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1.  Cancer Theranostics with Near-Infrared Light-Activatable Multimodal Nanoparticles 
Accounts of chemical research  2011;44(10):947-956.
Nanomaterials that interact with light provide a unique opportunity for biophotonic nanomedicine. Multifunctional nanoparticles (NPs) that have strong and tunable surface plasmon resonance absorption in the near-infrared region combined with visibility with multiple imaging modalities (magnetic resonance imaging, nuclear imaging, and photoacoustic imaging) have great potential in image-guided therapies. These novel nanostructures, once introduced, are expected to home to solid tumors via the enhanced permeability and retention effect (a passive targeting mechanism) or via targeting ligands bound to their surfaces (an active targeting mechanism). The primary mode of action for photothermal conducting NPs is to convert photoenergy into heat, causing temperature in the treatment volume to be elevated above the thermal damage threshold, which results in irreversible cell killing. It is now recognized that this process, termed photothermal ablation therapy or PTA, although very effective, is unlikely to kill all tumor cells when used alone. In addition to PTA, photothermal conducting NPs can also efficiently trigger drug release and activate RNA interference. Such a multimodal approach, which permits simultaneous PTA therapy, chemotherapy, and therapeutic RNA interference, should provide an opportunity for complete eradication of residual disease.
In this Account, we provide an up-to-date review of the synthesis and characterization, functionalization, and in vitro and in vivo evaluation of NIR light-activatable multifunctional nanostructures used for imaging and therapy, with an emphasis on hollow gold nanospheres, magnetic core–shell gold nanoshells, and semiconductor copper monosulfide NPs. We discuss three types novel drug delivery systems in which hollow gold nanospheres are used to mediate controlled drug release.
PMCID: PMC3196765  PMID: 21848277
Theranostics; hollow gold nanospheres; copper sulfide nanoparticles; near-infrared; drug delivery
2.  Theranostic Nanoshells: From Probe Design to Imaging and Treatment of Cancer 
Accounts of chemical research  2011;44(10):936-946.
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.
PMCID: PMC3888233  PMID: 21612199
3.  Scalable routes to gold nanoshells with tunable sizes and their response to near infrared pulsed laser irradiation 
We present a simplified synthesis of hollow gold nanoshells 20-50 nm in diameter via the well-established templated galvanic replacement reaction of silver for gold. The surface plasmon resonance absorbance of nanoshells made in this fashion can be tuned using basic colloid chemistry to control the size of the silver templates. The gold nanoshells can be varied in size and shell thickness depending on silver/gold reagent ratios and have an aqueous core. The template replacement chemistry is rapid, highly scalable, uses minimal amounts of toxic reagents, and in many cases is a true `one pot' synthesis. The smallest nanoshells (20 nm diameter, 7 nm wall thickness) reach the highest temperature on irradiation with femtosecond light pulses in the near infrared and anneal to form spherical nanoparticles fastest, even though their plasmon resonance does not overlap as well as the larger nanoshells (50 nm diameter, 7 nm wall thickness) with the 800 nm wavelength excitation. Optimizing a nanoshell structure to reach the highest nanoshell temperature is not the same as optimizing the structure for maximum energy absorbance.
PMCID: PMC2692070  PMID: 18623295
Nanoparticles; galvanic replacement reactions; silver
4.  Synthesis of Silver Nanostructures by Multistep Methods 
Sensors (Basel, Switzerland)  2014;14(4):5860-5889.
The shape of plasmonic nanostructures such as silver and gold is vital to their physical and chemical properties and potential applications. Recently, preparation of complex nanostructures with rich function by chemical multistep methods is the hotspot of research. In this review we introduce three typical multistep methods to prepare silver nanostructures with well-controlled shapes, including the double reductant method, etching technique and construction of core-shell nanostructures. The growth mechanism of double the reductant method is that different favorable facets of silver nanocrystals are produced in different reductants, which can be used to prepare complex nanostructures such as nanoflags with ultranarrow resonant band bandwidth or some silver nanostructures which are difficult to prepare using other methods. The etching technique can selectively remove nanoparticles to achieve the aim of shape control and is widely used for the synthesis of nanoflowers and hollow nanostructures. Construction of core-shell nanostructures is another tool to control shape and size. The three methods can not only prepare various silver nanostructures with well-controlled shapes, which exhibit unique optical properties, such as strong surface-enhanced Raman scattering (SERS) signal and localized surface plasmon resonance (LSPR) effect, but also have potential application in many areas.
