:10.1088/0957-4484/22/4/045502
PMCID: PMC3059156  PMID: 21157009
2.  In vivo Pulsed Magneto-motive Ultrasound Imaging Using High-performance Magnetoactive Contrast Nanoagents 
Nanoscale  2013;5(22):11179-11186.
Previously, pulsed magneto-motive ultrasound (pMMUS) imaging has been introduced as a contrast-agent-assisted ultrasound-based imaging modality capable of visualizing biological events at the cellular and molecular level. In pMMUS imaging, a high intensity pulsed magnetic field is used to excite cells or tissue labeled with magnetic nanoparticles. Then, ultrasound (US) imaging is used to monitor the mechanical response of the tissue to an externally applied magnetic field (i.e., tissue displacement). Signal to noise ratio (SNR) in pMMUS imaging can be improved by using superparamagnetic nanoparticles with larger saturation magnetization. Metal-doped magnetic nanoparticles with enhanced tunable nanomagnetism are suitable candidates to improve the SNR and, therefore, sensitivity of pMMUS imaging, which is essential for in vivo pMMUS imaging. In this study, we demonstrate the capability of pMMUS imaging to identify the presence and distribution of zinc-doped iron oxide nanoparticles in live nude mice bearing A431 (human epithelial carcinoma) xenograft tumors.
doi:10.1039/c3nr03669c
PMCID: PMC3916332  PMID: 24080913
3.  Contrast-enhanced magneto-photo-acoustic imaging in vivo using dual-contrast nanoparticles☆ 
Photoacoustics  2014;2(2):55-62.
By mapping the distribution of targeted plasmonic nanoparticles (NPs), photoacoustic (PA) imaging offers the potential to detect the pathologies in the early stages. However, optical absorption of the endogenous chromophores in the background tissue significantly reduces the contrast resolution of photoacoustic imaging. Previously, we introduced MPA imaging – a synergistic combination of magneto-motive ultrasound (MMUS) and PA imaging, and demonstrated MPA contrast enhancement using cell culture studies. In the current study, contrast enhancement was investigated in vivo using the magneto-photo-acoustic (MPA) imaging augmented with dual-contrast nanoparticles. Liposomal nanoparticles (LNPs) possessing both optical absorption and magnetic properties were injected into a murine tumor model. First, photoacoustic signals were generated from both the endogenous absorbers in the tissue and the liposomal nanoparticles in the tumor. Then, given significant differences in magnetic properties of tissue and LNPs, the magnetic response of LNPs (i.e. MMUS signal) was utilized to suppress the unwanted PA signals from the background tissue thus improving the PA imaging contrast. In this study, we demonstrated the 3D MPA imaging of LNP-labeled xenografted tumor in a live animal. Compared to conventional PA imaging, the MPA imaging show significantly enhanced contrast between the nanoparticle-labeled tumor and the background tissue. Our results suggest the feasibility of MPA imaging for high contrast in vivo mapping of dual-contrast nanoparticles.
doi:10.1016/j.pacs.2013.12.003
PMCID: PMC3956135  PMID: 24653976
PA, photoacoustic; MMUS, magneto-motive ultrasound; MPA, magneto-photo-acoustic; NPs, nanoparticles; LNPs, liposomal nanoparticles; Contrast enhancement; Magneto-photoacoustic imaging; Nanoparticle distribution; Dual-contrast nanoparticles
4.  Pulsed Magneto-motive Ultrasound Imaging Using Ultrasmall Magnetic Nanoprobes 
Molecular imaging  2011;10(2):102-110.
Nano-sized particles are widely regarded as a tool to study biologic events at the cellular and molecular levels. However, only some imaging modalities can visualize interaction between nanoparticles and living cells. We present a new technique, pulsed magneto-motive ultrasound imaging, which is capable of in vivo imaging of magnetic nanoparticles in real time and at sufficient depth. In pulsed magneto-motive ultrasound imaging, an external high-strength pulsed magnetic field is applied to induce the motion within the magnetically labeled tissue and ultrasound is used to detect the induced internal tissue motion. Our experiments demonstrated a sufficient contrast between normal and iron-laden cells labeled with ultrasmall magnetic nanoparticles. Therefore, pulsed magneto-motive ultrasound imaging could become an imaging tool capable of detecting magnetic nanoparticles and characterizing the cellular and molecular composition of deep-lying structures.
PMCID: PMC3101631  PMID: 21439255
5.  Quantum dots incorporated magnetic nanoparticles for imaging colon carcinoma cells 
Background
Engineered multifunctional nanoparticles (NPs) have made a tremendous impact on the biomedical sciences, with advances in imaging, sensing and bioseparation. In particular, the combination of optical and magnetic responses through a single particle system allows us to serve as novel multimodal molecular imaging contrast agents in clinical settings. Despite of essential medical imaging modalities and of significant clinical application, only few nanocomposites have been developed with dual imaging contrast. A new method for preparing quantum dots (QDs) incorporated magnetic nanoparticles (MNPs) based on layer-by-layer (LbL) self-assembly techniques have developed and used for cancer cells imaging.
Methods
Here, citrate - capped negatively charged Fe3O4 NPs were prepared and coated with positively - charged hexadecyltrimethyl ammonium bromide (CTAB). Then, thiol - capped negatively charged CdTe QDs were electrostatically bound with CTAB. Morphological, optical and magnetic properties of the fluorescent magnetic nanoparticles (FMNPs) were characterized. Prepared FMNPs were additionally conjugated with hCC49 antibodies fragment antigen binding (Fab) having binding affinity to sialylated sugar chain of TAG-72 region of LS174T cancer cells, which was prepared silkworm expression system, and then were used for imaging colon carcinoma cells.
