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1.  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.
PMCID: PMC2901184  PMID: 20625540
Magnetic nanoparticles; MRI; rotating magnetic field; interactive magnetization; magnetic particle imaging
2.  A Magnetic Nanoparticle-Based Multiple-Gene Delivery System for Transfection of Porcine Kidney Cells 
PLoS ONE  2014;9(7):e102886.
Superparamagnetic nanoparticles are promising candidates for gene delivery into mammalian somatic cells and may be useful for reproductive cloning using the somatic cell nuclear transfer technique. However, limited investigations of their potential applications in animal genetics and breeding, particularly multiple-gene delivery by magnetofection, have been performed. Here, we developed a stable, targetable and convenient system for delivering multiple genes into the nuclei of porcine somatic cells using magnetic Fe3O4 nanoparticles as gene carriers. After surface modification by polyethylenimine, the spherical magnetic Fe3O4 nanoparticles showed strong binding affinity for DNA plasmids expressing the genes encoding a green (DNAGFP) or red (DNADsRed) fluorescent protein. At weight ratios of DNAGFP or DNADsRed to magnetic nanoparticles lower than or equal to 10∶1 or 5∶1, respectively, the DNA molecules were completely bound by the magnetic nanoparticles. Atomic force microscopy analyses confirmed binding of the spherical magnetic nanoparticles to stretched DNA strands up to several hundred nanometers in length. As a result, stable and efficient co-expression of GFP and DsRed in porcine kidney PK-15 cells was achieved by magnetofection. The results presented here demonstrate the potential application of magnetic nanoparticles as an attractive delivery system for animal genetics and breeding studies.
PMCID: PMC4105564  PMID: 25048709
3.  Molecular Imaging with Theranostic Nanoparticles 
Accounts of chemical research  2011;44(10):1050-1060.
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.
PMCID: PMC3196845  PMID: 21919457
Theranostic; Nanoparticle; Molecular Imaging
4.  Lipidoid-coated Iron Oxide Nanoparticles for Efficient DNA and siRNA delivery 
Nano letters  2013;13(3):1059-1064.
The safe, targeted and effective delivery of gene therapeutics remains a significant barrier to their broad clinical application. Here we develop a magnetic nucleic acid delivery system composed of iron oxide nanoparticles and cationic lipid-like materials termed lipidoids. Coated nanoparticles are capable of delivering DNA and siRNA to cells in culture. The mean hydrodynamic size of these nanoparticles was systematically varied and optimized for delivery. While nanoparticles of different sizes showed similar siRNA delivery efficiency, nanoparticles of 50–100 nm displayed optimal DNA delivery activity. The application of an external magnetic field significantly enhanced the efficiency of nucleic acid delivery, with performance exceeding that of the commercially available lipid-based reagent, Lipofectamine 2000. The iron oxide nanoparticle delivery platform developed here offers the potential for magnetically guided targeting, as well as an opportunity to combine gene therapy with MRI imaging and magnetic hyperthermia.
PMCID: PMC3992974  PMID: 23394319
siRNA delivery; DNA delivery; iron oxide nanoparticle; magnetofection; gene therapy
5.  Applications of Magnetic Microbubbles for Theranostics 
Theranostics  2012;2(1):103-112.
Compared with other diagnostic methods, ultrasound is proven to be a safe, simple, non-invasive and cost-effective imaging technique, but the resolution is not comparable to that of magnetic resonance imaging (MRI). Contrast-enhanced ultrasound employing microbubbles can gain a better resolution and is now widely used to diagnose a number of diseases in the clinic. For the last decade, microbubbles have been widely used as ultrasound contrast agents, drug delivery systems and nucleic acid transfection tools. However, microbubbles are not fairly stable enough in some conditions and are not well administrated distributed in the circulation system. On the other hand, magnetic nanoparticles, as MRI contrast agents, can non-specifically penetrate into normal tissues because of their relatively small sizes. By taking advantage of these two kinds of agents, the magnetic microbubbles which couple magnetic iron oxides nanoparticles in the microbubble structure have been explored. The stability of microbubbles can be raised by encapsulating magnetic nanoparticles into the bubble shells and with the guidance of magnetic field, magnetic microbubbles can be delivered to regions of interest, and after appropriate ultrasound exposure, the nanoparticles can be released to the desired area while the magnetic microbubbles collapse. In this review, we summarize magnetic microbubbles used in diagnostic and therapeutic fields, and predict the potential applications of magnetic microbubbles in the future.
PMCID: PMC3267385  PMID: 22287990
Magnetic microbubble; Dual-modality imaging; Drug delivery system; Molecular imaging.
6.  Acceleration of gene transfection efficiency in neuroblastoma cells through polyethyleneimine/poly(methyl methacrylate) core-shell magnetic nanoparticles 
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.
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.
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.
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.
PMCID: PMC3373300  PMID: 22701321
magnetic nanoparticle; non-viral vector; gene delivery; tryptophan hydroxylase-2; LAN-5; neuronal cells
7.  Morphology, Structure and Function Characterization of PEI Modified Magnetic Nanoparticles Gene Delivery System 
PLoS ONE  2014;9(6):e98919.