PMCID: PMC4029645  PMID: 24670722
reductant; nanoparticle etching; composited nanostructures; shape control; plasmonic sensors
5.  Ligand-Mediated Self-Assembly of Hybrid Plasmonic and Superparamagnetic Nanostructures 
Hybrid nanostructures with unique optical and magnetic properties have attracted considerable interest as effective mediators for medical imaging and therapy. An aqueous-based, self-assembly approach to synthesizing hybrid plasmonic-superparamagnetic nanostructures is presented. The building blocks of the hybrid nanostructure include plasmonic gold nanorods (AuNRs) and superparamagnetic iron oxide nanoparticles (SPIONs). The AuNRs were functionalized via carboxyl-bearing surface ligands, while the SPIONs were kept “bare” after synthesis via a surfactant-free, thermal decomposition reaction in triethylene glycol. Hybrid SPION-studded AuNR nanostructures were produced upon simple mixing of the components due to chemisorption of the AuNRs’ free carboxyl groups to the SPIONs’ surfaces. The reported synthesis strategy is modular in nature and can be expanded to build hybrid nanostructures with a multitude of other plasmonic nanoparticles. With tunable near-infrared absorption peaks and a sufficient number of bound SPIONs, the self-assembled hybrid nanostructures are suitable for biomedical imaging and therapy applications.
PMCID: PMC3594096  PMID: 23362922
Hybrid nanostructures; self-assembly; gold nanoparticles; iron oxide; silica; plasmonic nanoparticles; superparamagnetic nanoparticles
6.  Magnetic and optical properties of multifunctional core-shell radioluminescence nanoparticles 
Journal of materials chemistry  2012;22(25):12802-12809.
When X-rays irradiate radioluminescence nanoparticles, they generate visible and near infrared light that can penetrate through centimeters of tissue. X-ray luminescence tomography (XLT) maps the location of these radioluminescent contrast agents at high resolution by scanning a narrow X-ray beam through the tissue sample and collecting the luminescence at every position. Adding magnetic functionality to these radioluminescent particles would enable them to be guided, oriented, and heated using external magnetic fields, while their location and spectrum could be imaged with XLT and complementary magnetic resonance imaging. In this work, multifunctional monodispersed magnetic radioluminescent nanoparticles were developed as potential drug delivery carriers and radioluminescence imaging agents. The particles consisted of a spindle-shaped magnetic γ-Fe2O3 core and a radioluminescent europium-doped gadolinium oxide shell. Particles with solid iron oxide cores displayed saturation magnetizations consistent with their ~13% core volume, however, the iron oxide quenched their luminescence. In order to increase the luminescence, we partially etched the iron oxide core in oxalic acid while preserving the radioluminescent shell. The core size was controlled by the etching time which in turn affected the particles’ luminescence and magnetic properties. Particles with intermediate core sizes displayed both strong magnetophoresis and luminescence properties. They also served as MRI contrast agents with relaxivities of up to 58 mM−1s−1 (r2) and 120 mM−1s−1 (r2*). These particles offer promising multimodal MRI/fluorescence/X-ray luminescence contrast agents. Our core-shell synthesis technique offers a flexible method to control particle size, shape, and composition for a wide range of biological applications of magnetic/luminescent nanoparticles.
PMCID: PMC3918467  PMID: 24520183
7.  Externally modulated theranostic nanoparticles 
Translational cancer research  2013;2(4):292-308.
Externally modulated nanoparticles comprise a rapidly advancing class of cancer nanotherapeutics, which combine the favorable tumor accumulation of nanoparticles, with external spatio-temporal control on therapy delivery via optical, magnetic, or ultrasound modalities. The local control on therapy enables higher tumor treatment efficacy, while simultaneously reducing off-target effects. The nanoparticle interactions with external fields have an additional advantage of frequently generating an imaging signal, and thus such agents provide theranostic (both diagnostic and therapeutic) capabilities. In this review, we classify the emerging externally modulated theranostic nanoparticles according to the mode of external control and describe the physiochemical mechanisms underlying the external control of therapy, and illustrate the major embodiments of nanoparticles in each class with proven biological efficacy: (I) electromagnetic radiation in visible and near-infrared range is being exploited for gold based and carbon nanostructures with tunable surface plasmon resonance (SPR) for imaging and photothermal therapy (PTT) of cancer, photochemistry based manipulations are employed for light sensitive liposomes and porphyrin based nanoparticles; (II) Magnetic field based manipulations are being developed for iron-oxide based nanostructures for magnetic resonance imaging (MRI) and magnetothermal therapy; (III) ultrasound based methods are primarily being employed to increase delivery of conventional drugs and nanotherapeutics to tumor sites.