Results
The prepared nanocomposites were magnetically responsive and fluorescent, simultaneously that are useful for efficient cellular imaging, optical sensing and magnetic separation. Transmission electron microscopy (TEM) and dynamic light scattering (DLS) revealed that the particle size is around 50 nm in diameter with inner magnetic core and outer CdTe QDs core-shell structure. Cytotoxicity test of prepared FMNPs indicates high viability in Vero cells. NPs conjugated with anti cancer antibodies were successfully labeled on colon carcinoma cells (LS174) in vitro and showed significant specificity to target cells.
Conclusion
The present report demonstrates a simple synthesis of CdTe QDs-Fe3O4 NPs. The surface of the prepared FMNPs was enabled simple conjugation to monoclonal antibodies by electrostatic interaction. This property further extended their in vitro applications as cellular imaging contrast agents. Such labeling of cells with new fluorescent-magneto nanoprobes for living detection is of interest to various biomedical applications and has demonstrated the potential for future medical use.
doi:10.1186/1477-3155-11-28
PMCID: PMC3751691  PMID: 23957878
Core-shell structure; Magnetic nanoparticles; Quantum dots; Fluorescent nanoparticles; Cell imaging
6.  Magneto-Optical Relaxation Measurements of Functionalized Nanoparticles as a Novel Biosensor 
Sensors (Basel, Switzerland)  2009;9(6):4022-4033.
Measurements of magneto-optical relaxation signals of magnetic nanoparticles functionalized with biomolecules are a novel biosensing tool. Upon transmission of a laser beam through a nanoparticle suspension in a pulsed magnetic field, the properties of the laser beam change. This can be detected by optical methods. Biomolecular binding events leading to aggregation of nanoparticles are ascertainable by calculating the relaxation time and from this, the hydrodynamic diameters of the involved particles from the optical signal. Interaction between insulin-like growth factor 1 (IGF-1) and its antibody was utilized for demonstration of the measurement setup applicability as an immunoassay. Furthermore, a formerly developed kinetic model was utilized in order to determine kinetic parameters of the interaction. Beside utilization of the method as an immunoassay it can be applied for the characterization of diverse magnetic nanoparticles regarding their size and size distribution.
doi:10.3390/s90604022
PMCID: PMC3291896  PMID: 22408511
magnetic nanoparticles; magneto-optical relaxation; immunoassay; IGF-1 assay
7.  Biomedical Applications of Tetrazine Cycloadditions 
Accounts of chemical research  2011;44(9):816-827.
Conspectus
Disease mechanisms are increasingly being resolved at the molecular level. Biomedical success at this scale creates synthetic opportunities for combining specifically designed orthogonal reactions in applications such as imaging, diagnostics, and therapy. For practical reasons, it would be helpful if bioorthogonal coupling reactions proceeded with extremely rapid kinetics (k > 103 M−1 sec−1) and high specificity. Improving kinetics would minimize both the time and amount of labeling agent required to maintain high coupling yields. In this Account, we discuss our recent efforts to design extremely rapid bioorthogonal coupling reactions between tetrazines and strained alkenes.
These selective reactions were first used to covalently couple conjugated tetrazine near-infrared-emitting fluorophores to dienophile-modifed extracellular proteins on living cancer cells. Confocal fluorescence microscopy demonstrated efficient and selective labeling, and control experiments showed minimal background fluorescence. Multistep techniques were optimized to work with nanomolar concentrations of labeling agent over a timescale of minutes: the result was successful real-time imaging of covalent modification. We subsequently discovered fluorogenic probes that increase in fluorescence intensity after the chemical reaction, leading to an improved signal-to-background ratio. Fluorogenic probes were used for intracellular imaging of dienophiles. We further developed strategies to react and image chemotherapeutics, such as trans-cyclooctene taxol analogs, inside living cells. Because the coupling partners are small molecules (<300 daltons), they offer unique steric advantages in multistep amplification.
We also describe recent success in using tetrazine reactions to label biomarkers on cells with magneto-fluorescent nanoparticles. Two-step protocols that use bioorthogonal chemistry can significantly amplify signals over both one-step labeling procedures as well as two-step procedures that use more sterically hindered biotin–avidin interactions. Nanoparticles can be detected with fluorescence or magnetic resonance techniques. These strategies are now being routinely used on clinical samples for biomarker profiling to predict malignancy and patient outcome.
Finally, we discuss recent results with tetrazine reactions used for in vivo molecular imaging applications. Rapid tetrazine cycloadditions allow modular labeling of small molecules with the most commonly used positron emission tomography isotope, 18F. Additionally, in recent work we have begun to apply this reaction directly in vivo for the pre-targeted imaging of solid tumors. Future work with tetrazine cycloadditions will undoubtedly lead to optimized protocols, improved probes, and additional biomedical applications.
doi:10.1021/ar200037t
PMCID: PMC3166440  PMID: 21627112
8.  Labeling TiO2 Nanoparticles with Dyes for Optical Fluorescence Microscopy and Determination of TiO2-DNA Nanoconjugate Stability 
Visualization of nanoparticles without intrinsic optical fluorescence properties is a significant problem when performing intracellular studies. Such is the case with titanium dioxide (TiO2) nanoparticles. These nanoparticles, when electronically linked to single stranded DNA oligonucleotides, have been proposed to be used both as gene knockout devices and as possible tumor imaging agents. By interacting with complementary target sequences in living cells, these photo-inducible TiO2-DNA nanoconjugates have the potential to cleave intracellular genomic DNA in a sequence specific and inducible manner. The nanoconjugates also become detectable by magnetic resonance imaging (MRI) with the addition of gadolinium Gd(III) contrast agents. Herein we describe two approaches for labeling TiO2 nanoparticles and TiO2-DNA nanoconjugates with optically fluorescent agents. This permits, for the first time, direct quantification of fluorescently labeled TiO2 nanoparticle uptake in a large population of living cells (>104 cells). X-Ray Fluorescence Microscopy (XFM) was combined with fluorescent microscopy to determine the relative intracellular stability of the nanoconjugates. It was also used to quantify intracellular nanoparticles. Imaging the DNA component of the TiO2-DNA nanoconjugate by fluorescent confocal microscopy within the same cell showed an overlap with the titanium signal as mapped by XFM. This strongly implies the intracellular integrity of the TiO2-DNA nanoconjugates in malignant cells.
