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1.  Surface-Engineered Magnetic Nanoparticle Platforms for Cancer Imaging and Therapy 
Accounts of chemical research  2011;44(10):883-892.
Conspectus
Enormous efforts have been made toward translating nanotechnology into medical practice, including cancer management. The approaches have generally been classifiable into two categories--those for diagnosis and those for therapy. The targets for diagnostic probes and therapy are often the same, however, and separate approaches to develop diagnostic and therapeutic agents can miss opportunities to improve the efficiency and effectiveness of both. A close and continuous linkage between therapy and diagnosis is also important, because a patient’s diagnosis/prognosis will evolve during treatment.
The unique physical properties of nanomaterials enable them to serve as 1) bases for superior imaging probes to locate and report cancerous lesions, and 2) vehicles to deliver therapeutics preferentially to those lesions. These technologies for probes and vehicles have converged in the current efforts to develop nano-theranostics—that is, nanoplatforms with both imaging and therapeutic functionalities. These latest multimodal platforms are highly versatile and valuable components of the emerging beneficial trend toward personalized medicine, which emphasizes tailoring practices to individual needs so as to optimize outcomes. Unlike conventional methods, imaging and therapeutic functions are seamlessly unified in nano-theranostics, thereby permitting updates to diagnosis/prognosis along with treatment, and enabling opportunities to switch to alternative, possibly more suitable, regimens.
Magnetic nanoparticles, especially superparamagnetic iron oxide nanoparticles (hereafter referred to as IONPs), have long been studied as contrast agents for magnetic resonance imaging (MRI). Owing to recent progress in synthesis and surface modification, many new avenues have opened, though, for this class of biomaterials. The idea is to conceptualize the nanoparticles not as merely tiny magnetic crystals, but rather as platforms with large surface-to-volume ratios. By taking advantage of the well developed surface chemistry of these materials, one can load a wide range of functionalities, such as targeting, imaging and therapeutic features, onto their surfaces. This makes magnetic nanoparticles excellent scaffolds to construct theranostic agents and has attracted many efforts toward this goal.
In this account we will summarize the progress made in our recent studies. We will introduce the surface engineering techniques that we and others have developed, with an emphasis on how the techniques affect the role of nanoparticles as imaging or therapeutic agents.
doi:10.1021/ar200044b
PMCID: PMC3166427  PMID: 21548618
2.  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.
doi:10.7150/thno.4006
PMCID: PMC3263519  PMID: 22272222
magnetic nanoparticles; engineering; functionalizing; magnetic resonance imaging
3.  Multifunctional gold nanoparticles for diagnosis and therapy of disease 
Molecular pharmaceutics  2013;10(3):831-847.
Gold nanoparticles (AuNPs) have a number of physical properties that make them appealing for medical applications. For example, the attenuation of X-rays by gold nanoparticles has led to their use in computed tomography imaging and as adjuvants for radiotherapy. AuNPs have numerous other applications in imaging, therapy and diagnostic systems. The advanced state of synthetic chemistry of gold nanoparticles offers precise control over physicochemical and optical properties. Furthermore gold cores are inert and are considered to be biocompatible and non-toxic. The surface of gold nanoparticles can easily be modified for a specific application and ligands for targeting, drugs or biocompatible coatings can be introduced. AuNPs can be incorporated into larger structures such as polymeric nanoparticles or liposomes that deliver large payloads for enhanced diagnostic applications, efficiently encapsulate drugs for concurrent therapy or add additional imaging labels. This array of features has led to the afore-mentioned applications in biomedical fields, but more recently in approaches where multifunctional gold nanoparticles are used for multiple methods, such as concurrent diagnosis and therapy, so called theranostics. The following review covers basic principles and recent findings in gold nanoparticle applications for imaging, therapy and diagnostics, with a focus on reports of multifunctional AuNPs.
doi:10.1021/mp3005885
PMCID: PMC3593826  PMID: 23360440
nanoparticles; multimodality; imaging; gold; theranostics; diagnostics
4.  Inorganic Janus particles for biomedical applications 
Summary
Based on recent developments regarding the synthesis and design of Janus nanoparticles, they have attracted increased scientific interest due to their outstanding properties. There are several combinations of multicomponent hetero-nanostructures including either purely organic or inorganic, as well as composite organic–inorganic compounds. Janus particles are interconnected by solid state interfaces and, therefore, are distinguished by two physically or chemically distinct surfaces. They may be, for instance, hydrophilic on one side and hydrophobic on the other, thus, creating giant amphiphiles revealing the endeavor of self-assembly. Novel optical, electronic, magnetic, and superficial properties emerge in inorganic Janus particles from their dimensions and unique morphology at the nanoscale. As a result, inorganic Janus nanoparticles are highly versatile nanomaterials with great potential in different scientific and technological fields. In this paper, we highlight some advances in the synthesis of inorganic Janus nanoparticles, focusing on the heterogeneous nucleation technique and characteristics of the resulting high quality nanoparticles. The properties emphasized in this review range from the monodispersity and size-tunability and, therefore, precise control over size-dependent features, to the biomedical application as theranostic agents. Hence, we show their optical properties based on plasmonic resonance, the two-photon activity, the magnetic properties, as well as their biocompatibility and interaction with human blood serum.
