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The unique optical, magnetic, and electronic properties of nanocrystals enable them to be key probes and vectors in the next generation of biomedical applications. Semiconductor quantum dots have been demonstrated as excellent fluorescent probes. However, they suffer from the intrinsic limitations of optical imaging systems such as low penetration depth and large background fluorescence. Magnetic nanocrystals are now emerging in biomedical applications with new possibilities. We have demonstrated the production of high quality water-soluble iron oxide (WSIO) nanocrystals by thermal decomposition method. One of the current challenges now is how to develop well-defined magnetic nanocrystals with optimal nanoscale magnetism, high bio-stability to withstand harsh biological conditions, Conjugation of biologically functional molecules to nanocrystals produce nanohybrids that have multi-functionality such as detection, diagnosis, and therapeutics. However, further development of in vivo imaging applications of these molecules has been very limited with very few successful in vivo demonstrations. In addition to therapeutic antibody, the ability to incorporate genes or drugs into detectable site-targeted nanosystems may represent a whole new paradigm in therapeutics. The application for molecular and cellar imaging in nanoscience have not been fully developed. However, it has enormous potential for development and nanocrystals will bring improvement in bio-medical sciences.

The unique properties of magnetic nanocrystals provide them with high potential as key probes and vectors in the next generation of biomedical applications. Although superparamagnetic iron oxide nanocrystals have been extensively studied as excellent magnetic resonance imaging (MRI) probes for various cell trafficking, gene expression, and cancer diagnosis, further development of in vivo MRI applications has been very limited. Here, we describe in vivo diagnosis of cancer, utilizing a well-defined magnetic nanocrystal probe system with multiple capabilities, such as small size, strong magnetism, high biocompatibility, and the possession of active functionality for desired receptors. Our magnetic nanocrystals are conjugated to a cancer-targeting antibody, Herceptin, and subsequent utilization of these conjugates as MRI probes has been successfully demonstrated for the monitoring of in vivo selective targeting events of human cancer cells implanted in live mice. Further conjugation of these nanocrystal probes with fluorescent dye-labeled antibodies enables both in vitro and ex vivo optical detection of cancer as well as in vivo MRI, which are potentially applicable for an advanced multimodal detection system. Our study finds that high performance in vivo MR diagnosis of cancer is achievable by utilizing improved and multifunctional material properties of iron oxide nanocrystal probes.

Background: Soft-tissue impingement syndrome is now increasingly being recognized as a significant cause of chronic ankle pain. The aim of this study was to investigate the diagnostic accuracy of contrast-enhanced, fat-suppressed, three-dimensional (3D), fast-gradient-recalled acquisition in the steady state with radio-frequency-spoiling (CE 3D-FSPGR) magnetic resonance imaging (MRI), and to evaluate the clinical outcome of arthroscopic treatment of soft-tissue impingement associated with the ankle trauma. Methods: This study reviewed 38 patients who had preoperative MRI and arthroscopic treatment of chronic ankle pain after trauma. The CE 3D-FSPGR MRI was used to evaluate the chronic ankle pain, and the American Orthopedic Foot and Ankle Society (AOFAS) Ankle-Hindfoot Score was used to evaluate the clinical results after arthroscopic treatment. Results: The CE 3D-FSPGR MRI showed a sensitivity of 91.9%, a specificity of 84.4%, and an accuracy of 87.5% in diagnosing synovitis and soft tissue impingement. All patients had excellent or good outcomes after arthroscopic debridement. Conclusion: The results of this study suggest that a preoperative fat-suppressed CE 3D-FSPGR MRI is highly beneficial in diagnosing synovitis and soft-tissue impingement and that arthroscopic debridement of the synovitis or soft-tissue impingement has a good clinical outcome.

Telomerase has attracted much attention as a universal cancer biomarker because telomerase is overexpressed in more than 85% of human cancer cells while suppressed in normal somatic cells. Since a strong association exists between telomerase activity and human cancers, the development of effective telomerase activity assay is critically important. Here, a nanogap-rich Au nanowire (NW) surface-enhanced Raman scattering (SERS) sensor is reported for detection of telomerase activity in various cancer cells and tissues. The nanogap-rich Au NWs are constructed by deposition of nanoparticles on single-crystalline Au NWs and provided highly reproducible SERS spectra. The telomeric substrate (TS) primer-attached nanogap-rich Au NWs can detect telomerase activity through SERS measurement after the elongation of TS primers, folding into G-quadruplex structures, and intercalation of methylene blue. This sensor enables us to detect telomerase activity from various cancer cell lines with a detection limit of 0.2 cancer cells mL−1. Importantly, the nanogap-rich Au NW sensor can diagnose gastric and breast cancer tissues accurately. The nanogap-rich Au NW sensors show strong SERS signals only in the presence of tumor tissues excised from 16 tumor-bearing mice, while negligible signals in the presence of heated tumor tissues or normal tissues. It is anticipated that nanogap-rich Au NW SERS sensors can be used for a universal cancer diagnosis and further biomedical applications including a diverse biomarker sensing.