doi:10.1002/smll.200801458
PMCID: PMC2787618  PMID: 19242946
TiO2-DNA Nanoconjugate; Nanoparticle; X-Ray Fluorescence Microscopy; Titanium Dioxide
9.  Fluorescence Modified Chitosan-Coated Magnetic Nanoparticles for High-Efficient Cellular Imaging 
Nanoscale Research Letters  2009;4(4):287-295.
Labeling of cells with nanoparticles for living detection is of interest to various biomedical applications. In this study, novel fluorescent/magnetic nanoparticles were prepared and used in high-efficient cellular imaging. The nanoparticles coated with the modified chitosan possessed a magnetic oxide core and a covalently attached fluorescent dye. We evaluated the feasibility and efficiency in labeling cancer cells (SMMC-7721) with the nanoparticles. The nanoparticles exhibited a high affinity to cells, which was demonstrated by flow cytometry and magnetic resonance imaging. The results showed that cell-labeling efficiency of the nanoparticles was dependent on the incubation time and nanoparticles’ concentration. The minimum detected number of labeled cells was around 104by using a clinical 1.5-T MRI imager. Fluorescence and transmission electron microscopy instruments were used to monitor the localization patterns of the magnetic nanoparticles in cells. These new magneto-fluorescent nanoagents have demonstrated the potential for future medical use.
doi:10.1007/s11671-008-9239-9
PMCID: PMC2893437  PMID: 20596545
Magnetic nanoparticle; Fluorescence; Chitosan; Magnetic resonance imaging
10.  Fluorescence Modified Chitosan-Coated Magnetic Nanoparticles for High-Efficient Cellular Imaging 
Nanoscale Research Letters  2009;4(4):287-295.
Labeling of cells with nanoparticles for living detection is of interest to various biomedical applications. In this study, novel fluorescent/magnetic nanoparticles were prepared and used in high-efficient cellular imaging. The nanoparticles coated with the modified chitosan possessed a magnetic oxide core and a covalently attached fluorescent dye. We evaluated the feasibility and efficiency in labeling cancer cells (SMMC-7721) with the nanoparticles. The nanoparticles exhibited a high affinity to cells, which was demonstrated by flow cytometry and magnetic resonance imaging. The results showed that cell-labeling efficiency of the nanoparticles was dependent on the incubation time and nanoparticles’ concentration. The minimum detected number of labeled cells was around 104 by using a clinical 1.5-T MRI imager. Fluorescence and transmission electron microscopy instruments were used to monitor the localization patterns of the magnetic nanoparticles in cells. These new magneto-fluorescent nanoagents have demonstrated the potential for future medical use.
doi:10.1007/s11671-008-9239-9
PMCID: PMC2893437  PMID: 20596545
Magnetic nanoparticle; Fluorescence; Chitosan; Magnetic resonance imaging
11.  Acceleration of gene transfection efficiency in neuroblastoma cells through polyethyleneimine/poly(methyl methacrylate) core-shell magnetic nanoparticles 
Background
The purpose of this study was to demonstrate the potential of magnetic poly(methyl methacrylate) (PMMA) core/polyethyleneimine (PEI) shell (mag-PEI) nanoparticles, which possess high saturation magnetization for gene delivery. By using mag-PEI nanoparticles as a gene carrier, this study focused on evaluation of transfection efficiency under magnetic induction. The potential role of this newly synthesized nanosphere for therapeutic delivery of the tryptophan hydroxylase-2 (TPH-2) gene was also investigated in cultured neuronal LAN-5 cells.
Methods
The mag-PEI nanoparticles were prepared by one-step emulsifier-free emulsion polymerization, generating highly loaded and monodispersed magnetic polymeric nanoparticles bearing an amine group. The physicochemical properties of the mag-PEI nanoparticles and DNA-bound mag-PEI nanoparticles were investigated using the gel retardation assay, atomic force microscopy, and zeta size measurements. The gene transfection efficiencies of mag-PEI nanoparticles were evaluated at different transfection times. Confocal laser scanning microscopy confirmed intracellular uptake of the magnetoplex. The optimal conditions for transfection of TPH-2 were selected for therapeutic gene transfection. We isolated the TPH-2 gene from the total RNA of the human medulla oblongata and cloned it into an expression vector. The plasmid containing TPH-2 was subsequently bound onto the surfaces of the mag-PEI nanoparticles via electrostatic interaction. Finally, the mag-PEI nanoparticle magnetoplex was delivered into LAN-5 cells. Reverse-transcriptase polymerase chain reaction was performed to evaluate TPH-2 expression in a quantitative manner.
Results
The study demonstrated the role of newly synthesized high-magnetization mag-PEI nanoparticles for gene transfection in vitro. The expression signals of a model gene, luciferase, and a therapeutic gene, TPH-2, were enhanced under magnetic-assisted transfection. An in vitro study in neuronal cells confirmed that using mag-PEI nanoparticles as a DNA carrier for gene delivery provided high transfection efficiency with low cytotoxicity.
Conclusion
The mag-PEI nanoparticle is a promising alternative gene transfection reagent due to its ease of use, effectiveness, and low cellular toxicity. The mag-PEI nanoparticle is not only practical for gene transfection in cultured neuronal cells but may also be suitable for transfection in other cells as well.
doi:10.2147/IJN.S32311
PMCID: PMC3373300  PMID: 22701321
magnetic nanoparticle; non-viral vector; gene delivery; tryptophan hydroxylase-2; LAN-5; neuronal cells
12.  M13-templated magnetic nanoparticles for targeted in vivo imaging of prostate cancer 
Nature nanotechnology  2012;7(10):677-682.