Modified magnetic nanoparticles are used as non-viral gene carriers in biological applications. To achieve successful gene delivery, it is critical that nanoparticles effectually assemble with nucleic acids. However, relatively little work has been conducted on the assemble mechanisms between nanoparticles and DNA, and its effects on transfection efficiency. Using biophysical and biochemical characterization, along with Atomic force microscopy (AFM) and Transmission electron microscopy (TEM), we investigate the morphologies, assembling structures and gene delivering abilities of the PEI modified magnetic nanoparticles (MNPs) gene delivery system. In this gene delivery system, MNP/DNA complexes are formed via binding of DNA onto the surface of MNPs. MNPs are favorable to not only increase DNA concentration but also prevent DNA degradation. Magnetofection experiments showed that MNPs has low cytotoxicity and introduces highly stable transfection in mammalian somatic cells. In addition, different binding ratios between MNPs and DNA result in various morphologies of MNP/DNA complexes and have an influence on transfection efficiency. Dose–response profile indicated that transfection efficiency positively correlate with MNP/DNA ratio. Furthermore, intracellular tracking demonstrate that MNPs move though the cell membranes, deliver and release exogenous DNA into the nucleus.
PMCID: PMC4049641  PMID: 24911360
8.  Increased Cellular Uptake of Biocompatible Superparamagnetic Iron Oxide Nanoparticles into Malignant Cells by an External Magnetic Field 
The Journal of Membrane Biology  2010;236(1):167-179.
Superparamagnetic iron oxide nanoparticles (SPIONs) are used as delivery systems for different therapeutics including nucleic acids for magnetofection-mediated gene therapy. The aim of our study was to evaluate physicochemical properties, biocompatibility, cellular uptake and trafficking pathways of the custom-synthesized SPIONs for their potential use in magnetofection. Custom-synthesized SPIONs were tested for size, shape, crystalline composition and magnetic behavior using a transmission electron microscope, X-ray diffractometer and magnetometer. SPIONs were dispersed in different aqueous media to obtain ferrofluids, which were tested for pH and stability using a pH meter and zetameter. Cytotoxicity was determined using the MTS and clonogenic assays. Cellular uptake and trafficking pathways were qualitatively evaluated by transmission electron microscopy and quantitatively by inductively coupled plasma atomic emission spectrometry. SPIONs were composed of an iron oxide core with a diameter of 8–9 nm, coated with a 2-nm-thick layer of silica. SPIONs, dispersed in 0.9% NaCl solution, resulted in a stable ferrofluid at physiological pH for several months. SPIONs were not cytotoxic in a broad range of concentrations and were readily internalized into different cells by endocytosis. Exposure to neodymium-iron-boron magnets significantly increased the cellular uptake of SPIONs, predominantly into malignant cells. The prepared SPIONs displayed adequate physicochemical and biomedical properties for potential use in magnetofection. Their cellular uptake was dependent on the cell type, and their accumulation within the cells was dependent on the duration of exposure to an external magnetic field.
PMCID: PMC2914263  PMID: 20602230
Superparamagnetic nanoparticles; Endocytosis; Magnetic field; Malignant cells; Internalization
9.  PRINT: A Novel Platform Toward Shape and Size Specific Nanoparticle Theranostics 
Accounts of chemical research  2011;44(10):990-998.
Nanotheranostics represents the next generation of medicine, fusing nanotechnology, therapeutics, and diagnostics. By integrating therapeutic and imaging agents into one nanoparticle, this new treatment strategy has the potential not only to detect and diagnose disease but also to treat and monitor the therapeutic response. This capability could have a profound impact in both the research setting as well as in a clinical setting. In the research setting, such a capability will allow research scientists to rapidly assess the performance of new therapeutics in an effort to iterate their designs for increased therapeutic index and efficacy. In the clinical setting, theranostics offers the ability to determine whether patients enrolling in clinical trials are responding, or are expected to respond, to a given therapy based on the hypothesis associated with the biological mechanisms being tested. If not, patients can be more quickly removed from the clinical trial and shifted to other therapeutic options. To be effective, these theranostic agents must be highly site specific. Optimally, they will carry relevant cargo, demonstrate controlled release of that cargo, and include imaging probes with a high signal-to-noise ratio.
There are many biological barriers in the human body that challenge the efficacy of nanoparticle delivery vehicles. These barriers include, but are not limited to, the walls of blood vessels, the physical entrapment of particles in organs, and the removal of particles by phagocytic cells. The rapid clearance of circulating particles during systemic delivery is a major challenge; current research seeks to define key design parameters that govern the performance of nanocarriers, such as size, surface chemistry, elasticity, and shape. The effect of particle size and surface chemistry on in vivo biodistribution of nanocarriers has been extensively studied, and general guidelines have been established. Recently it has been documented that shape and elasticity can have a profound effect on the behavior of delivery vehicles. Thus, having the ability to independently control shape, size, matrix, surface chemistry, and modulus is crucial for designing successful delivery agents.