PMCID: PMC4019206  PMID: 24834381
Cancer nanotechnology; theranostics; hyperthermia; NIR therapy; gold nanoparticles (AuNPs)
8.  Synthesis and characterization of core-shell Fe3O4-gold-chitosan nanostructure 
Fe3O4-gold-chitosan core-shell nanostructure can be used in biotechnological and biomedical applications such as magnetic bioseparation, water and wastewater treatment, biodetection and bioimaging, drug delivery, and cancer treatment.
Magnetite nanoparticles with an average size of 9.8 nm in diameter were synthesized using the chemical co-precipitation method. A gold-coated Fe3O4 monotonous core-shell nanostructure was produced with an average size of 15 nm in diameter by glucose reduction of Au3+ which is then stabilized with a chitosan cross linked by formaldehyde. The results of analyses with X-ray diffraction (XRD), Fourier Transformed Infrared Spectroscopy (FTIR), Transmission Electron Microscopy (TEM), and Atomic Force Microscopy (AFM) indicated that the nanoparticles were regularly shaped, and agglomerate-free, with a narrow size distribution.
A rapid, mild method for synthesizing Fe3O4-gold nanoparticles using chitosan was investigated. A magnetic core-shell-chitosan nanocomposite, including both the supermagnetic properties of iron oxide and the optical characteristics of colloidal gold nanoparticles, was synthesized.
PMCID: PMC3265409  PMID: 22221555
bioseparation; core-shell; Fe3O4-gold-chitosan; hydrogel; magnetic; nanocomposite; nanoparticle
9.  Bimetallic Nanoshells for Metal – Enhanced Fluorescence with Broad Band Fluorophores 
In this article, we reported the near-field interactions between the Ru(bpy)32+ complexes and plasmon resonances from the bimetallic nanoshells. The metallic nanoshells were fabricated on 20 nm silica spheres as cores by depositing 10 nm monometallic or bimetallic shells. There were approx. 15 Ru(bpy)32+ complexes in the silica core. The metal shells were constituted of silver or/and gold. The bimetallic shells could be generated in homogeneous or heterogeneous geometries. The homogeneous bimetallic shells contained 10 nm silver-gold alloys. The heterogeneous bimetallic shells contained successive 5 nm gold and 5 nm silver shells, or alternatively, 5 nm silver and 5 nm gold shells. Optical properties of metal nanoshells were studied on both the ensemble spectra and single nanoparticle imaging measurements. The heterogeneous bimetallic shells were found to have a large scale of metal-enhanced emission relative to the monometallic or homogeneous bimetallic shells. It is because the heterogeneous bimetallic shells may display split dual plasmon resonances which can interact with the excitation and emission bands of the Ru(bpy)32+ complexes in the silica cores leading to more efficient near-field interactions. The prediction can be demonstrated by the lifetimes. Therefore, it is suggested that both the compositions and geometries of the metal shells can influence the interactions with the fluorophores in the cores. This observation also offers us an opportunity for developing plasmon-based fluorescence metal nanoparticles as novel nanoparticle imaging agents which have high performances in fluorescence cell or tissue imaging.
PMCID: PMC3516846  PMID: 23230456
fluorescence; bimetallic nanoshell; plasmon resonance; Ru(bpy)32+ complexes; optical properties of single nanoparticle; time-resolved confocal microscope; and near-field interaction
10.  Nanoparticle-mediated photothermal therapy: A comparative study of heating for different particle types 
Lasers in surgery and medicine  2012;44(8):675-684.
Near infrared absorbing plasmonic nanoparticles enhance photothermal therapy of tumors. In this procedure, systemically delivered gold nanoparticles preferentially accumulate at the tumor site and when irradiated using laser light, produce localized heat sufficient to damage tumor cells. Gold nanoshells and nanorods have been widely studied for this purpose, and while both exhibit strong NIR absorption, their overall absorption and scattering properties differ widely due to their geometry. In this paper, we compared the photothermal response of both nanoparticle types including the heat generation and photothermal efficiency.
Tissue simulating phantoms, with varying concentrations of gold nanoparticles, were irradiated with a near-infrared diode laser while concurrently monitoring the surface temperature with an infrared camera. We calculated nanoshell and nanorod optical properties using the Mie solution and the discrete dipole approximation, respectively. In addition, we measured the heat generation of nanoshells and nanorods at the same optical density to determine the photothermal transduction efficiency for both nanoparticle types.