Molecular imaging allows clinicians to visualize the progression of tumours and obtain relevant information for patient diagnosis and treatment1. Owing to their intrinsic optical, electrical and magnetic properties, nanoparticles are promising contrast agents for imaging dynamic molecular and cellular processes such as protein-protein interactions, enzyme activity or gene expression2. Until now, nanoparticles have been engineered with targeting ligands such as antibodies and peptides to improve tumour specificity and uptake. However, excessive loading of ligands can reduce the targeting capabilities of the ligand3,4,5 and reduce the ability of the nanoparticle to bind to a finite number of receptors on cells6. Increasing the number of nanoparticles delivered to cells by each targeting molecule would lead to higher signal-to-noise ratios and improve image contrast. Here, we show that M13 filamentous bacteriophage can be used as a scaffold to display targeting ligands and multiple nanoparticles for magnetic resonance imaging of cancer cells and tumours in mice. Monodisperse iron oxide magnetic nanoparticles assemble along the M13 coat, and its distal end is engineered to display a peptide that targets SPARC glycoprotein, which is overexpressed in various cancers. Compared with nanoparticles that are directly functionalized with targeting peptides, our approach improves contrast because each SPARC-targeting molecule delivers a large number of nanoparticles into the cells. Moreover, the targeting ligand and nanoparticles could be easily exchanged for others, making this platform attractive for in vivo high-throughput screening and molecular detection.
doi:10.1038/nnano.2012.146
PMCID: PMC4059198  PMID: 22983492
13.  Quantification of the internalization patterns of superparamagnetic iron oxide nanoparticles with opposite charge 
Time-resolved quantitative colocalization analysis is a method based on confocal fluorescence microscopy allowing for a sophisticated characterization of nanomaterials with respect to their intracellular trafficking. This technique was applied to relate the internalization patterns of nanoparticles i.e. superparamagnetic iron oxide nanoparticles with distinct physicochemical characteristics with their uptake mechanism, rate and intracellular fate.
The physicochemical characterization of the nanoparticles showed particles of approximately the same size and shape as well as similar magnetic properties, only differing in charge due to different surface coatings. Incubation of the cells with both nanoparticles resulted in strong differences in the internalization rate and in the intracellular localization depending on the charge. Quantitative and qualitative analysis of nanoparticles-organelle colocalization experiments revealed that positively charged particles were found to enter the cells faster using different endocytotic pathways than their negative counterparts. Nevertheless, both nanoparticles species were finally enriched inside lysosomal structures and their efficiency in agarose phantom relaxometry experiments was very similar.
This quantitative analysis demonstrates that charge is a key factor influencing the nanoparticle-cell interactions, specially their intracellular accumulation. Despite differences in their physicochemical properties and intracellular distribution, the efficiencies of both nanoparticles as MRI agents were not significantly different.
doi:10.1186/1477-3155-10-28
PMCID: PMC3431280  PMID: 22781560
Superparamagnetic iron oxide nanoparticles (SPIONs); Intracellular distribution; Charge; Coating; Size; Quantitative correlation analysis; Colocalization
14.  Theranostic Nanoshells: From Probe Design to Imaging and Treatment of Cancer 
Accounts of chemical research  2011;44(10):936-946.
CONSPECTUS
Recent advances in theranostics have expanded our ability to design and construct multifunctional nanoparticles that will ultimately allow us to image and treat diseases in a single clinical procedure. Theranostic nanoparticles, combining targeting, therapeutic and diagnostic functions within a single nanoscale complex, have emerged as a result of this confluence of nanoscience and biomedicine. The theranostic capabilities of gold nanoshells -spherical, silica core, gold shell nanoparticles- have attracted tremendous attention over the past decade as nanoshells have emerged as a promising tool for cancer therapy and bioimaging enhancement. This account examines the design and synthesis of nanoshell-based theranostic agents, their plasmon-derived optical properties and their corresponding applications. Nanoshells illuminated with resonant light are either strong optical absorbers or scatterers, properties which give rise to their unique capabilities. In this account, we discuss the underlying physical principles contributing to the photothermal response of nanoshells. We elucidate the photophysics of nanoshell-induced fluorescence enhancement of weak near-infrared fluorophores. We then describe the application of nanoshells as a contrast agent for optical coherence tomography of breast carcinoma cells in vivo. We also examine the recent progress of nanoshells as a multimodal theranostic probe for near-infrared fluorescence and magnetic resonance imaging (MRI) combined with photothermal ablation of cancer cells. The design and preparation of nanoshell complexes is discussed, and their ability to enhance the photoluminescence of fluorophores while incorporating MR contrast is described. We show the theranostic potential of the multimodal nanoshells in vivo for imaging subcutaneous breast cancer tumors in animal models and their biodistribution in various tissues.
We then discuss the potential of nanoshells as light-triggered gene therapy vectors. The plasmonic properties of nanoshells make them highly effective as light controlled delivery vectors, adding temporal control to the spatial control characteristic of nanoparticle-based gene therapy approaches. We describe the fabrication of DNA-conjugated nanoshell complexes and compare the efficiency of light-induced and thermally-induced DNA release of DNA. We examine light-triggered release of DAPI (4',6-diamidino-2-phenylindole) molecules, which bind reversibly to double-stranded DNA, to visualize intracellular light-induced release. Finally, we look at future prospects of nanoshell-based theranostics, the potential impact and near-term challenges of theranostic nanomedicine in the next decade.
doi:10.1021/ar200023x
PMCID: PMC3888233  PMID: 21612199
15.  Imaging of Her2-Targeted Magnetic Nanoparticles for Breast Cancer Detection: Comparison of SQUID-detected Magnetic Relaxometry and MRI 
Contrast media & molecular imaging  2012;7(3):10.1002/cmmi.499.