Correction for ‘Stent containing CD44-targeting polymeric prodrug nanoparticles that release paclitaxel and gemcitabine in a time interval-controlled manner for synergistic human biliary cancer therapy’ by Dayeon Yun et al., J. Mater. Chem. B, 2017, 5, 6317–6324.

In nanomaterials synthesis, Ostwald ripening is a postsynthetic problem that is one obstacle for common utilization of nanomaterials. Herein, we report an unprecedented Ostwald ripening mechanism resulting from the simple combination of hydrogen peroxide (H2O2) and cetyltrimethylammonium bromide (CTAB)-stabilized gold nanoparticles (AuNPs) at room temperature. In this ripening process, H2O2 redox induces simultaneous dissolution and growth of AuNPs where bromide (Br–) from CTAB helps to form AuBr2– in aqueous solution at room temperature. This understanding will provide basic strategies for advanced designs and development of various nanomaterials.

We have investigated basic properties of normal gastrointestinal (GI) tract tissues, including glandular stomach (GS), fore stomach (FS), large intestine (LI), small intestine (SI), and esophagus (ESO), from a rat model using terahertz (THz) reflection imaging and spectroscopy. The THz images collected from stratified squamous epithelia (SSE) of FS and ESO show a lower peak-to-peak value compared to those from columnar epithelia (CE) of GS, LI, or SI because the SSE contains less water than CE. The refractive index and absorption coefficient of FS were less than those of GS or LI, both having values similar to those of water. Additionally, we report internal reflection THz signals from ESO, although we were unable to determine the exact interface for this internal reflection. (C) 2014 Optical Society of America

We developed Pyrene-Gadolinium (Py-Gd) nanoparticles as pH-sensitive magnetic resonance imaging (MRI) contrast agents capable of showing a high-Mr signal in cancer-specific environments, such as acidic conditions. Py-Gd nanoparticles were prepared by coating Py-Gd, which is a complex of gadolinium with pyrenyl molecules, with pyrenyl polyethyleneglycol PEG using a nano-emulsion method. These particles show better longitudinal relaxation time (T1) MR signals in acidic conditions than they do in neutral conditions. Furthermore, the particles exhibit biocompatibility and MR contrast effects in both in vitro and in vivo studies. From these results, we confirm that Py-Gd nanoparticles have the potential to be applied for accurate cancer diagnosis and therapy.

Oleyl dextran-coated magnetic nanoclusters (ODMCs) are fabricated for the accurate detection of macrophage-rich atherosclerotic plaques using magnetic resonance (MR) imaging. Dextran is introduced to the cluster surface of magnetic nanocrystals (MNCs) through self-assembly using amphiphilic oleic acid-conjugated dextran (ODex) to provide not only hydrophilicity but also a high affinity to macrophages. Enhanced magnetism of the ODMCs is engineered by optimizing the degree of substitution (DS) of the oleyl group in ODex and the concentration of ODex used for the synthesis of ODMC. Consequently, ODMCs exhibit significantly increased T2 relaxivity and excellent macrophage-targeting ability without cytotoxicity, in vitro. Moreover, in vivo T2-weighted MR imaging after intravenous injection of ODMCs into a rat artery balloon injury model demonstrates considerable MR contrast strength efficacy in the plaques of the injured carotid artery. These novel ODMCs may offer a highly efficient MR imaging nanoprobes for the selective diagnosis of atherosclerosis.