We found that the gold nanoshells produced more heat than gold nanorods at equivalent number densities (# of nanoparticles/mL), whereas the nanorods generated more heat than nanoshells at equivalent extinction values at the irradiance wavelength. To reach an equivalent heat generation, we found that it was necessary to have ~36x more nanorods than nanoshells. However, the gold nanorods were found to have two times the photothermal transduction efficiency than the gold nanoshells.
For the NPs tested, the nanoshells generated more heat, per nanoparticle, than nanorods, primarily due to their overall larger geometric cross section. Conversely, we found that the gold nanorods had a higher photothermal efficiency than the gold nanoshells. In conclusion, the ideal choice of plasmonic nanoparticle requires not only per particle efficiency, but also the in vivo particle targeting ability under study.
PMCID: PMC3512106  PMID: 22933382
Cancer; Gold Nanorods; Gold Nanoshells; Infrared Imaging; Photothermal Therapy; Photothermal Efficiency
11.  Gold Nanocages: From Synthesis to Theranostic Applications 
Accounts of chemical research  2011;44(10):914-924.
Gold nanostructures have garnered considerable attention in recent years for their potential to enhance both the diagnosis and treatment of cancer through their advantageous chemical and physical properties. The key feature of Au nanostructures for enabling this diverse array of biomedical applications is their attractive optical properties, i.e. the scattering and absorption of light at resonant wavelengths due to the excitation of plasmon oscillations. This phenomenon is commonly known as localized surface plasmon resonance (LSPR) and is the source of the ruby red color of conventional Au colloids. The resonant wavelength is highly dependent on the size, shape, and geometry of the nanostructures, providing a set of knobs to maneuver the optical properties as needed. For in vivo applications, especially when optical excitation or transduction is involved, the LSPR peaks of the Au nanostructures have to be tuned to the transparent window of soft tissues in the near-infrared (NIR) region (from 700–900 nm) in order to maximize the penetration depth.
One class of nanostructures with tunable LSPR peaks in the NIR region is Au nanocages. These versatile nanostructures are characterized by hollow interiors, ultrathin and porous walls, and can be prepared in relatively large quantities using a remarkably simple procedure based on the galvanic replacement between Ag nanocubes and aqueous chloroauric acid. The LSPR peaks of Au nanocages can be readily and precisely tuned to any wavelength in the NIR region by controlling their size and/or wall thickness. Other significant features of Au nanocages that make them particularly intriguing materials for biomedical applications include their compact sizes, large absorption cross sections (almost five orders of magnitude greater than those of conventional organic dyes), bio-inertness, as well as a robust and straightforward procedure for surface modification based on the Au-thiolate chemistry. In this article, we present some of the most recent advances in the use of Au nanocages for a broad range of theranostic applications, including their use: i) as tracers for tracking by multi-photon luminescence; ii) as contrast agents for photoacoustic (PA) and mutimodal (PA/fluorescence) imaging; iii) as photothermal agents for the selective destruction of cancerous or diseased tissue; and iv) as drug delivery vehicles for controlled and localized release in response to external stimuli such as NIR radiation or high-intensity focused ultrasound (HIFU).
PMCID: PMC3168958  PMID: 21528889
12.  Plasmon-Resonant Nanoparticles and Nanostars With Magnetic Cores: Synthesis and Magnetomotive Imaging 
ACS nano  2010;4(9):5163-5173.
Plasmon-resonant gold nanostars (NSTs) with magnetic cores were synthesized by a multistep sequence from superparamagnetic Fe3O4 nanoparticles (NPs), and evaluated as optical contrast agents under magnetomotive (MM) imaging conditions. Core–shell Fe3O4@Au NPs were prepared in nonpolar organic solvents with nanometer control over shell thickness, and with good epitaxy to the Fe3O4 surface. Anisotropic growth was performed in micellar solutions of cetyltrimethylammonium bromide (CTAB) under mildly reducing conditions, resulting in NSTs with physical features similar to those produced from colloidal gold seeds. NSTs could be produced below 100 nm from tip to tip but seed size had a significant impact on growth habit, with larger seed particles producing submicron-sized “morning stars.” Both NSTs and aggregated core–shell NPs are responsive to in-plane magnetic field gradients and can provide enhanced near-infrared (NIR) contrast under MM conditions, but do so by different mechanisms. NSTs can modulate polarized NIR scattering with minimal translational motion, giving the appearance of a periodic but stationary “blinking,” whereas core–shell NP aggregates require lateral displacement for signal modulation. The polarization-sensitive MM imaging modality offers the dual advantage of enhanced signal quality and reduced background signal, and can be applied toward the detection of magnetomotive NSTs in heterogenous biological samples, as illustrated by their detection inside of granular cells such as macrophages.