In this Account, we describe the use of particle replication in nonwetting templates (PRINT) to fabricate shape- and size-specific microparticles and nanoparticles. A particular strength of the PRINT method is that it affords precise control over shape, size, surface chemistry, and modulus. We have demonstrated the loading of PRINT particles with chemotherapeutics, magnetic resonance contrast agents, and fluorophores. The surface properties of the PRINT particles can be easily modified with “stealth” poly(ethylene glycol) chains to increase blood circulation time, with targeting moieties for targeted delivery or with radiolabels for nuclear imaging. These particles have tremendous potential for applications in nanomedicine and diagnostics.
PMCID: PMC4157651  PMID: 21809808
10.  Nanoparticles as Smart Treatment-delivery Systems in Plants: Assessment of Different Techniques of Microscopy for their Visualization in Plant Tissues 
Annals of Botany  2007;101(1):187-195.
Background and Aims
The great potential of using nanodevices as delivery systems to specific targets in living organisms was first explored for medical uses. In plants, the same principles can be applied for a broad range of uses, in particular to tackle infections. Nanoparticles tagged to agrochemicals or other substances could reduce the damage to other plant tissues and the amount of chemicals released into the environment. To explore the benefits of applying nanotechnology to agriculture, the first stage is to work out the correct penetration and transport of the nanoparticles into plants. This research is aimed (a) to put forward a number of tools for the detection and analysis of core-shell magnetic nanoparticles introduced into plants and (b) to assess the use of such magnetic nanoparticles for their concentration in selected plant tissues by magnetic field gradients.
Cucurbita pepo plants were cultivated in vitro and treated with carbon-coated Fe nanoparticles. Different microscopy techniques were used for the detection and analysis of these magnetic nanoparticles, ranging from conventional light microscopy to confocal and electron microscopy.
Key Results
Penetration and translocation of magnetic nanoparticles in whole living plants and into plant cells were determined. The magnetic character allowed nanoparticles to be positioned in the desired plant tissue by applying a magnetic field gradient there; also the graphitic shell made good visualization possible using different microscopy techniques.
The results open a wide range of possibilities for using magnetic nanoparticles in general plant research and agronomy. The nanoparticles can be charged with different substances, introduced within the plants and, if necessary, concentrated into localized areas by using magnets. Also simple or more complex microscopical techniques can be used in localization studies.
PMCID: PMC2701844  PMID: 17998213
Nanotechnology; nanoparticles; drug delivery; smart delivery systems; microscopy techniques
11.  Magnetic Nanoparticle Drug Carriers and their Study by Quadrupole Magnetic Field-Flow Fractionation 
Molecular pharmaceutics  2009;6(5):1290-1306.
Magnetic nanoparticle drug carriers continue to attract considerable interest for drug targeting in the treatment of cancers and other pathological conditions. The efficient delivery of therapeutic levels of drug to a target site while limiting nonspecific, systemic toxicity requires optimization of the drug delivery materials, the applied magnetic field, and the treatment protocol. The history and current state of magnetic drug targeting is reviewed. While initial studies involved micron-sized and larger carriers, and work with these microcarriers continues, it is the sub-micron carriers or nanocarriers that are of increasing interest. An aspect of magnetic drug targeting using nanoparticle carriers that has not been considered is then addressed. This aspect involves the variation in the magnetic properties of the nanocarriers. Quadrupole magnetic field-flow fractionation (QMgFFF) is a relatively new technique for characterizing magnetic nanoparticles. It is unique in its capability of determining the distribution in magnetic properties of a nanoparticle sample in suspension. The development and current state of this technique is also reviewed. Magnetic nanoparticle drug carriers have been found by QMgFFF analysis to be highly polydisperse in their magnetic properties, and the strength of response of the particles to magnetic field gradients is predicted to vary by orders of magnitude. It is expected that the least magnetic fraction of a formulation will contribute the most to systemic toxicity, and the depletion of this fraction will result in a more effective drug carrying material. A material that has a reduced systemic toxicity will allow higher doses of cytotoxic drugs to be delivered to the tumor with reduced side effects. Preliminary experiments involving a novel method of refining a magnetic nanoparticle drug carrier to achieve this result are described. QMgFFF is used to characterize the refined and unrefined material.
PMCID: PMC2757515  PMID: 19591456
Magnetic nanoparticles; Magnetic drug targeting; Drug carriers; Magnetic field-flow fractionation; Magnetic refinement
12.  Preclinical Studies To Understand Nanoparticle Interaction with the Immune System and Its Potential Effects on Nanoparticle Biodistribution 
Molecular pharmaceutics  2008;5(4):487-495.