doi:10.3762/bjnano.5.244
PMCID: PMC4273258  PMID: 25551063
bioimaging (CT; MRI; Multi-photon); hetero-nanoparticles; Janus particles; protein corona; synthesis
5.  Engineering Nanomaterial Surfaces for Biomedical Applications 
Nanomaterials, possessing unique physical and chemical properties, have attracted much interest and generated wide varieties of applications. Recent investigations of functionalized nanomaterials have expanded into the biological area, providing a versatile platform in biomedical applications such as biomolecular sensing, biological imaging, drug delivery and disease therapy. Bio-functions and bio-compatibility of nanomaterials are realized by introducing synthetic ligands or natural biomolecules onto nanomaterials, and combining ligand-receptor biological interactions with intrinsic nanomaterial properties. Common strategies of engineering nanomaterial surfaces involve physisorption or chemisorption of desired ligands. We developed a photochemically initiated surface coupling chemistry, bringing versatility and simplicity to nanomaterial functionalization. The method was applied to attach underivatized carbohydrates efficiently on gold and iron oxide nanoparticles, and the resulting glyconanoparticles were successfully used as a sensitive biosensing system probing specific interactions between carbohydrates and proteins as well as bacteria.
doi:10.3181/0904-MR-134
PMCID: PMC4037294  PMID: 19596820
nanomaterials; surface functionalization; gold nanoparticles; iron oxide nanoparticles; carbohydrates; perfluorophenylazide
6.  Quantum dots incorporated magnetic nanoparticles for imaging colon carcinoma cells 
Background
Engineered multifunctional nanoparticles (NPs) have made a tremendous impact on the biomedical sciences, with advances in imaging, sensing and bioseparation. In particular, the combination of optical and magnetic responses through a single particle system allows us to serve as novel multimodal molecular imaging contrast agents in clinical settings. Despite of essential medical imaging modalities and of significant clinical application, only few nanocomposites have been developed with dual imaging contrast. A new method for preparing quantum dots (QDs) incorporated magnetic nanoparticles (MNPs) based on layer-by-layer (LbL) self-assembly techniques have developed and used for cancer cells imaging.
Methods
Here, citrate - capped negatively charged Fe3O4 NPs were prepared and coated with positively - charged hexadecyltrimethyl ammonium bromide (CTAB). Then, thiol - capped negatively charged CdTe QDs were electrostatically bound with CTAB. Morphological, optical and magnetic properties of the fluorescent magnetic nanoparticles (FMNPs) were characterized. Prepared FMNPs were additionally conjugated with hCC49 antibodies fragment antigen binding (Fab) having binding affinity to sialylated sugar chain of TAG-72 region of LS174T cancer cells, which was prepared silkworm expression system, and then were used for imaging colon carcinoma cells.
Results
The prepared nanocomposites were magnetically responsive and fluorescent, simultaneously that are useful for efficient cellular imaging, optical sensing and magnetic separation. Transmission electron microscopy (TEM) and dynamic light scattering (DLS) revealed that the particle size is around 50 nm in diameter with inner magnetic core and outer CdTe QDs core-shell structure. Cytotoxicity test of prepared FMNPs indicates high viability in Vero cells. NPs conjugated with anti cancer antibodies were successfully labeled on colon carcinoma cells (LS174) in vitro and showed significant specificity to target cells.
Conclusion
The present report demonstrates a simple synthesis of CdTe QDs-Fe3O4 NPs. The surface of the prepared FMNPs was enabled simple conjugation to monoclonal antibodies by electrostatic interaction. This property further extended their in vitro applications as cellular imaging contrast agents. Such labeling of cells with new fluorescent-magneto nanoprobes for living detection is of interest to various biomedical applications and has demonstrated the potential for future medical use.
doi:10.1186/1477-3155-11-28
PMCID: PMC3751691  PMID: 23957878
Core-shell structure; Magnetic nanoparticles; Quantum dots; Fluorescent nanoparticles; Cell imaging
7.  New Paradigm Shift for the Green Synthesis of Antibacterial Silver Nanoparticles Utilizing Plant Extracts 
Toxicological Research  2014;30(3):169-178.