PMCID: PMC2947563  PMID: 20690598
imaging; magnetic nanoparticles; nanomedicine; nanostars; plasmonics; synthesis
13.  VCAM-1-targeted core/shell nanoparticles for selective adhesion and delivery to endothelial cells with lipopolysaccharide-induced inflammation under shear flow and cellular magnetic resonance imaging in vitro 
Multifunctional nanomaterials with unique magnetic and luminescent properties have broad potential in biological applications. Because of the overexpression of vascular cell adhesion molecule-1 (VCAM-1) receptors in inflammatory endothelial cells as compared with normal endothelial cells, an anti-VCAM-1 monoclonal antibody can be used as a targeting ligand. Herein we describe the development of multifunctional core-shell Fe3O4@SiO2 nanoparticles with the ability to target inflammatory endothelial cells via VCAM-1, magnetism, and fluorescence imaging, with efficient magnetic resonance imaging contrast characteristics. Superparamagnetic iron oxide and fluorescein isothiocyanate (FITC) were loaded successfully inside the nanoparticle core and the silica shell, respectively, creating VCAM-1-targeted Fe3O4@SiO2(FITC) nanoparticles that were characterized by scanning electron microscopy, transmission electron microscopy, fluorescence spectrometry, zeta potential assay, and fluorescence microscopy. The VCAM-1-targeted Fe3O4@SiO2(FITC) nanoparticles typically had a diameter of 355 ± 37 nm, showed superparamagnetic behavior at room temperature, and cumulative and targeted adhesion to an inflammatory subline of human umbilical vein endothelial cells (HUVEC-CS) activated by lipopolysaccharide. Further, our data show that adhesion of VCAM-1-targeted Fe3O4@SiO2(FITC) nanoparticles to inflammatory HUVEC-CS depended on both shear stress and duration of exposure to stress. Analysis of internalization into HUVEC-CS showed that the efficiency of delivery of VCAM-1-targeted Fe3O4@SiO2(FITC) nanoparticles was also significantly greater than that of nontargeted Fe3O4@SiO2(FITC)-NH2 nanoparticles. Magnetic resonance images showed that the superparamagnetic iron oxide cores of the VCAM-1-targeted Fe3O4@SiO2(FITC) nanoparticles could also act as a contrast agent for magnetic resonance imaging. Taken together, the cumulative adhesion and uptake potential of these VCAM-1-targeted Fe3O4@SiO2(FITC) nanoparticles targeted to inflammatory endothelial cells could be used in the transfer of therapeutic drugs/genes into these cells or for diagnosis of vascular disease at the molecular and cellular levels in the future.
PMCID: PMC3658441  PMID: 23696701
silica nanoparticles; vascular cell adhesion molecule-1; endothelial cells; adhesion; magnetic resonance imaging
14.  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.
PMCID: PMC3211881  PMID: 21774807
nanostructures; oxides; cobalt ferrite; cobalt zinc ferrite; zinc ferrite; magnetic properties; diffuse reflectance.
15.  Plasmonic enhanced emissions from cubic NaYF4:Yb: Er/Tm nanophosphors 
A metal shell was used in this study to provide significant enhancement of the up-converted emission from cubic NaYF4 nanoparticles, creating a valuable composite material for labeling in biology and other applications – use of the cubic form of the material obviates the need to undertake a high temperature transformation to the naturally more efficient hexagonal phase. The NaYF4 matrix contained ytterbium sensitizer and an Erbium (Er) or Thulium (Tm) activator. The particle sizes of the as-synthesized nanoparticles were in the range of 20–40 nm with a gold shell thickness of 4–8 nm. The gold shell was macroscopically amorphous. The synthesis method was based on a citrate chelation. In this approach, we exploited the ability of the citrate ion to act as a reductant and stabilizer. Confining the citrate ion reductant on the nanophosphor surface rather than in the solution was critical to the gold shell formation. The plasmonic shell enhanced the up-conversion emission of Tm from visible and near-infrared regions by up to a factor of 8, in addition to imparting a visible color arising from the plasmon absorption of the gold shell. The up-conversion enhancement observed with Tm and Er were different for similar gold coverages, with local crystal field changes as a possible route to enhance up-conversion emission from high symmetry structural hosts. These novel up-converting nanophosphor particles combine the phosphor and features of a gold shell, providing a unique platform for many biological imaging and labeling applications.
PMCID: PMC3119558  PMID: 21709812
Cubic-NaYF4; Up-converting nanophosphor; Citrate method; Gold coating; Up-conversion emission; Plasmonic enhancement
16.  Gold-Based Magneto/Optical Nanostructures: Challenges for In Vivo Applications in Cancer Diagnostics and Therapy 
Materials research bulletin  2009;34(6):415-421.