Nanoparticles have unique physicochemical properties which make them promising platforms for drug delivery. However, immune cells in the bloodstream (such as monocytes, platelets, leukocytes, and dendritic cells) and in tissues (such as resident phagocytes) have a propensity to engulf and eliminate certain nanoparticles. A nanoparticle’s interaction with plasma proteins (opsonins) and blood components (via hemolysis, thrombogenicity and complement activation) may influence uptake and clearance and hence potentially affect distribution and delivery to the intended target sites. Nanoparticle uptake by the immune cells is influenced by many factors. Different nanoparticles have been shown to act on different pathways, while various characteristics/properties also affect which pathway is employed for particle internalization. Nanoparticle protein binding occurs almost instantaneously once the particle enters biological medium, and the physical properties of such a particle–protein complex are often different than those of the formulated particle. These new properties can contribute to different biological responses and change nanoparticle biodistribution. Therefore, in the situation when specific delivery to immune cells is not desired, the ideal nanoparticle platform is the one whose integrity is not disturbed in the complex biological environment, which provides extended circulation in the blood to maximize delivery to the target site, is not toxic to blood cellular components, and is “invisible” to the immune cells which can remove it from circulation. This review discusses the most recent data on nanoparticle interactions with blood components and how particle size and surface charge define their hematocompatibility. This includes properties which determine particle interaction with plasma proteins and uptake by macrophages. We will also provide an overview of in vitro methods useful in identifying interactions with components of the immune system and the potential effects of such interaction on particle distribution to tissues.
PMCID: PMC2613572  PMID: 18510338
Nanoparticles; immunology; biodistribution; preclinical characterization
13.  Stability and magnetically induced heating behavior of lipid-coated Fe3O4 nanoparticles 
Nanoscale Research Letters  2013;8(1):426.
Magnetic nanoparticles that are currently explored for various biomedical applications exhibit a high propensity to minimize total surface energy through aggregation. This study introduces a unique, thermoresponsive nanocomposite design demonstrating substantial colloidal stability of superparamagnetic Fe3O4 nanoparticles (SPIONs) due to a surface-immobilized lipid layer. Lipid coating was accomplished in different buffer systems, pH 7.4, using an equimolar mixture of 1,2-dipalmitoyl-sn-glycero-3-phosphocholine (DPPC) and l-α-dipalmitoylphosphatidyl glycerol (DPPG). Particle size and zeta potential were measured by dynamic laser light scattering. Heating behavior within an alternating magnetic field was compared between the commercial MFG-1000 magnetic field generator at 7 mT (1 MHz) and an experimental, laboratory-made magnetic hyperthermia system at 16.6 mT (13.7 MHz). The results revealed that product quality of lipid-coated SPIONs was significantly dependent on the colloidal stability of uncoated SPIONs during the coating process. Greatest stability was achieved at 0.02 mg/mL in citrate buffer (mean diameter = 80.0 ± 1.7 nm; zeta potential = -47.1 ± 2.6 mV). Surface immobilization of an equimolar DPPC/DPPG layer effectively reduced the impact of buffer components on particle aggregation. Most stable suspensions of lipid-coated nanoparticles were obtained at 0.02 mg/mL in citrate buffer (mean diameter = 179.3 ± 13.9 nm; zeta potential = -19.1 ± 2.3 mV). The configuration of the magnetic field generator significantly affected the heating properties of fabricated SPIONs. Heating rates of uncoated nanoparticles were substantially dependent on buffer composition but less influenced by particle concentration. In contrast, thermal behavior of lipid-coated nanoparticles within an alternating magnetic field was less influenced by suspension vehicle but dramatically more sensitive to particle concentration. These results underline the advantages of lipid-coated SPIONs on colloidal stability without compromising magnetically induced hyperthermia properties. Since phospholipids are biocompatible, these unique lipid-coated Fe3O4 nanoparticles offer exciting opportunities as thermoresponsive drug delivery carriers for targeted, stimulus-induced therapeutic interventions.
7550Mw; 7575Cd; 8185Qr
PMCID: PMC3853621  PMID: 24134544
SPION; Magnetic field generator; Hyperthermia; Phospholipid; Thermoresponsive; Colloid
14.  Recent Advances in Non-viral Vectors for Gene Delivery 
Accounts of Chemical Research  2011;45(7):971-979.
Non-viral vectors, typically based on cationic lipids or polymers, are preferred due to safety concerns with viral vectors. So far, non-viral vectors can proficiently transfect cells in culture, but obtaining efficient nanomedicines is far from evident. To overcome the hurdles associated with non-viral vectors is significant for improving delivery efficiency and therapeutic effect of nucleic acid. The drawbacks include the strong interaction of cationic delivery vehicles with blood components, uptake by the reticuloendothelial system (RES), toxicity, targeting ability of the carriers to the cells of interest, and so on. PEGylation is the predominant method used to reduce the binding of plasma proteins with non-viral vectors and minimize the clearance by RES after intravenous administration. The nanoparticles that are not rapidly cleared from the circulation accumulate in the tumors due to the enhanced permeability and retention effect, and the targeting ligands attached to the distal end of the PEGylated components allow binding to the receptors on the target cell surface. Neutral or anionic liposomes have been also developed for systemic delivery of nucleic acids in experimental animal model. Designing and synthesizing novel cationic lipids and polymers, and binding nucleic acid with peptides, targeting ligands, polymers, or environmentally sensitive moieties also attract many attentions for resolving the problems encountered by non-viral vectors. The application of inorganic nanoparticles in nucleic acid delivery is an emerging field, too.