This review covers general information regarding the green synthesis of antibacterial silver nanoparticles. Owing to their antibacterial properties, silver nanoparticles are widely used in many areas, especially biomedical applications. In green synthesis practices, the chemical reducing agents are eliminated, and biological entities are utilized to convert silver ions to silver nanoparticles. Among the various biological entities, natural plant extracts have emerged as green reducing agents, providing eco-friendly routes for the preparation of silver nanomaterials. The most obvious merits of green synthesis are the increased biocompatibility of the resulting silver nanoparticles and the ease with which the reaction can be carried out. This review summarizes some of the plant extracts that are used to produce antibacterial silver nanoparticles. Additionally, background information regarding the green synthesis and antibacterial activity of silver nanoparticles is provided. Finally, the toxicological aspects of silver nanoparticles are briefly mentioned.
doi:10.5487/TR.2014.30.3.169
PMCID: PMC4206743  PMID: 25343010
Plant extracts; Green synthesis; Silver nanoparticles; Antibacterial activity
8.  Cytotoxicity and antibacterial activity of gold-supported cerium oxide nanoparticles 
Background
Cerium oxide nanoparticles (CeO2) have been shown to be a novel therapeutic in many biomedical applications. Gold (Au) nanoparticles have also attracted widespread interest due to their chemical stability and unique optical properties. Thus, decorating Au on CeO2 nanoparticles would have potential for exploitation in the biomedical field.
Methods
In the present work, CeO2 nanoparticles synthesized by a chemical combustion method were supported with 3.5% Au (Au/CeO2) by a deposition-precipitation method. The as-synthesized Au, CeO2, and Au/CeO2 nanoparticles were evaluated for antibacterial activity and cytotoxicity in RAW 264.7 normal cells and A549 lung cancer cells.
Results
The as-synthesized nanoparticles were characterized by X-ray diffraction, scanning and transmission electron microscopy, and ultraviolet-visible measurements. The X-ray diffraction study confirmed the formation of cubic fluorite-structured CeO2 nanoparticles with a size of 10 nm. All synthesized nanoparticles were nontoxic towards RAW 264.7 cells at doses of 0–1,000 μM except for Au at >100 μM. For A549 cancer cells, Au/CeO2 had the highest inhibitory effect, followed by both Au and CeO2 which showed a similar effect at 500 and 1,000 μM. Initial binding of nanoparticles occurred through localized positively charged sites in A549 cells as shown by a shift in zeta potential from positive to negative after 24 hours of incubation. A dose-dependent elevation in reactive oxygen species indicated that the pro-oxidant activity of the nanoparticles was responsible for their cytotoxicity towards A549 cells. In addition, cellular uptake seen on transmission electron microscopic images indicated predominant localization of nanoparticles in the cytoplasmic matrix and mitochondrial damage due to oxidative stress. With regard to antibacterial activity, both types of nanoparticles had the strongest inhibitory effect on Bacillus subtilis in monoculture systems, followed by Salmonella enteritidis, Escherichia coli, and Staphylococcus aureus, while, in coculture tests with Lactobacillus plantarum, S. aureus was inhibited to a greater extent than the other bacteria.
Conclusion
Gold-supported CeO2 nanoparticles may be a potential nanomaterial for in vivo application owing to their biocompatible and antibacterial properties.
doi:10.2147/IJN.S70087
PMCID: PMC4251533  PMID: 25473288
cerium oxide nanoparticles; gold supported cerium oxide; cytotoxicity; antibacterial activity; cellular uptake; reactive oxygen species
9.  Optimization of Immunolabeled Plasmonic Nanoparticles for Cell Surface Receptor Analysis 
Methods (San Diego, Calif.)  2011;56(2):310-316.
Noble metal nanoparticles hold great potential as optical contrast agents due to a unique feature, known as the plasmon resonance, which produces enhanced scattering and absorption at specific frequencies. The plasmon resonance also provides a spectral tunability that is not often found in organic fluorophores or other labeling methods. The ability to functionalize these nanoparticles with antibodies has led to their development as contrast agents for molecular optical imaging. In this review article, we present methods for optimizing the spectral agility of these labels. We discuss synthesis of gold nanorods, a plasmonic nanoparticle in which the plasmonic resonance can be tuned during synthesis to provide imaging within the spectral window commonly utilized in biomedical applications. We describe recent advances in our group to functionalize gold and silver nanoparticles using distinct antibodies, including EGFR, HER-2 and IGF-1, selected for their relevance to tumor imaging. Finally, we present characterization of these nanoparticle labels to verify their spectral properties and molecular specificity.
doi:10.1016/j.ymeth.2011.08.017
PMCID: PMC3271166  PMID: 21911063
Plasmonic nanoparticles; cell imaging; microscpectroscopy; darkfield microscopy
10.  Cytotoxicity of iron oxide nanoparticles made from the thermal decomposition of organometallics and aqueous phase transfer with Pluronic F127 
Magnetic nanoparticles are promising molecular imaging agents due to their relative high relaxivity and the potential to modify surface functionality to tailor biodistribution. In this work we describe the synthesis of magnetic nanoparticles using organic solvents with organometallic precursors. This method results in nanoparticles that are highly crystalline, and have uniform size and shape. The ability to create a monodispersion of particles of the same size and shape results in unique magnetic properties that can be useful for biomedical applications with MR imaging. Before these nanoparticles can be used in biological applications, however, means are needed to make the nanoparticles soluble in aqueous solutions and the toxicity of these nanoparticles needs to be studied.