Both magnetic relaxometry and magnetic resonance imaging (MRI) can be used to detect and locate targeted magnetic nanoparticles, non-invasively and without ionizing radiation. Magnetic relaxometry offers advantages in terms of its specificity (only nanoparticles are detected) and the linear dependence of the relaxometry signal on the number of nanoparticles present. In this study, detection of single-core iron oxide nanoparticles by Superconducting Quantum Interference Device (SQUID)-detected magnetic relaxometry and standard 4.7 T MRI are compared. The nanoparticles were conjugated to a Her2 monoclonal antibody and targeted to Her2-expressing MCF7/Her2-18 breast cancer cells); binding of the nanoparticles to the cells was assessed by magnetic relaxometry and iron assay. The same nanoparticle-labeled cells, serially diluted, were used to assess the detection limits and MR relaxivities. The detection limit of magnetic relaxometry was 125,000 nanoparticle-labeled cells at 3 cm from the SQUID sensors. T2-weighted MRI yielded a detection limit of 15,600 cells in a 150 μl volume, with r1 = 1.1 mM−1s−1 and r2 = 166 mM−1s−1. Her2-targeted nanoparticles were directly injected into xenograft MCF7/Her2-18 tumors in nude mice, and magnetic relaxometry imaging and 4.7 T MRI were performed, enabling direct comparison of the two techniques. Co-registration of relaxometry images and MRI of mice resulted in good agreement. A method for obtaining accurate quantification of microgram quantities of iron in the tumors and liver by relaxometry was also demonstrated. These results demonstrate the potential of SQUID-detected magnetic relaxometry imaging for the specific detection of breast cancer and the monitoring of magnetic nanoparticle-based therapies.
doi:10.1002/cmmi.499
PMCID: PMC3883306  PMID: 22539401
Magnetite; Nanoparticle; Magnetorelaxometry; SQUID; Magnetic Resonance Imaging; Magnetometry; Magnetic Susceptibility; Antibody targeting
16.  Multifunctional polymeric nanoparticles doubly loaded with SPION and ceftiofur retain their physical and biological properties 
Background
Advances in nanostructure materials are leading to novel strategies for drug delivery and targeting, contrast media for magnetic resonance imaging (MRI), agents for hyperthermia and nanocarriers. Superparamagnetic iron oxide nanoparticles (SPIONs) are useful for all of these applications, and in drug-release systems, SPIONs allow for the localization, direction and concentration of drugs, providing a broad range of therapeutic applications. In this work, we developed and characterized polymeric nanoparticles based on poly (3-hydroxybutyric acid-co-hydroxyvaleric acid) (PHBV) functionalized with SPIONs and/or the antibiotic ceftiofur. These nanoparticles can be used in multiple biomedical applications, and the hybrid SPION–ceftiofur nanoparticles (PHBV/SPION/CEF) can serve as a multifunctional platform for the diagnosis and treatment of cancer and its associated bacterial infections.
Results
Morphological examination using transmission electron microscopy (TEM) showed nanoparticles with a spherical shape and a core-shell structure. The particle size was evaluated using dynamic light scattering (DLS), which revealed a diameter of 243.0 ± 17 nm. The efficiency of encapsulation (45.5 ± 0.6% w/v) of these polymeric nanoparticles was high, and their components were evaluated using spectroscopy. UV–VIS, FTIR and DSC showed that all of the nanoparticles contained the desired components, and these compounds interacted to form a nanocomposite. Using the agar diffusion method and live/dead bacterial viability assays, we demonstrated that these nanoparticles have antimicrobial properties against Escherichia coli, and they retain their magnetic properties as measured using a vibrating sample magnetometer (VSM). Cytotoxicity was assessed in HepG2 cells using live/dead viability assays and MTS, and these assays showed low cytotoxicity with IC50 > 10 mg/mL nanoparticles.
Conclusions
Our results indicate that hybrid and multifunctional PHBV/SPION/CEF nanoparticles are suitable as a superparamagnetic drug delivery system that can guide, concentrate and site–specifically release drugs with antibacterial activity.
Electronic supplementary material
The online version of this article (doi:10.1186/s12951-015-0077-5) contains supplementary material, which is available to authorized users.
doi:10.1186/s12951-015-0077-5
PMCID: PMC4334767
PHBV; SPION; Ceftiofur; Polymeric nanoparticles; Drug delivery; Superparamagnetic nanoparticles
17.  Actively-targeted LTVSPWY peptide-modified magnetic nanoparticles for tumor imaging 
Background
Magnetic resonance imaging (MRI) is widely used in modern clinical medicine as a diagnostic tool, and provides noninvasive and three-dimensional visualization of biological phenomena in living organisms with high spatial and temporal resolution. Therefore, considerable attention has been paid to magnetic nanoparticles as MRI contrast agents with efficient targeting ability and cellular internalization ability, which make it possible to offer higher contrast and information-rich images for detection of disease.
Methods
LTVSPWY peptide-modified PEGylated chitosan (LTVSPWY-PEG-CS) was synthesized by chemical reaction, and the chemical structure was confirmed by 1H-NMR. LTVSPWY-PEG-CS-modified magnetic nanoparticles were prepared successfully using the solvent diffusion method. Their particle size, size distribution, and zeta potential were measured by dynamic light scattering and electrophoretic mobility, and their surface morphology was investigated by transmission electron microscopy. To investigate their selective targeting ability, the cellular uptake of the LTVSPWY-PEG-CS-modified magnetic nanoparticles was observed in a cocultured system of SKOV-3 cells which overexpress HER2 and A549 cells which are HER2-negative. The in vitro cytotoxicity of these nanoparticles in SKOV-3 and A549 cells was measured using the MTT method. The SKOV-3-bearing nude mouse model was used to investigate the tumor targeting ability of the magnetic nanoparticles in vivo.