Recently, different classes of non-viral vectors appear to be converging and the features of different classes of non-viral vectors could be combined in one strategy. More hurdles associated with efficient nucleic acid delivery therefore might be expected to be overcome.
In this account, we will focus on these novel non-viral vectors, which are classified into multifunctional hybrid nucleic acid vectors, novel membrane/core nanoparticles for nucleic acid delivery and ultrasound-responsive nucleic acid vectors. The systemic delivery studies are highlighted. Finally, we bring forward the prospect for nucleic acid delivery. We think a better understandings of the fate of the nanoparticles inside the cell and of the interactions between the parts of hybrid particles will lead to a delivery system suitable for clinical use. We also underscore the value of sustained release of nucleic acid and presume making vectors targeted to cells with sustained release in vivo should be an interesting research challenge.
PMCID: PMC3240701  PMID: 21870813
non-viral vectors; gene delivery; liposome
15.  Development of Receptor Targeted Magnetic Iron Oxide Nanoparticles for Efficient Drug Delivery and Tumor Imaging 
The development of multifunctional nanoparticles that have dual capabilities of tumor imaging and delivering therapeutic agents into tumor cells holds great promises for novel approaches for tumor imaging and therapy. We have engineered urokinase plasminogen activator receptor (uPAR) targeted biodegradable nanoparticles using a size uniform and amphiphilic polymer-coated magnetic iron oxide (IO) nanoparticle conjugated with the amino-terminal fragment (ATF) of urokinase plasminogen activator (uPA), which is a high affinity natural ligand for uPAR. We further developed methods to encapsulate hydrophobic chemotherapeutic drugs into the polymer layer on the IO nanoparticles, making these targeted magnetic resonance imaging (MRI) sensitive nanoparticles drug delivery vehicles. Using a fluorescent drug doxorubicin (Dox) as a model system, we showed that this hydrophobic drug can be efficiently encapsulated into the uPAR-targeted IO nanoparticles. This class of Dox-loaded nanoparticles has a compact size and is stable in pH 7.4 buffer. However, encapsulated Doxcan be released from the nanoparticles at pH 4.0 to 5.0 within 2 hrs. In comparison with the effect of equivalent dosage of free drug or non-targeted IO-Dox nanoparticles, uPAR-targeted IO-Dox nanoparticles deliver higher levels of Dox into breast cancer cells and produce a stronger inhibitory effect on tumor cell growth. Importantly, Dox-loaded IO nanoparticles maintain their T2 MRI contrast effect after being internalized into the tumor cells due to their significant susceptibility effect in the cells, indicating that this drug delivery nanoparticle has the potential to be used as targeted therapeutic imaging probes for monitoring the drug delivery using MRI.
PMCID: PMC4139059  PMID: 25152701
Magnetic Iron Oxide Nanoparticles; uPAR; Targeted Nanoparticle; Breast Cancer; Drug Delivery Nanoparticle; Doxorubicin
16.  Improving the Magnetic Resonance Imaging Contrast and Detection Methods with Engineered Magnetic Nanoparticles 
Theranostics  2012;2(1):86-102.
Engineering and functionalizing magnetic nanoparticles have been an area of the extensive research and development in the biomedical and nanomedicine fields. Because their biocompatibility and toxicity are well investigated and better understood, magnetic nanoparticles, especially iron oxide nanoparticles, are better suited materials as contrast agents for magnetic resonance imaging (MRI) and for image-directed delivery of therapeutics. Given tunable magnetic properties and various surface chemistries from the coating materials, most applications of engineered magnetic nanoparticles take advantages of their superb MRI contrast enhancing capability as well as surface functionalities. It has been found that MRI contrast enhancement by magnetic nanoparticles is highly dependent on the composition, size and surface properties as well as the degree of aggregation of the nanoparticles. Therefore, understanding the relationships between these intrinsic parameters and the relaxivities that contribute to MRI contrast can lead to establishing essential guidance that may direct the design of engineered magnetic nanoparticles for theranostics applications. On the other hand, new contrast mechanism and imaging strategy can be developed based on the novel properties of engineered magnetic nanoparticles. This review will focus on discussing the recent findings on some chemical and physical properties of engineered magnetic nanoparticles affecting the relaxivities as well as the impact on MRI contrast. Furthermore, MRI methods for imaging magnetic nanoparticles including several newly developed MRI approaches aiming at improving the detection and quantification of the engineered magnetic nanoparticles are described.
PMCID: PMC3263519  PMID: 22272222
magnetic nanoparticles; engineering; functionalizing; magnetic resonance imaging
17.  Nanoparticle based cancer treatment: can delivered dose and biological dose be reliably modeled and quantified? 
Proceedings of SPIE  2011;7901:10.1117/12.877026.