We have developed two methods to surface modify and transfer these nanoparticles to the aqueous phase using the biocompatible co-polymer, Pluronic F127. Cytotoxicity was found to be dependent on the coating procedure used. Nanoparticle effects on a cell-culture model was quantified using concurrent assaying; a LDH assay to determine cytotoxicity and an MTS assay to determine viability for a 24 hour incubation period. Concurrent assaying was done to insure that nanoparticles did not interfere with the colorimetric assay results.
This report demonstrates that a monodispersion of nanoparticles of uniform size and shape can be manufactured. Initial cytotoxicity testing of new molecular imaging agents need to be carefully constructed to avoid interference and erroneous results.
doi:10.1002/cmmi.391
PMCID: PMC3020093  PMID: 20623517
MRI; molecular imaging; nanoparticles; superparamagnetic agents; cytotoxicity; Colorimetric Assay; Pluronics
11.  Targeted magnetic iron oxide nanoparticles for tumor imaging and therapy 
Magnetic iron oxide (IO) nanoparticles with a long blood retention time, biodegradability and low toxicity have emerged as one of the primary nanomaterials for biomedical applications in vitro and in vivo. IO nanoparticles have a large surface area and can be engineered to provide a large number of functional groups for cross-linking to tumor-targeting ligands such as monoclonal antibodies, peptides, or small molecules for diagnostic imaging or delivery of therapeutic agents. IO nanoparticles possess unique paramagnetic properties, which and generate significant susceptibility effects resulting in strong T2 and T2* contrast, as well as T1 effects at very low concentrations for magnetic resonance imaging (MRI), which is widely used for clinical oncology imaging. We review recent advances in the development of targeted IO nanoparticles for tumor imaging and therapy.
PMCID: PMC2626938  PMID: 18990940
iron oxide nanoparticles; tumor imaging; MRI; therapy
12.  Theranostic Nanoshells: From Probe Design to Imaging and Treatment of Cancer 
Accounts of chemical research  2011;44(10):936-946.
CONSPECTUS
Recent advances in theranostics have expanded our ability to design and construct multifunctional nanoparticles that will ultimately allow us to image and treat diseases in a single clinical procedure. Theranostic nanoparticles, combining targeting, therapeutic and diagnostic functions within a single nanoscale complex, have emerged as a result of this confluence of nanoscience and biomedicine. The theranostic capabilities of gold nanoshells -spherical, silica core, gold shell nanoparticles- have attracted tremendous attention over the past decade as nanoshells have emerged as a promising tool for cancer therapy and bioimaging enhancement. This account examines the design and synthesis of nanoshell-based theranostic agents, their plasmon-derived optical properties and their corresponding applications. Nanoshells illuminated with resonant light are either strong optical absorbers or scatterers, properties which give rise to their unique capabilities. In this account, we discuss the underlying physical principles contributing to the photothermal response of nanoshells. We elucidate the photophysics of nanoshell-induced fluorescence enhancement of weak near-infrared fluorophores. We then describe the application of nanoshells as a contrast agent for optical coherence tomography of breast carcinoma cells in vivo. We also examine the recent progress of nanoshells as a multimodal theranostic probe for near-infrared fluorescence and magnetic resonance imaging (MRI) combined with photothermal ablation of cancer cells. The design and preparation of nanoshell complexes is discussed, and their ability to enhance the photoluminescence of fluorophores while incorporating MR contrast is described. We show the theranostic potential of the multimodal nanoshells in vivo for imaging subcutaneous breast cancer tumors in animal models and their biodistribution in various tissues.
We then discuss the potential of nanoshells as light-triggered gene therapy vectors. The plasmonic properties of nanoshells make them highly effective as light controlled delivery vectors, adding temporal control to the spatial control characteristic of nanoparticle-based gene therapy approaches. We describe the fabrication of DNA-conjugated nanoshell complexes and compare the efficiency of light-induced and thermally-induced DNA release of DNA. We examine light-triggered release of DAPI (4',6-diamidino-2-phenylindole) molecules, which bind reversibly to double-stranded DNA, to visualize intracellular light-induced release. Finally, we look at future prospects of nanoshell-based theranostics, the potential impact and near-term challenges of theranostic nanomedicine in the next decade.
doi:10.1021/ar200023x
PMCID: PMC3888233  PMID: 21612199
13.  Molecular Diagnostic and Drug Delivery Agents based on Aptamer-Nanomaterial Conjugates 
Advanced drug delivery reviews  2010;62(6):592-605.