We demonstrated that tumors in freshly excised whole brain tissue could be differentiated clearly from normal brain tissue using a reflection-type terahertz (THz) imaging system. THz binary images of brain tissues with tumors indicated that the tumor boundaries in the THz images corresponded well to those in visible images. Grey and white-matter regions were distinguishable owing to the different distribution of myelin in the brain tissue. THz images corresponded closely with magnetic resonance imaging (MRI) results. The MRI and hematoxylin and eosin-stained microscopic images were investigated to account for the intensity differences in the THz images for fresh and paraffin-embedded brain tissue. Our results indicated that the THz signals corresponded to the cell density when water was removed. Thus, THz imaging could be used as a tool for label-free and real-time imaging of brain tumors, which would be helpful for physicians to determine tumor margins during brain surgery. (C)2014 Optical Society of America

Cancer stem cells (CSCs) have been reported to be critical in the initiation, maintenance, and progression of cancers. The expression of stem cell markers, such as podoplanin (PDPN), CD133, and nestin, may have been correlated with malignant progression. However, the effects of CSCs and stem cell markers on clinical outcomes in cancer patients remain unclear. In this study, we assessed the prognostic roles of glioma CSCs (gCSCs) isolation and stem cell markers in patients with primary glioblastoma (pGBM). A cohort of 39 patients with pGBM was separated into two groups, those positive or negative for gCSCs, and the correlation between gCSC and patient survival was evaluated. We observed significantly different cumulative survival (P=0.045) when comparing patients positive for gCSCs patients and negative for gCSC. Among the patients positive for gCSCs, we observed no significant differences in survival between those whose gCSCs were each positive or negative for PDPN, CD133, or nestin. This study strongly supports the prognostic value of gCSCs isolation on the survival of patients with pGBM.

We present structural and molecular-contrast imaging of mouse brain tumors using photo-thermal optical coherence tomography (PT-OCT) in vivo. Based on strong PT response of gold nanostars, we demonstrate clear visualization of brain cancer margins.

Smart drug delivery systems that are triggered by environmental conditions have been developed to enhance cancer therapeutic efficacy while limiting unwanted effects. Because cancer exhibits abnormally high local acidities compared to normal tissues (pH 7.4) due to Warburg effects, pH-sensitive systems have been researched for effective cancer therapy. Chitosan-based intelligent theragnosis nanocomposites, N-naphthyl-O-dimethymaleoyl chitosan-based drug-loaded magnetic nanoparticles (N Chitosan-DMNPs), were developed in this study. N Chitosan-DMNPs are capable of pH-sensitive drug release with MR-guided images because doxorubicin (DOX) and magnetic nanocrystals (MNCs) are encapsulated into the designed N-naphthyl-O-dimethymaleoyl chitosan (N-nap-O-MalCS). This system exhibits rapid DOX release as acidity increases, high stability under high pH conditions, and sufficient capacity for diagnosing and monitoring therapeutic responses. These results demonstrate that N Chitosan-DMNPs have potential as theragnosis nanocomposites for effective cancer therapy.

Cancer cells can express specific biomarkers, such as cell membrane proteins and signaling factors. Thus, finding biomarkers and delivering diagnostic agents are important in the diagnosis of cancer. In this study, we investigated a biomarker imaging agent for the diagnosis of hepatic cancers. The asialoglycoprotein receptor (ASGPr) was selected as a biomarker for hepatoma cells and the ASGPr-targetable imaging agent bearing a galactosyl group was prepared using manganese ferrite nanoparticles (MFNP) and galactosylgluconic acid. The utility of the ASGPr-targetable imaging agent, galactosylated MFNP (G-MFNP) was assessed by several methods in ASGPr-expressing HepG2 cells as target cells and ASGPr-deficient MCF7 cells. Physical and chemical properties of G-MFNP were examined using Fourier-transform infrared spectroscopy, dynamic light scattering, zeta potential analysis, and transmission electron microscopy. No significant cytotoxicity was observed in either cell line. Targeting ability was assessed using flow cytometry, magnetic resonance imaging, inductively coupled plasma atomic emission spectroscopy, absorbance analysis, dark-field microscopy, Prussian blue staining, and transmission electron microscopy. We demonstrated that G-MFNP target successfully and bind to ASGPr-expressing HepG2 cells specifically. We suggest that these results will be useful in strategies for cancer diagnoses based on magnetic resonance imaging.