Essential developments in the reliable and effective use of heat in medicine include: 1) the ability to model energy deposition and the resulting thermal distribution and tissue damage (Arrhenius models) over time in 3D, 2) the development of non-invasive thermometry and imaging for tissue damage monitoring, and 3) the development of clinically relevant algorithms for accurate prediction of the biological effect resulting from a delivered thermal dose in mammalian cells, tissues, and organs. The accuracy and usefulness of this information varies with the type of thermal treatment, sensitivity and accuracy of tissue assessment, and volume, shape, and heterogeneity of the tumor target and normal tissue. That said, without the development of an algorithm that has allowed the comparison and prediction of the effects of hyperthermia in a wide variety of tumor and normal tissues and settings (cumulative equivalent minutes/ CEM), hyperthermia would never have achieved clinical relevance. A new hyperthermia technology, magnetic nanoparticle-based hyperthermia (mNPH), has distinct advantages over the previous techniques: the ability to target the heat to individual cancer cells (with a nontoxic nanoparticle), and to excite the nanoparticles noninvasively with a non-injurious magnetic field, thus sparing associated normal cells and greatly improving the therapeutic ratio. As such, this modality has great potential as a primary and adjuvant cancer therapy. Although the targeted and safe nature of the noninvasive external activation (hysteretic heating) are a tremendous asset, the large number of therapy based variables and the lack of an accurate and useful method for predicting, assessing and quantifying mNP dose and treatment effect is a major obstacle to moving the technology into routine clinical practice. Among other parameters, mNPH will require the accurate determination of specific nanoparticle heating capability, the total nanoparticle content and biodistribution in the target cells/tissue, and an effective and matching alternating magnetic field (AMF) for optimal and safe excitation of the nanoparticles. Our initial studies have shown that appropriately delivered and targeted nanoparticles are capable of achieving effective tumor cytotoxicity at measured thermal doses significantly less than the understood thermal dose values necessary to achieve equivalent treatment effects using conventional heat delivery techniques. Therefore conventional CEM based thermal dose - tissues effect relationships will not hold for mNPH. The goal of this effort is to provide a platform for determining the biological and physical parameters that will be necessary for accurately planning and performing safe and effective mNPH, creating a new, viable primary or adjuvant cancer therapy.
PMCID: PMC3877314  PMID: 24392199
Iron oxide; nanoparticle; hyperthermia; dosimetry; treatment plan; CEM; thermal therapy; thermal dose; tissue assessment
18.  Surface engineering of iron oxide nanoparticles for targeted cancer therapy 
Accounts of chemical research  2011;44(10):853-862.
Nanotechnology provides a flexible platform for the development of effective therapeutic nanomaterials that can interact specifically with a target in a biological system and provoke a desired biological response. Of the nanomaterials studied, iron oxide nanoparticles have emerged as one of top candidates for cancer therapy due to their intrinsic superparamagnetism that enables no-invasive magnetic resonance imaging (MRI) and biodegradability favorable for in vivo application. A therapeutic superparamagnetic iron oxide nanoparticle (SPION) typically consists of three primary components: an iron oxide nanoparticle core that serves as both a carrier for therapeutics and contrast agent for MRI, a coating on the iron oxide nanoparticle that promotes favorable interactions between the SPION and biological system, and a therapeutic payload that performs designated function in vivo. Often, a targeting ligand is also included in the design that recognizes the receptors over-expressed on cancer cells. The body is a highly complex system that imposes multiple physiological and cellular barriers to foreign objects. Thus, the success of a therapeutic SPION largely relies on the proper design of the iron oxide core to ensure MRI detectability and more critically, the coating to render the ability to bypass these barriers.
Strategies to bypass the physiological barriers such as liver, kidneys, and spleen, involve tuning the overall size and surface chemistry of the SPION to maximize blood half-life and facilitate the navigation in the body. Strategies to bypass cellular barriers include the use of targeting agents to maximize uptake of the SPION by cancer cells, and employing materials that promote desired intracellular trafficking and enable controlled drug release.
The payload can be genes, proteins, chemotherapy drugs, or a combination of them. Each therapeutic requires a specific coating design to maximize the loading and achieve effective delivery and release. In this Account, we discuss the primary design parameters in developing therapeutic SPIONs with a focus on surface coating design to overcome the barriers imposed by the body’s defense system and provide examples of how these design parameters have been implemented to produce therapeutic SPIONs for specific therapeutic applications.
Although there are still challenges to be addressed, SPIONs show great promise in successful diagnosis and treatment of the most devastating cancers. Once critical design parameters have been optimized, these nanoparticles, combined with imaging modalities, can serve as a truly multi-functional theranostic agent that not only performs a therapeutic function, but provides instant treatment feedback for the physician to adjust the treatment plan.