Recent progress in an emerging area of designing aptamer and nanomaterial conjugates as molecular diagnostic and drug delivery agents in biomedical applications is summarized. Aptamers specific for a wide range of targets are first introduced and compared to antibodies. Methods of integrating these aptamers with a variety of nanomaterials, such as gold nanoparticles, quantum dots, carbon nanotubes, and superparamagnetic iron oxide nanoparticles, each with unique optical, magnetic, and electrochemical properties, are reviewed. Applications of these systems as fluorescent, colorimetric, magnetic resonance imaging, and electrochemical sensors in medical diagnostics are given, along with new applications as smart drug delivery agents.
doi:10.1016/j.addr.2010.03.003
PMCID: PMC2924639  PMID: 20338204
DNA; aptamer; nanomaterials; diagnostics; biosensor; drug delivery; biomedical; targeted therapeutics
14.  Rapid Pharmacokinetic and Biodistribution Studies Using Cholorotoxin-Conjugated Iron Oxide Nanoparticles: A Novel Non-Radioactive Method 
PLoS ONE  2010;5(3):e9536.
Background
Recent advances in nanotechnology have led to the development of biocompatible nanoparticles for in vivo molecular imaging and targeted therapy. Many nanoparticles have undesirable tissue distribution or unacceptably low serum half-lives. Pharmacokinetic (PK) and biodistribution studies can help inform decisions determining particle size, coatings, or other features early in nanoparticle development. Unfortunately, these studies are rarely done in a timely fashion because many nanotechnology labs lack the resources and expertise to synthesize radioactive nanoparticles and evaluate them in mice.
Methodology/Principal Findings
To address this problem, we developed an economical, radioactivity-free method for assessing serum half-life and tissue distribution of nanoparticles in mice. Iron oxide nanoparticles coated with chitosan and polyethylene glycol that utilize chlorotoxin as a targeting molecule have a serum half-life of 7–8 hours and the particles remain stable for extended periods of time in physiologic fluids and in vivo. Nanoparticles preferentially distribute to spleen and liver, presumably due to reticuloendothelial uptake. Other organs have very low levels of nanoparticles, which is ideal for imaging most cancers in the future. No acute toxicity was attributed to the nanoparticles.
Conclusions/Significance
We report here a simple near-infrared fluorescence based methodology to assess PK properties of nanoparticles in order to integrate pharmacokinetic data into early nanoparticle design and synthesis. The nanoparticles tested demonstrate properties that are excellent for future clinical imaging strategies and potentially suitable for targeted therapy.
doi:10.1371/journal.pone.0009536
PMCID: PMC2832013  PMID: 20209054
15.  Analysis of SiO2 nanoparticles binding proteins in rat blood and brain homogenate 
International Journal of Nanomedicine  2014;9(Suppl 2):207-215.
A multitude of nanoparticles, such as titanium oxide (TiO2), zinc oxide, aluminum oxide, gold oxide, silver oxide, iron oxide, and silica oxide, are found in many chemical, cosmetic, pharmaceutical, and electronic products. Recently, SiO2 nanoparticles were shown to have an inert toxicity profile and no association with an irreversible toxicological change in animal models. Hence, exposure to SiO2 nanoparticles is on the increase. SiO2 nanoparticles are routinely used in numerous materials, from strengthening filler for concrete and other construction composites, to nontoxic platforms for biomedical application, such as drug delivery and theragnostics. On the other hand, recent in vitro experiments indicated that SiO2 nanoparticles were cytotoxic. Therefore, we investigated these nanoparticles to identify potentially toxic pathways by analyzing the adsorbed protein corona on the surface of SiO2 nanoparticles in the blood and brain of the rat. Four types of SiO2 nanoparticles were chosen for investigation, and the protein corona of each type was analyzed using liquid chromatography-tandem mass spectrometry technology. In total, 115 and 48 plasma proteins from the rat were identified as being bound to negatively charged 20 nm and 100 nm SiO2 nanoparticles, respectively, and 50 and 36 proteins were found for 20 nm and 100 nm arginine-coated SiO2 nanoparticles, respectively. Higher numbers of proteins were adsorbed onto the 20 nm sized SiO2 nanoparticles than onto the 100 nm sized nanoparticles regardless of charge. When proteins were compared between the two charges, higher numbers of proteins were found for arginine-coated positively charged SiO2 nanoparticles than for the negatively charged nanoparticles. The proteins identified as bound in the corona from SiO2 nanoparticles were further analyzed with ClueGO, a Cytoscape plugin used in protein ontology and for identifying biological interaction pathways. Proteins bound on the surface of nanoparticles may affect functional and conformational properties and distributions in complicated biological processes.
doi:10.2147/IJN.S58203
PMCID: PMC4279766  PMID: 25565838
silica; nanoparticles; protein corona; plasma; brain homogenate; nanotoxicity
16.  Bioorthogonal chemistry amplifies nanoparticle binding and enhances the sensitivity of cell detection 
Nature nanotechnology  2010;5(9):660-665.