Nanoparticles with gold shell and iron core have unique optical and magnetic properties which can be utilized for simultaneous detection and treatment strategies. Several nanoparticles have been synthesized and shown to mediate a variety of potential applications in biomedicine, including cancer molecular optical and magnetic resonance imaging, controlled drug delivery, and photothermal ablation therapy. However, to be effective, these nanoparticles must be delivered efficiently into their targets. In this review, we will provide an updated summary of the gold-shelled magnetic nanoparticles that have been synthesized, methods for characterization, and their potential for cancer diagnosis and treatment. We will also discuss the biological barriers that need to be overcome for the effective delivery of these nanoparticles. The desired nanoparticle characteristics needed to evade these biological barriers were also explained. Hopefully, this review will help researchers in designing nanoparticles by carefully choosing the optimum size, shape, surface charge, and surface coating.
PMCID: PMC2891272  PMID: 20582234
17.  Sombrero-Shaped Plasmonic Nanoparticles with Molecular-Level Sensitivity and Multifunctionality 
ACS Nano  2011;5(8):6449-6457.
We demonstrate top-down synthesis of monodisperse plasmonic nanoparticles designed to contain internal Raman hot spots. Our Raman-active nanoparticles are fabricated using nanoimprint lithography and thin-film deposition and are composed of novel internal structures with sublithographic dimensions: a disk-shaped Ag core, a Petri-dish-shaped SiO2 base whose inner surface is coated with Ag film, and a sub-10 nm scale circular gap between the core and the base. Confocal Raman measurements and electromagnetic simulations show that Raman hot spots appear at the inside perimeter of individual nanoparticles and serve as the source of a 1000-fold improvement of minimum molecular detection level that enables detection of signals from a few molecules near hot spots. A multimodality version of these nanoparticles, which includes the functionality offered by magnetic multilayers, is also demonstrated. These results illustrate the potential of direct fabrication for creating exotic monodisperse nanoparticles, which combine engineered internal nanostructures and multilayer composite materials, for use in nanoparticle-based molecular imaging and detection.
PMCID: PMC3160147  PMID: 21732686
surface-enhanced Raman scattering; plasmonic; nanoparticle; magnetic
18.  Hybrid, silica-coated, Janus-like plasmonic-magnetic nanoparticles 
Hybrid plasmonic-magnetic nanoparticles possess properties that are attractive in bioimaging, targeted drug delivery, in vivo diagnosis and therapy. The stability and toxicity, however, of such nanoparticles challenge their safe use today. Here, biocompatible, SiO2-coated, Janus-like Ag/Fe2O3 nanoparticles are prepared by one-step, scalable flame aerosol technology. A nanothin SiO2 shell around these multifunctional nanoparticles leaves intact their morphology, magnetic and plasmonic properties but minimizes the release of toxic Ag+ ions from the nanosilver surface and its direct contact with live cells. Furthermore, this silica shell hinders flocculation and allows for easy dispersion of such nanoparticles in aqueous and biological buffer (PBS) solutions without any extra functionalization step. As a result, these hybrid particles exhibited no cytotoxicity during bioimaging and remained stable in suspension with no signs of agglomeration and sedimentation or settling. Their performance as biomarkers was explored by selectively binding them with live tagged Raji and HeLa cells enabling their detection under dark-filed illumination. Therefore, these SiO2-coated Ag/Fe2O3 nanoparticles do not exhibit the limiting physical properties of each individual component but retain their desired functionalities facilitating thus, the safe use of such hybrid nanoparticles in bio-applications.
PMCID: PMC3667481  PMID: 23729990
silver; iron oxide; silicon dioxide; cancer cell detection; heterodimer
19.  A gold nanoshell with a silica inner shell synthesized using liposome templates for doxorubicin loading and near-infrared photothermal therapy 
Gold (Au) nanoshells with solid silica cores have great potential for cancer photothermal therapy. However, this nanostructure cannot carry enough drugs. Here, we report a Au nanoshell with a hollow silica core for drug loading and cancer therapy. The silica shells were synthesized using nanoliposome templates, and then Au nanoshells were grown on the outer surface of the silica shells. Transmission-electron and scanning-electron microscopy showed that the Au nanoshells were successfully fabricated, and that the liposome/SiO2/Au core-shell nanocomposites were spherical with a narrow size distribution. Images of several broken spheres, and the fact that hollow templates (liposomes) were used, suggest that the fabricated Au nanoshells were hollow. After doxorubicin (DOX) was incorporated into liposome/SiO2/Au, the DOX-loaded Au nanoshells killed cancer cells with high therapeutic efficacy when irradiated with near-infrared light, suggesting that the Au nanoshells delivered both DOX chemotherapy and photothermal therapy with a synergistic effect.