PMCID: PMC3192288  PMID: 21528865
19.  Inhibition of Tumor Cell Invasion with Chlorotoxin-Bound Superparamagnetic Nanoparticles 
Nanoparticles have been investigated as drug delivery vehicles, contrast agents, and multifunctional devices for patient care. Current nanoparticle-based therapeutic strategies for cancer treatment have been mainly based on delivery of chemotherapeutic agents to induce apoptosis or DNA/siRNA to regulate oncogene expression. Here, we present a nanoparticle system that demonstrates an alternative approach to the treatment of cancers, through the inhibition of cell invasion, while serving as a magnetic resonance and optical imaging contrast agent. The nanoparticle is comprised of an iron oxide nanoparticle core, conjugated with an amine-functionalized PEG silane and a small peptide, chlorotoxin (CTX), which enables the tumor cell-specific binding of the nanoparticle. We show that the nanoparticle exhibits substantially enhanced cellular uptake and an invasion inhibition rate of ~98% compared to unbound CTX (~45%). Significantly, our investigation from flow cytometry analysis, transmission electron microscopy and fluorescent imaging revealed that the CTX-enabled nanoparticles deactivated the membrane-bound matrix metalloproteinase 2 (MMP-2) and induced increased internalization of lipid rafts that contain surface-expressed MMP-2 and volume-regulating ion channels through receptor-mediated endocytosis, leading to enhanced prohibitory effects. Since upregulation and activity of MMP-2 have been observed in tumors of neuroectodermal origin, and in cancers of the breast, colon, skin, lung, prostate, ovaries and a host of others, this nanoparticle system can be potentially used for non-invasive diagnosis and treatment of a variety of cancer types.
PMCID: PMC2692352  PMID: 19089837
nanoparticles; chlorotoxin; invasion inhibition; specific targeting; cancer; imaging; biological activity
20.  Magnetofection: A Reproducible Method for Gene Delivery to Melanoma Cells 
BioMed Research International  2013;2013:209452.
Magnetofection is a nanoparticle-mediated approach for transfection of cells, tissues, and tumors. Specific interest is in using superparamagnetic iron oxide nanoparticles (SPIONs) as delivery system of therapeutic genes. Magnetofection has already been described in some proof-of-principle studies; however, fine tuning of the synthesis of SPIONs is necessary for its broader application. Physicochemical properties of SPIONs, synthesized by the co-precipitation in an alkaline aqueous medium, were tested after varying different parameters of the synthesis procedure. The storage time of iron(II) sulfate salt, the type of purified water, and the synthesis temperature did not affect physicochemical properties of SPIONs. Also, varying the parameters of the synthesis procedure did not influence magnetofection efficacy. However, for the pronounced gene expression encoded by plasmid DNA it was crucial to functionalize poly(acrylic) acid-stabilized SPIONs (SPIONs-PAA) with polyethyleneimine (PEI) without the adjustment of its elementary alkaline pH water solution to the physiological pH. In conclusion, the co-precipitation of iron(II) and iron(III) sulfate salts with subsequent PAA stabilization, PEI functionalization, and plasmid DNA binding is a robust method resulting in a reproducible and efficient magnetofection. To achieve high gene expression is important, however, the pH of PEI water solution for SPIONs-PAA functionalization, which should be in the alkaline range.
PMCID: PMC3686069  PMID: 23862136
21.  Recent Advances in Superparamagnetic Iron Oxide Nanoparticles for Cellular Imaging and Targeted Therapy Research 
Current Pharmaceutical Design  2013;19(37):6575-6593.
Advances of nanotechnology have led to the development of nanomaterials with both potential diagnostic and therapeutic applications. Among them, superparamagnetic iron oxide (SPIO) nanoparticles have received particular attention. Over the past decade, various SPIOs with unique physicochemical and biological properties have been designed by modifying the particle structure, size and coating. This article reviews the recent advances in preparing SPIOs with novel properties, the way these physicochemical properties of SPIOs influence their interaction with cells, and the development of SPIOs in liver and lymph nodes magnetic resonance imaging (MRI) contrast. Cellular uptake of SPIO can be exploited in a variety of potential clinical applications, including stem cell and inflammation cell tracking and intra-cellular drug delivery to cancerous cells which offers higher intra-cellular concentration. When SPIOs are used as carrier vehicle, additional advantages can be achieved including magnetic targeting and hyperthermia options, as well as monitoring with MRI. Other potential applications of SPIO include magnetofection and gene delivery, targeted retention of labeled stem cells, sentinel lymph nodes mapping, and magnetic force targeting and cell orientation for tissue engineering.
PMCID: PMC4082310  PMID: 23621536
Superparamagnetic; iron oxide nanoparticles; SPIO; cell labeling; surface coatings; MRI; targeted drug delivery; magnetic targeting; hyperthermia.
22.  Magnetic nanoparticle-based hyperthermia for cancer treatment 
Nanotechnology involves the study of nature at a very small scale, searching new properties and applications. The development of this area of knowledge affects greatly both biotechnology and medicine disciplines. The use of materials at the nanoscale, in particular magnetic nanoparticles, is currently a prominent topic in healthcare and life science. Due to their size-tunable physical and chemical properties, magnetic nanoparticles have demonstrated a wide range of applications ranging from medical diagnosis to treatment. Combining a high saturation magnetization with a properly functionalized surface, magnetic nanoparticles are provided with enhanced functionality that allows them to selectively attach to target cells or tissues and play their therapeutic role in them. In particular, iron oxide nanoparticles are being actively investigated to achieve highly efficient carcinogenic cell destruction through magnetic hyperthermia treatments. Hyperthermia in different approaches has been used combined with radiotherapy during the last decades, however, serious harmful secondary effects have been found in healthy tissues to be associated with these treatments. In this framework, nanotechnology provides a novel and original solution with magnetic hyperthermia, which is based on the use of magnetic nanoparticles to remotely induce local heat when a radiofrequency magnetic field is applied, provoking a temperature increase in those tissues and organs where the tumoral cells are present. Therefore, one important factor that determines the efficiency of this technique is the ability of magnetic nanoparticles to be driven and accumulated in the desired area inside the body. With this aim, magnetic nanoparticles must be strategically surface functionalized to selectively target the injured cells and tissues.