Nanoparticles have emerged as key materials for biomedical applications because of their unique and tunable physical properties, multivalent targeting capability, and high cargo capacity1,2. Motivated by these properties and by current clinical needs, numerous diagnostic3–10 and therapeutic11–13 nanomaterials have recently emerged. Here we describe a novel nanoparticle targeting platform that uses a rapid, catalyst-free cycloaddition as the coupling mechanism. Antibodies against biomarkers of interest were modified with trans-cyclooctene and used as scaffolds to couple tetrazine-modified nanoparticles onto live cells. We show that the technique is fast, chemoselective, adaptable to metal nanomaterials, and scalable for biomedical use. This method also supports amplification of biomarker signals, making it superior to alternative targeting techniques including avidin/biotin.
doi:10.1038/nnano.2010.148
PMCID: PMC2934903  PMID: 20676091
17.  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
18.  Drug targeting to infectious diseases by nanoparticles surface functionalized with special biomolecules 
Current Medicinal Chemistry  2012;19(19):3196-3202.
The potential to deliver nanoparticles directly into the targeted cells is important in the therapeutic applications for infectious diseases. The possibility of therapeutic agent being attached to the nanoparticles by chemical modification has provided a novel drug delivery option. Interestingly, the discovery of carbon nanotubes and graphene has given an excellent imaging and therapeutic agent for the biomedical applications. In spite of continuous advancement in pharmaceutical drug delivery viz. micelles, vesicles and liquid crystals etc. during the past decades, their prohibitive production has limited their use. Nanomaterials with their properties of biodegradation, equal biodistribution, mass production and long time storage make them attractive alternative for future biomedical applications. Nanoparticles surface functionalized with specific biomolecules based drug delivery has driven new direction for modulating the pharmacokinetics and pharmacodynamics, biorecognition; and increasing the efficacy of targeted drugs. These new strategies are likely to minimize drug degradation and loss, increase drug availability, and opens up new vistas for drug delivery.
PMCID: PMC3384774  PMID: 22612703
Nanoparticle; infectious diseases; drug delivery; therapeutic; nanotherapy
19.  Potential of magnetic nanoparticles for targeted drug delivery 
Nanoparticles (NPs) play an important role in the molecular diagnosis, treatment, and monitoring of therapeutic outcomes in various diseases. Their nanoscale size, large surface area, unique capabilities, and negligible side effects make NPs highly effective for biomedical applications such as cancer therapy, thrombolysis, and molecular imaging. In particular, nontoxic superparamagnetic magnetic NPs (MNPs) with functionalized surface coatings can conjugate chemotherapeutic drugs or be used to target ligands/proteins, making them useful for drug delivery, targeted therapy, magnetic resonance imaging, transfection, and cell/protein/DNA separation. To optimize the therapeutic efficacy of MNPs for a specific application, three issues must be addressed. First, the efficacy of magnetic targeting/guidance is dependent on particle magnetization, which can be controlled by adjusting the reaction conditions during synthesis. Second, the tendency of MNPs to aggregate limits their therapeutic use in vivo; surface modifications to produce high positive or negative charges can reduce this tendency. Finally, the surface of MNPs can be coated with drugs which can be rapidly released after injection, resulting in targeting of low doses of the drug. Drugs therefore need to be conjugated to MNPs such that their release is delayed and their thermal stability enhanced. This chapter describes the creation of nanocarriers with a high drug-loading capacity comprised of a high-magnetization MNP core and a shell of aqueous, stable, conducting polyaniline derivatives and their applications in cancer therapy. It further summarizes some newly developed methods to synthesize and modify the surfaces of MNPs and their biomedical applications.
doi:10.2147/NSA.S35506
PMCID: PMC3781723  PMID: 24198498
magnetic nanoparticles; drug delivery; biomedical applications; cancer therapy
20.  Multifunctional polymeric nanoparticles doubly loaded with SPION and ceftiofur retain their physical and biological properties 
Background
Advances in nanostructure materials are leading to novel strategies for drug delivery and targeting, contrast media for magnetic resonance imaging (MRI), agents for hyperthermia and nanocarriers. Superparamagnetic iron oxide nanoparticles (SPIONs) are useful for all of these applications, and in drug-release systems, SPIONs allow for the localization, direction and concentration of drugs, providing a broad range of therapeutic applications. In this work, we developed and characterized polymeric nanoparticles based on poly (3-hydroxybutyric acid-co-hydroxyvaleric acid) (PHBV) functionalized with SPIONs and/or the antibiotic ceftiofur. These nanoparticles can be used in multiple biomedical applications, and the hybrid SPION–ceftiofur nanoparticles (PHBV/SPION/CEF) can serve as a multifunctional platform for the diagnosis and treatment of cancer and its associated bacterial infections.