PMCID: PMC3090277  PMID: 21589648
gold nanoshell; liposome template; synthesis; doxorubicin; cancer therapy
20.  Light trapping and surface plasmon enhanced high-performance NIR photodetector 
Scientific Reports  2014;4:3914.
Heterojunctions near infrared (NIR) photodetectors have attracted increasing research interests for their wide-ranging applications in many areas such as military surveillance, target detection, and light vision. A high-performance NIR light photodetector was fabricated by coating the methyl-group terminated Si nanowire array with plasmonic gold nanoparticles (AuNPs) decorated graphene film. Theoretical simulation based on finite element method (FEM) reveals that the AuNPs@graphene/CH3-SiNWs array device is capable of trapping the incident NIR light into the SiNWs array through SPP excitation and coupling in the AuNPs decorated graphene layer. What is more, the coupling and trapping of freely propagating plane waves from free space into the nanostructures, and surface passivation contribute to the high on-off ratio as well.
PMCID: PMC3904145  PMID: 24468857
21.  Plasmonic fluorescent quantum dots 
Nature nanotechnology  2009;4(9):571-576.
Combining multiple discrete components into a single multifunctional nanoparticle could be useful in a variety of applications. Retaining the unique optical and electrical properties of each component after nanoscale integration is, however, a long-standing problem1,2. It is particularly difficult when trying to combine fluorophores such as semiconductor quantum dots with plasmonic materials such as gold, because gold and other metals can quench the fluorescence3,4. So far, the combination of quantum dot fluorescence with plasmonically active gold has only been demonstrated on flat surfaces5. Here, we combine fluorescent and plasmonic activities in a single nanoparticle by controlling the spacing between a quantum dot core and an ultrathin gold shell with nanometre precision through layer-by-layer assembly. Our wet-chemistry approach provides a general route for the deposition of ultrathin gold layers onto virtually any discrete nanostructure or continuous surface, and should prove useful for multimodal bioimaging6, interfacing with biological systems7, reducing nanotoxicity8, modulating electromagnetic fields5 and contacting nanostructures9,10.
PMCID: PMC2773548  PMID: 19734929
22.  Manufacture of IRDye800CW-coupled Fe3O4 nanoparticles and their applications in cell labeling and in vivo imaging 
In recent years, near-infrared fluorescence (NIRF)-labeled iron nanoparticles have been synthesized and applied in a number of applications, including the labeling of human cells for monitoring the engraftment process, imaging tumors, sensoring the in vivo molecular environment surrounding nanoparticles and tracing their in vivo biodistribution. These studies demonstrate that NIRF-labeled iron nanoparticles provide an efficient probe for cell labeling. Furthermore, the in vivo imaging studies show excellent performance of the NIR fluorophores. However, there is a limited selection of NIRF-labeled iron nanoparticles with an optimal wavelength for imaging around 800 nm, where tissue autofluorescence is minimal. Therefore, it is necessary to develop additional alternative NIRF-labeled iron nanoparticles for application in this area.
This study manufactured 12-nm DMSA-coated Fe3O4 nanoparticles labeled with a near-infrared fluorophore, IRDye800CW (excitation/emission, 774/789 nm), to investigate their applicability in cell labeling and in vivo imaging. The mouse macrophage RAW264.7 was labeled with IRDye800CW-labeled Fe3O4 nanoparticles at concentrations of 20, 30, 40, 50, 60, 80 and 100 μg/ml for 24 h. The results revealed that the cells were efficiently labeled by the nanoparticles, without any significant effect on cell viability. The nanoparticles were injected into the mouse via the tail vein, at dosages of 2 or 5 mg/kg body weight, and the mouse was discontinuously imaged for 24 h. The results demonstrated that the nanoparticles gradually accumulated in liver and kidney regions following injection, reaching maximum concentrations at 6 h post-injection, following which they were gradually removed from these regions. After tracing the nanoparticles throughout the body it was revealed that they mainly distributed in three organs, the liver, spleen and kidney. Real-time live-body imaging effectively reported the dynamic process of the biodistribution and clearance of the nanoparticles in vivo.
IRDye800CW-labeled Fe3O4 nanoparticles provide an effective probe for cell-labeling and in vivo imaging.