Results
The average diameter and zeta potential of the LTVSPWY-PEG-CS-modified magnetic nanoparticles was 267.3 ± 23.4 nm and 30.5 ± 7.0 mV, respectively, with a narrow size distribution and spherical morphology. In vitro cytotoxicity tests demonstrated that these magnetic nanoparticles were carriers suitable for use in cancer diagnostics with low toxicity. With modification of the LTVSPWY homing peptide, magnetic nanoparticles could be selectively taken up by SKOV-3 cells overexpressing HER2 when cocultured with HER2-negative A549 cells. In vivo biodistribution results suggest that treatment with LTVSPWY-PEG-CS-modified magnetic nanoparticles/DiR enabled tumors to be identified and diagnosed more rapidly and efficiently in vivo.
Conclusion
LTVSPWY-PEG-CS-modified magnetic nanoparticles are a promising contrast agent for early detection of tumors overexpressing HER2 and further diagnostic application.
doi:10.2147/IJN.S33593
PMCID: PMC3410692  PMID: 22866005
LTVSPWY peptide; HER2; poly(ethylene glycol); chitosan; magnetic nanoparticles; tumor targeting
18.  Molecular Imaging with Theranostic Nanoparticles 
Accounts of chemical research  2011;44(10):1050-1060.
Conspectus
Nanoparticles offer diagnostic and therapeutic capabilities impossible with small molecules or micro-scale tools. As molecular biology merges with medical imaging to form the field of molecular imaging, nanoparticle imaging is increasingly common with both therapeutic and diagnostic applications. The term theranostic indicates technology with concurrent and complementary diagnostic and therapeutic capabilities. When performed with sub-micron materials, the field may be termed theranostic nanomedicine. Although nanoparticles have been FDA-approved for clinical use as transport vehicles for nearly 15 years, full translation of their theranostic potential is incomplete. Still, remarkable successes with nanoparticles have been realized in the areas of drug delivery and magnetic resonance imaging. Emerging applications include image-guided resection, optical/photoacoustic imaging in vivo, contrast-enhanced ultrasound, and thermoablative therapy.
Diagnosis with nanoparticles in molecular imaging involves correlating signal to a phenotype. The disease’s size, stage, and biochemical signature can be gleaned from the location and intensity of nanoparticle signal emanating from a living subject. Therapy with NP uses the image for resection or delivery of small molecule or RNA thererapeutic. Ablation of the affected area is also possible via heat or radioactivity.
The ideal theranostic NP: (1) selectively and rapidly accumulates in diseased tissue, (2) reports biochemical and morphological characteristics of the area, (3) delivers a non-invasive therapeutic, and (4) is safe and biodegrades with non-toxic byproducts. Above is a schematic of such a system which contains a central imaging core (yellow) surrounded by small molecule therapeutics (red). The system targets via ligands such as IgG (pink) and is protected from immune scavengers by a cloak of protective polymer (green). While no nanoparticle has achieved all of the above features, many NPs do fulfill one or more. While the most clinically translatable nanoparticles have been used in the field of magnetic resonance imaging, other types are quickly becoming more biocompatible by overcoming toxicity and biodistribution concerns. The document details diagnostic imaging and therapeutic uses of nanoparticles. We propose five main types of nanoparticles with concurrent diagnostic and thereapeutic uses and offer examples of each.
doi:10.1021/ar200106e
PMCID: PMC3196845  PMID: 21919457
Theranostic; Nanoparticle; Molecular Imaging
19.  Effect of large mechanical stress on the magnetic properties of embedded Fe nanoparticles 
Summary
Magnetic nanoparticles are promising candidates for next generation high density magnetic data storage devices. Data storage requires precise control of the magnetic properties of materials, in which the magnetic anisotropy plays a dominant role. Since the total magneto-crystalline anisotropy energy scales with the particle volume, the storage density in media composed of individual nanoparticles is limited by the onset of superparamagnetism. One solution to overcome this limitation is the use of materials with extremely large magneto-crystalline anisotropy. In this article, we follow an alternative approach by using magneto-elastic interactions to tailor the total effective magnetic anisotropy of the nanoparticles. By applying large biaxial stress to nanoparticles embedded in a non-magnetic film, it is demonstrated that a significant modification of the magnetic properties can be achieved. The stress is applied to the nanoparticles through expansion of the substrate during hydrogen loading. Experimental evidence for stress induced magnetic effects is presented based on temperature-dependent magnetization curves of superparamagnetic Fe particles. The results show the potential of the approach for adjusting the magnetic properties of nanoparticles, which is essential for application in future data storage media.
doi:10.3762/bjnano.2.31
PMCID: PMC3148048  PMID: 21977439
hydrogen in metals; magnetic anisotropy; magnetic data storage; magneto-elastic interactions; nanoparticles; superparamagnetism; thin films
20.  In situ High Throughput Scattering Light Analysis of Single Plasmonic Nanoparticles in Living Cells 
Theranostics  2015;5(2):188-195.