Results
Morphological examination using transmission electron microscopy (TEM) showed nanoparticles with a spherical shape and a core-shell structure. The particle size was evaluated using dynamic light scattering (DLS), which revealed a diameter of 243.0 ± 17 nm. The efficiency of encapsulation (45.5 ± 0.6% w/v) of these polymeric nanoparticles was high, and their components were evaluated using spectroscopy. UV–VIS, FTIR and DSC showed that all of the nanoparticles contained the desired components, and these compounds interacted to form a nanocomposite. Using the agar diffusion method and live/dead bacterial viability assays, we demonstrated that these nanoparticles have antimicrobial properties against Escherichia coli, and they retain their magnetic properties as measured using a vibrating sample magnetometer (VSM). Cytotoxicity was assessed in HepG2 cells using live/dead viability assays and MTS, and these assays showed low cytotoxicity with IC50 > 10 mg/mL nanoparticles.
Conclusions
Our results indicate that hybrid and multifunctional PHBV/SPION/CEF nanoparticles are suitable as a superparamagnetic drug delivery system that can guide, concentrate and site–specifically release drugs with antibacterial activity.
Electronic supplementary material
The online version of this article (doi:10.1186/s12951-015-0077-5) contains supplementary material, which is available to authorized users.
doi:10.1186/s12951-015-0077-5
PMCID: PMC4334767
PHBV; SPION; Ceftiofur; Polymeric nanoparticles; Drug delivery; Superparamagnetic nanoparticles
21.  Introduction to metallic nanoparticles 
Metallic nanoparticles have fascinated scientist for over a century and are now heavily utilized in biomedical sciences and engineering. They are a focus of interest because of their huge potential in nanotechnology. Today these materials can be synthesized and modified with various chemical functional groups which allow them to be conjugated with antibodies, ligands, and drugs of interest and thus opening a wide range of potential applications in biotechnology, magnetic separation, and preconcentration of target analytes, targeted drug delivery, and vehicles for gene and drug delivery and more importantly diagnostic imaging. Moreover, various imaging modalities have been developed over the period of time such as MRI, CT, PET, ultrasound, SERS, and optical imaging as an aid to image various disease states. These imaging modalities differ in both techniques and instrumentation and more importantly require a contrast agent with unique physiochemical properties. This led to the invention of various nanoparticulated contrast agent such as magnetic nanoparticles (Fe3O4), gold, and silver nanoparticles for their application in these imaging modalities. In addition, to use various imaging techniques in tandem newer multifunctional nanoshells and nanocages have been developed. Thus in this review article, we aim to provide an introduction to magnetic nanoparticles (Fe3O4), gold nanoparticles, nanoshells and nanocages, and silver nanoparticles followed by their synthesis, physiochemical properties, and citing some recent applications in the diagnostic imaging and therapy of cancer.
doi:10.4103/0975-7406.72127
PMCID: PMC2996072  PMID: 21180459
Fe3O4; gold nanoparticles; iron oxide nanoparticles; metallic nanoparticles; nanocages; nanoshells; silver nanoparticles
22.  Inorganic-Organic Hybrid Nanomaterials for Therapeutic and Diagnostic Imaging Applications 
Nanotechnology offers outstanding potential for future biomedical applications. In particular, due to their unique characteristics, hybrid nanomaterials have recently been investigated as promising platforms for imaging and therapeutic applications. This class of nanoparticles can not only retain valuable features of both inorganic and organic moieties, but also provides the ability to systematically modify the properties of the hybrid material through the combination of functional elements. Moreover, the conjugation of targeting moieties on the surface of these nanomaterials gives them specific targeted imaging and therapeutic properties. In this review, we summarize the recent reports in the synthesis of hybrid nanomaterials and their applications in biomedical areas. Their applications as imaging and therapeutic agents in vivo will be highlighted.
doi:10.3390/ijms12063888
PMCID: PMC3131598  PMID: 21747714
hybrid nanoparticles; therapeutic and diagnostic imaging applications; nanomedicine
23.  Synthesis and optimization of chitosan nanoparticles: Potential applications in nanomedicine and biomedical engineering 
Background: Chitosan nanoparticles have become of great interest for nanomedicine, biomedical engineering and development of new therapeutic drug release systems with improved bioavailability, increased specificity and sensitivity, and reduced pharmacological toxicity. The aim of the present study was to synthesis and optimize of the chitosan nanoparticles for industrial and biomedical applications.