PMCID: PMC2984479  PMID: 21034487
23.  Bifunctional Gold Nanoshells with a Superparamagnetic Iron Oxide-Silica Core Suitable for Both MR Imaging and Photothermal Therapy 
We describe the synthesis, characterization, and use of hybrid nanoparticles with a superparamagnetic iron oxide (SPIO) core and a gold nanoshell. These multifunctional nanoparticles, designated SPIO-Au nanoshells, displayed superparamagnetic characteristics and a significant absorbance in the near-infrared (NIR) region of the electromagnetic spectrum. In addition, they exhibited high transverse relaxivity, r2, and a large r2/r1 ratio and therefore could be imaged by MRI to obtain T2-weighted images. Moreover, SPIO-Au nanoshells showed efficient photo-thermal effect when exposed to NIR light. The use of SPIO-Au nanoshells, with their combination of unique magnetic and optical properties, should enhance the efficacy of nanoshell-mediated photo-thermal therapy by making it possible to direct more nanoparticles to tumors through the application of external magnetic field and by permitting real-time in vivo MRI imaging of the distribution of the nanoparticles before, during, and after photo-thermal therapy.
PMCID: PMC2822349  PMID: 20165552
Near-infrared; Nanoshells; Magnetic resonance imaging; Photo-thermal therapy
24.  Targeting Gold Nanocages to Cancer Cells for Photothermal Destruction and Drug Delivery 
Expert opinion on drug delivery  2010;7(5):577-587.
(i) Importance of the field
Plasmonic nanoparticles provide a novel route to treat cancer due to their ability to effectively convert light into heat for photothermal destruction. Combined with the targeting mechanisms possible with nanoscale materials, this technique has the potential to enable highly targeted therapies to minimize undesirable side effects.
(ii) Areas covered in this review
This review discusses the use of gold nanocages, a novel class of plasmonic nanoparticles, for photothermal applications. Gold nanocages are hollow, porous structures with compact sizes, precisely controlled plasmonic properties and surface chemistry. Additionally, we discuss a recent study of gold nanocages as drug-release carriers by externally controlling the opening and closing of the pores with a smart polymer whose conformation changes at a specific temperature. Release of the contents can be initiated remotely through near-infrared irradiation. Together, these topics cover the years from 2002-2009.
(iii) What the reader will gain
The reader will be exposed to different aspects of gold nanocages, including synthesis, surface modification, in vitro studies, intial in vivo data, and perspectives on future studies.
(iv) Take home message
Gold nanocages are a promising platform for cancer therapy in terms of both photothermal destruction and drug delivery.
PMCID: PMC2858262  PMID: 20345327
photothermal therapy; drug delivery; nanotechnology; nanomedicine
25.  Lipid-Based Nanoparticles as Pharmaceutical Drug Carriers: From Concepts to Clinic 
In recent years, various nanotechnology platforms in the area of medical biology, including both diagnostics and therapy, have gained remarkable attention. Moreover, research and development of engineered multifunctional nanoparticles as pharmaceutical drug carriers have spurred exponential growth in applications to medicine in the last decade. Design principles of these nanoparticles, including nano-emulsions, dendrimers, nano-gold, liposomes, drug-carrier conjugates, antibody-drug complexes, and magnetic nanoparticles, are primarily based on unique assemblies of synthetic, natural, or biological components, including but not limited to synthetic polymers, metal ions, oils, and lipids as their building blocks. However, the potential success of these particles in the clinic relies on consideration of important parameters such as nanoparticle fabrication strategies, their physical properties, drug loading efficiencies, drug release potential, and, most importantly, minimum toxicity of the carrier itself. Among these, lipid-based nanoparticles bear the advantage of being the least toxic for in vivo applications, and significant progress has been made in the area of DNA/RNA and drug delivery using lipid-based nanoassemblies. In this review, we will primarily focus on the recent advances and updates on lipid-based nanoparticles for their projected applications in drug delivery. We begin with a review of current activities in the field of liposomes (the so-called honorary nanoparticles), and challenging issues of targeting and triggering will be discussed in detail. We will further describe nanoparticles derived from a novel class of amphipathic lipids called bolaamphiphiles with unique lipid assembly features that have been recently examined as drug/DNA delivery vehicles. Finally, an overview of an emerging novel class of particles (based on lipid components other than phospholipids), solid lipid nanoparticles and nanostructured lipid carriers will be presented. We conclude with a few examples of clinically successful formulations of currently available lipid-based nanoparticles.
PMCID: PMC2885142  PMID: 20402623
lipid-based nanoparticles; drug delivery; solid lipid nanoparticles; liposomes; nanostructured lipid carriers; bolaamphiphiles; cancer therapy

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