Plasmonic nanoparticles have been widely applied in cell imaging, disease diagnosis, and photothermal therapy owing to their unique scattering and absorption spectra based on localized surface plasmon resonance (LSPR) property. Recently, it is still a big challenge to study the detailed scattering properties of single plasmonic nanoparticles in living cells and tissues, which have dynamic and complicated environment. The conventional approach for measuring the scattering light is based on a spectrograph coupled to dark-field microscopy (DFM), which is time-consuming and limited by the small sample capacity. Alternatively, RGB-based method is promising in high-throughput analysis of single plasmonic nanoparticles in dark-field images, but the limitation in recognition of nanoparticles hinders its application for intracellular analysis. In this paper, we developed an automatic and robust method for recognizing the plasmonic nanoparticles in dark-field image for RGB-based analysis. The method involves a bias-modified fuzzy C-means algorithm, through which biased illumination in the image could be eliminated. Thus, nearly all of the gold nanoparticles in the recorded image were recognized both on glass slide and in living cells. As confirmed, the distribution of peak wavelength obtained by our method is well agreed to the result measured by conventional method. Furthermore, we demonstrated that our method is profound in cell imaging studies, where its advantages in fast and high-throughput analysis of the plasmonic nanoparticles could be applied to confirm the presence and location of important biological molecules and provide efficiency information for cancer drug selection.
doi:10.7150/thno.10302
PMCID: PMC4279003  PMID: 25553107
Cell imaging; Bias-modified fuzzy C-means algorithm; localized surface plasmon resonance; plasmonic nanoparticle.
21.  Magneto-photo-acoustic imaging 
Biomedical Optics Express  2011;2(2):385-396.
Magneto-photo-acoustic imaging, a technique based on the synergy of magneto-motive ultrasound, photoacoustic and ultrasound imaging, is introduced. Hybrid nanoconstructs, liposomes encapsulating gold nanorods and iron oxide nanoparticles, were used as a dual-contrast agent for magneto-photo-acoustic imaging. Tissue-mimicking phantom and macrophage cells embedded in ex vivo porcine tissue were used to demonstrate that magneto-photo-acoustic imaging is capable of visualizing the location of cells or tissues labeled with dual-contrast nanoparticles with sufficient contrast, excellent contrast resolution and high spatial resolution in the context of the anatomical structure of the surrounding tissues. Therefore, magneto-photo-acoustic imaging is capable of identifying the nanoparticle-labeled pathological regions from the normal tissue, providing a promising platform to noninvasively diagnose and characterize pathologies.
doi:10.1364/BOE.2.000386
PMCID: PMC3038453  PMID: 21339883
(170.5120) Photoacoustic imaging; (110.7170) Ultrasound; (170.3880) Medical and biological imaging; (170.6960) Tomography
22.  Simulating Magnetic Nanoparticle Behavior in Low-field MRI under Transverse Rotating Fields and Imposed Fluid Flow 
In the presence of alternating-sinusoidal or rotating magnetic fields, magnetic nanoparticles will act to realign their magnetic moment with the applied magnetic field. The realignment is characterized by the nanoparticle’s time constant, τ. As the magnetic field frequency is increased, the nanoparticle’s magnetic moment lags the applied magnetic field at a constant angle for a given frequency, Ω, in rad/s. Associated with this misalignment is a power dissipation that increases the bulk magnetic fluid’s temperature which has been utilized as a method of magnetic nanoparticle hyperthermia, particularly suited for cancer in low-perfusion tissue (e.g., breast) where temperature increases of between 4°C and 7°C above the ambient in vivo temperature cause tumor hyperthermia. This work examines the rise in the magnetic fluid’s temperature in the MRI environment which is characterized by a large DC field, B0. Theoretical analysis and simulation is used to predict the effect of both alternating-sinusoidal and rotating magnetic fields transverse to B0. Results are presented for the expected temperature increase in small tumors (~1 cm radius) over an appropriate range of magnetic fluid concentrations (0.002 to 0.01 solid volume fraction) and nanoparticle radii (1 to 10 nm). The results indicate that significant heating can take place, even in low-field MRI systems where magnetic fluid saturation is not significant, with careful The goal of this work is to examine, by means of analysis and simulation, the concept of interactive fluid magnetization using the dynamic behavior of superparamagnetic iron oxide nanoparticle suspensions in the MRI environment. In addition to the usual magnetic fields associated with MRI, a rotating magnetic field is applied transverse to the main B0 field of the MRI. Additional or modified magnetic fields have been previously proposed for hyperthermia and targeted drug delivery within MRI. Analytical predictions and numerical simulations of the transverse rotating magnetic field in the presence of B0 are investigated to demonstrate the effect of Ω, the rotating field frequency, and the magnetic field amplitude on the fluid suspension magnetization. The transverse magnetization due to the rotating transverse field shows strong dependence on the characteristic time constant of the fluid suspension, τ. The analysis shows that as the rotating field frequency increases so that Ωτ approaches unity, the transverse fluid magnetization vector is significantly non-aligned with the applied rotating field and the magnetization’s magnitude is a strong function of the field frequency. In this frequency range, the fluid’s transverse magnetization is controlled by the applied field which is determined by the operator. The phenomenon, which is due to the physical rotation of the magnetic nanoparticles in the suspension, is demonstrated analytically when the nanoparticles are present in high concentrations (1 to 3% solid volume fractions) more typical of hyperthermia rather than in clinical imaging applications, and in low MRI field strengths (such as open MRI systems), where the magnetic nanoparticles are not magnetically saturated. The effect of imposed Poiseuille flow in a planar channel geometry and changing nanoparticle concentration is examined. The work represents the first known attempt to analyze the dynamic behavior of magnetic nanoparticles in the MRI environment including the effects of the magnetic nanoparticle spin-velocity. It is shown that the magnitude of the transverse magnetization is a strong function of the rotating transverse field frequency. Interactive fluid magnetization effects are predicted due to non-uniform fluid magnetization in planar Poiseuille flow with high nanoparticle concentrations.
doi:10.1016/j.jmmm.2010.03.029
PMCID: PMC2901184  PMID: 20625540
Magnetic nanoparticles; MRI; rotating magnetic field; interactive magnetization; magnetic particle imaging
23.  Synthesis, magnetic and optical properties of core/shell Co1-xZnxFe2O4/SiO2 nanoparticles 
Nanoscale Research Letters  2011;6(1):460.