Methods: Fe3O4 was synthesized and optimized as magnetic core nanoparticles and then chitosan covered this magnetic core. The size and morphology of the nano-magnetic chitosan was analyzed by scanning electron microscope (SEM). Topography and size distribution of the nanoparticles were shown with two-dimensional and three-dimensional images of atomic force microscopy (AFM). The nanoparticles were analyzed using transmission electron microscopy (TEM).
Results: The chitosan nanoparticles prepared in the experiment exhibited white powder shape. The SEM micrographs of the nano-magnetic chitosan showed that they were approximately uniform spheres. The unmodified chitosan nanoparticles composed of clusters of nanoparticles with sizes ranging from 10 nm to 80 nm. AFM provides a three-dimensional surface profile. The TEM image showed physical aggregation of the chitosan nanoparticles.
Conclusion: The results show that a novel chitosan nanoparticle was successfully synthesized and characterized. It seems that this nanoparticle like the other chitosan nano particles has potential applications for nanomedicine, biomedical engineering, industrial and pharmaceutical fields.
PMCID: PMC4143737  PMID: 25202443
Nanomedicine; Nanoparticle; Chitosan; Biomedical engineering.
24.  Radiolabeled Nanoparticles for Multimodality Tumor Imaging 
Theranostics  2014;4(3):290-306.
Each imaging modality has its own unique strengths. Multimodality imaging, taking advantages of strengths from two or more imaging modalities, can provide overall structural, functional, and molecular information, offering the prospect of improved diagnostic and therapeutic monitoring abilities. The devices of molecular imaging with multimodality and multifunction are of great value for cancer diagnosis and treatment, and greatly accelerate the development of radionuclide-based multimodal molecular imaging. Radiolabeled nanoparticles bearing intrinsic properties have gained great interest in multimodality tumor imaging over the past decade. Significant breakthrough has been made toward the development of various radiolabeled nanoparticles, which can be used as novel cancer diagnostic tools in multimodality imaging systems. It is expected that quantitative multimodality imaging with multifunctional radiolabeled nanoparticles will afford accurate and precise assessment of biological signatures in cancer in a real-time manner and thus, pave the path towards personalized cancer medicine. This review addresses advantages and challenges in developing multimodality imaging probes by using different types of nanoparticles, and summarizes the recent advances in the applications of radiolabeled nanoparticles for multimodal imaging of tumor. The key issues involved in the translation of radiolabeled nanoparticles to the clinic are also discussed.
doi:10.7150/thno.7341
PMCID: PMC3915092  PMID: 24505237
radiolabeled nanoparticles; molecular imaging; multimodality imaging; tumor diagnosis; cancer; theranostics
25.  Magnetomotive Molecular Nanoprobes 
Current Medicinal Chemistry  2011;18(14):2103-2114.
Tremendous developments in the field of biomedical imaging in the past two decades have resulted in the transformation of anatomical imaging to molecular-specific imaging. The main approaches towards imaging at a molecular level are the development of high resolution imaging modalities with high penetration depths and increased sensitivity, and the development of molecular probes with high specificity. The development of novel molecular contrast agents and their success in molecular optical imaging modalities have lead to the emergence of molecular optical imaging as a more versatile and capable technique for providing morphological, spatial, and functional information at the molecular level with high sensitivity and precision, compared to other imaging modalities. In this review, we discuss a new class of dynamic contrast agents called magnetomotive molecular nanoprobes for molecular-specific imaging. Magnetomotive agents are superparamagnetic nanoparticles, typically iron-oxide, that are physically displaced by the application of a small modulating external magnetic field. Dynamic phase-sensitive position measurements are performed using any high resolution imaging modality, including optical coherence tomography (OCT), ultrasonography, or magnetic resonance imaging (MRI). The dynamics of the magnetomotive agents can be used to extract the biomechanical tissue properties in which the nanoparticles are bound, and the agents can be used to deliver therapy via magnetomotive displacements to modulate or disrupt cell function, or hyperthermia to kill cells. These agents can be targeted via conjugation to antibodies, and in vivo targeted imaging has been shown in a carcinogen-induced rat mammary tumor model. The iron-oxide nanoparticles also exhibit negative T2 contrast in MRI, and modulations can produce ultrasound imaging contrast for multimodal imaging applications.
PMCID: PMC3319747  PMID: 21517766
Magnetomotion; molecular imaging; optical coherence tomography; hyperthermia; superparamagnetic iron oxide nanoparticles; targeting

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