PMCID: PMC3863197  PMID: 24416585
Nanotechnology; Hyperthermia; Nanoparticles
23.  Quantum dots as a platform for nanoparticle drug delivery vehicle design 
Advanced drug delivery reviews  2012;65(5):703-718.
Nanoparticle-based drug delivery (NDD) has emerged as a promising approach to improving upon the efficacy of existing drugs and enabling the development of new therapies. Proof-of-concept studies have demonstrated the potential for NDD systems to simultaneously achieve reduced drug toxicity, improved bio-availability, increased circulation times, controlled drug release, and targeting. However, clinical translation of NDD vehicles with the goal of treating particularly challenging diseases, such as cancer, will require a thorough understanding of how nanoparticle properties influence their fate in biological systems, especially in vivo. Consequently, a model system for systematic evaluation of all stages of NDD with high sensitivity, high resolution, and low cost is highly desirable. In theory, this system should maintain the properties and behavior of the original NDD vehicle, while providing mechanisms for monitoring intracellular and systemic nanocarrier distribution, degradation, drug release, and clearance. For such a model system, quantum dots (QDots) offer great potential. QDots feature small size and versatile surface chemistry, allowing their incorporation within virtually any NDD vehicle with minimal effect on overall characteristics, and offer superb optical properties for real-time monitoring of NDD vehicle transport and drug release at both cellular and systemic levels. Though the direct use of QDots for drug delivery remains questionable due to their potential long-term toxicity, the QDot core can be easily replaced with other organic drug carriers or more biocompatible inorganic contrast agents (such as gold and magnetic nanoparticles) by their similar size and surface properties, facilitating translation of well characterized NDD vehicles to the clinic, maintaining NDD imaging capabilities, and potentially providing additional therapeutic functionalities such as photothermal therapy and magneto-transfection. In this review we outline unique features that make QDots an ideal platform for nanocarrier design and discuss how this model has been applied to study NDD vehicle behavior for diverse drug delivery applications.
PMCID: PMC3541463  PMID: 23000745
Nanoparticle; Drug delivery vehicle; Nanocarrier; Quantum dot; Fluorescence imaging; Traceable drug delivery; Nanomedicine
24.  Nanoparticle-mediated thermal therapy: Evolving strategies for prostate cancer therapy 
Recent advances in nanotechnology have resulted in the manufacture of a plethora of nanoparticles with different sizes, shapes, core physicochemical properties and surface modifications that are being investigated for potential medical applications, particularly for the treatment of cancer. This review focuses on the therapeutic use of customized gold nanoparticles, magnetic nanoparticles and carbon nanotubes that efficiently generate heat upon electromagnetic (light and magnetic fields) stimulation after direct injection into tumors or preferential accumulation in tumors following systemic administration. This review will also focus on the evolving strategies to improve the therapeutic index of prostate cancer treatment using nanoparticle-mediated hyperthermia.
Nanoparticle-mediated thermal therapy is a new and minimally invasive tool in the armamentarium for the treatment of cancers. Unique challenges posed by this form of hyperthermia include the non-target biodistribution of nanoparticles in the reticuloendothelial system when administered systemically, the inability to visualize or quantify the global concentration and spatial distribution of these particles within tumors, the lack of standardized thermal modeling and dosimetry algorithms, and the concerns regarding their biocompatibility. Nevertheless, novel particle compositions, geometries, activation strategies, targeting techniques, payload delivery strategies, and radiation dose enhancement concepts are unique attributes of this form of hyperthermia that warrant further exploration. Capitalizing on these opportunities and overcoming these challenges offers the possibility of seamless and logical translation of this nanoparticle-mediated hyperthermia paradigm from the bench to the bedside.
PMCID: PMC3071560  PMID: 20858069
Nanoparticles; magnetic; optical; activatable; hyperthermia; prostate cancer
25.  Application of Magnetic Nanoparticles to Gene Delivery 
Nanoparticle technology is being incorporated into many areas of molecular science and biomedicine. Because nanoparticles are small enough to enter almost all areas of the body, including the circulatory system and cells, they have been and continue to be exploited for basic biomedical research as well as clinical diagnostic and therapeutic applications. For example, nanoparticles hold great promise for enabling gene therapy to reach its full potential by facilitating targeted delivery of DNA into tissues and cells. Substantial progress has been made in binding DNA to nanoparticles and controlling the behavior of these complexes. In this article, we review research on binding DNAs to nanoparticles as well as our latest study on non-viral gene delivery using polyethylenimine-coated magnetic nanoparticles.
PMCID: PMC3131585  PMID: 21747701
magnetic nanoparticles; Magnetofection; gene delivery; polyethylenimine

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