The optical properties of multi-functionalized cobalt ferrite (CoFe2O4), cobalt zinc ferrite (Co0.5Zn0.5Fe2O4), and zinc ferrite (ZnFe2O4) nanoparticles have been enhanced by coating them with silica shell using a modified Stöber method. The ferrites nanoparticles were prepared by a modified citrate gel technique. These core/shell ferrites nanoparticles have been fired at temperatures: 400°C, 600°C and 800°C, respectively, for 2 h. The composition, phase, and morphology of the prepared core/shell ferrites nanoparticles were determined by X-ray diffraction and transmission electron microscopy, respectively. The diffuse reflectance and magnetic properties of the core/shell ferrites nanoparticles at room temperature were investigated using UV/VIS double-beam spectrophotometer and vibrating sample magnetometer, respectively. It was found that, by increasing the firing temperature from 400°C to 800°C, the average crystallite size of the core/shell ferrites nanoparticles increases. The cobalt ferrite nanoparticles fired at temperature 800°C; show the highest saturation magnetization while the zinc ferrite nanoparticles coated with silica shell shows the highest diffuse reflectance. On the other hand, core/shell zinc ferrite/silica nanoparticles fired at 400°C show a ferromagnetic behavior and high diffuse reflectance when compared with all the uncoated or coated ferrites nanoparticles. These characteristics of core/shell zinc ferrite/silica nanostructures make them promising candidates for magneto-optical nanodevice applications.
doi:10.1186/1556-276X-6-460
PMCID: PMC3211881  PMID: 21774807
nanostructures; oxides; cobalt ferrite; cobalt zinc ferrite; zinc ferrite; magnetic properties; diffuse reflectance.
24.  Gd2O3 nanoparticles in hematopoietic cells for MRI contrast enhancement 
As the utility of magnetic resonance imaging (MRI) broadens, the importance of having specific and efficient contrast agents increases and in recent time there has been a huge development in the fields of molecular imaging and intracellular markers. Previous studies have shown that gadolinium oxide (Gd2O3) nanoparticles generate higher relaxivity than currently available Gd chelates: In addition, the Gd2O3 nanoparticles have promising properties for MRI cell tracking. The aim of the present work was to study cell labeling with Gd2O3 nanoparticles in hematopoietic cells and to improve techniques for monitoring hematopoietic stem cell migration by MRI. Particle uptake was studied in two cell lines: the hematopoietic progenitor cell line Ba/F3 and the monocytic cell line THP-1. Cells were incubated with Gd2O3 nanoparticles and it was investigated whether the transfection agent protamine sulfate increased the particle uptake. Treated cells were examined by electron microscopy and MRI, and analyzed for particle content by inductively coupled plasma sector field mass spectrometry. Results showed that particles were intracellular, however, sparsely in Ba/F3. The relaxation times were shortened with increasing particle concentration. Relaxivities, r1 and r2 at 1.5 T and 21°C, for Gd2O3 nanoparticles in different cell samples were 3.6–5.3 s−1 mM−1 and 9.6–17.2 s−1 mM−1, respectively. Protamine sulfate treatment increased the uptake in both Ba/F3 cells and THP-1 cells. However, the increased uptake did not increase the relaxation rate for THP-1 as for Ba/F3, probably due to aggregation and/or saturation effects. Viability of treated cells was not significantly decreased and thus, it was concluded that the use of Gd2O3 nanoparticles is suitable for this type of cell labeling by means of detecting and monitoring hematopoietic cells. In conclusion, Gd2O3 nanoparticles are a promising material to achieve positive intracellular MRI contrast; however, further particle development needs to be performed.
doi:10.2147/IJN.S23940
PMCID: PMC3252671  PMID: 22228991
gadolinium oxide; magnetic resonance imaging; contrast agent; cell labeling; Ba/F3 cells; THP-1 cells
25.  Copper nanoparticles exert size and concentration dependent toxicity on somatosensory neurons of rat 
Nanotoxicology  2010;4(2):150-160.
Metal nanoparticles, due to their unique properties and important applications in optical, magnetic, thermal, electrical, sensor devices and cosmetics, are beginning to be widely manufactured and used. This new and rapidly growing field of technology warrants a thorough examination of the material’s bio-compatibility and safety. Ultra-small particles may adversely affect living cells and organisms since they can easily penetrate the body through skin contact, inhalation and ingestion. Retrograde transport of copper nanoparticles from nerve endings on the skin can reach the somatosensory neurons in dorsal root ganglion (DRG). Since copper nanoparticles have industrial and healthcare applications, we determined the concentration and size-dependant effects of their exposure on survival of DRG neurons of rat in cell culture. The neurons were exposed to copper nanoparticles of increasing concentrations (10–100 μM) and sizes (40, 60 and 80 nm) for 24 h. Light microscopy, histochemical staining for copper, lactate dehydrogenase (LDH) assay for cell death, and MTS [3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide] assay for cell viability were performed to measure the resultant toxicity and cell survival. DRG neurons exposed to copper nanoparticles displayed vacuoles and detachment of some neurons from the substratum. Neurons also exhibited disrupted neurite network. LDH and MTS assays revealed that exposure to copper nanoparticles had significant toxic effect with all the sizes tested when compared to unexposed control cultures. Further analysis of the results showed that copper nanoparticles of smaller size and higher concentration exerted the maximum toxic effects. Rubeanic acid staining showed intracellular deposition of copper. These results demonstrate that copper nanoparticles are toxic in a size- and concentration-dependent manner to DRG neurons.
doi:10.3109/17435390903337693
PMCID: PMC2882306  PMID: 20543894
Copper nanoparticles; cytotoxicity; cell death; DRG neurons; histochemistry; neurotoxicity

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