The purpose of this study was to assess the role of inflamed synovial volume (ISV) in defining a state of remission in rheumatoid arthritis (RA) with contrast-enhanced, fatsuppression, three-dimensional (3D) gradient-recalled acquisition in the steady state with radiofrequency spoiling (SPGR) magnetic resonance (MR) imaging. Sixteen patients with RA (5 remission and 11 non-remission patients) were enrolled in this study. Contrast-enhanced, fat-suppression, 3D-SPGR MR imaging was performed before (n 5 12) and after (n 5 16) a mean 17 months of disease-modifying antirheumatic drugs (DMARDs). ISV was calculated by using a segmentation method. Statistical analysis of changes in ISVs and residual ISVs between the remission and the non-remission groups was performed. Intra- and interobserver reproducibility was tested. Residual ISVs and relative changes in ISVs were 3.23 6 1.84 cm3 and 51.4% (range 47.6‐55.2%) in the remission group and 6.26 6 2.03 cm 3 and 31.4% (range -73.5‐53.5%) in the non-remission group. Both values were significantly different between the two groups (P F 0.05 and 0.05, respectively). Volume measurement showed high reproducibility: Intra- and interobserver mean percentage errors were 5.04, 7.06, and 5.09%, respectively. Residual ISVs and relative changes in ISVs measured by MR imaging may provide objective and quantitative parameters in defining a state of remission in RA after therapy; however, the clinical utility of these measurements remains to be verified. J. Magn. Reson. Imaging 1999;10:202‐208. r 1999 Wiley-Liss, Inc.

We demonstrate the use of a THz penetration-enhancing agent (THz-PEA) to enhance the terahertz (THz) wave penetration depth in tissues. The THz-PEA is a biocompatible material having absorption lower than that of water, and it is easily absorbed into tissues. When using glycerol as a THz-PEA, the peak value of the THz signal which was transmitted through the fresh tissue and reflected by a metal target, was almost doubled compared to that of tissue without glycerol. THz time-of-flight imaging (B-scan) was used to display the sequential glycerol delivery images. Enhancement of the penetration depth was confirmed after an artificial tumor was located below fresh skin. We thus concluded that the THz-PEA technique can potentially be employed to enhance the image contrast of the abnormal lesions below the skin. (C)2013 Optical Society of America

The conducting polymer polyaniline (PANI) has a wide range of optoelectronic applications due to its unique electronic and optical characteristics. Although extensive works have been performed to understand the equilibrium properties, the nature of the charge type that governs its non-equilibrium optical response has been barely understood; a number of studies have debated the nature of photo-generated charge type in PANI, specifically whether it is polaron or exciton based. Here, we report experimental evidence that the charge relaxation dynamics of PANI are dominated by excitons. Utilizing ultrafast spin-resolved pump-probe spectroscopy, we observed that PANI charge dynamics are strongly spin-polarized, exhibiting a spin Pauli-blocking effect. Investigations including both spin-independent and spindependent dynamics reveal that there is no spin-flip process involved in charge relaxation. This provides compelling evidence of an exciton-dominated photo-response in PANI.

Poly(ethylene glycol)-coated cross-linked iron oxide nanoparticles (PCIONs) are developed for therapeutic engineering of mesenchymal stem cells (MSCs) and their monitoring via magnetic resonance (MR) imaging at a time. PCIONs successfully combine with plasmid DNA (pDNA) via ionic interaction. Accordingly, PCION/pDNA complexes mediate superior translocations of vascular endothelial growth factor (VEGF) pDNA into intracellular regions of MSCs under external magnetic field, which significantly elevate production of VEGF from MSCs. Genetically engineered MSCs are also clearly visualized via MR imaging after administration to rat cerebrovascular ischemia models, which enable tracking of MSCs migration from injected sites to injured ischemic area.

We show that terahertz (THz) time-domain spectroscopy (TDS) can be used to characterize the blood. The complex optical constants of blood and its constituents, such as water, plasma, and red blood cells (RBCs), were obtained in the THz frequency region. The volume percentage of RBCs in blood was extracted and compared with the conventional RBC counter results. The THz absorption constants are shown to vary linearly with the RBC concentration in both normal saline and whole blood. The excellent linearity between the THz signal and the RBC concentration was also confirmed in a polyurethane resin tube using a THz imaging method. These results demonstrate that THz-TDS imaging can facilitate the quantitative analysis of blood.

In this study, we describe the development of cancer biomarker-sensitive nanobiosensor based on localized surface plasmon resonance (LSPR) that enabling recognition for proteolytic activity of membrane type 1 matrix metalloproteinase (MT1-MMP) anchored on invasive cancer cells. First of all, we prepared biomarker-detectable substrate based on gold nanorods (GNRs) using nanoparticle adsorption method. The sensitivity of sensing chip was confirmed using various solvents that having different refractive indexes. Subsequently, MT1-MMP-specific cleavable peptide was conjugated onto surface of GNRs and molecular sensing about proteolytic activity was conducted using MT1-MMP and cell lysates. Collectively, we developed biomarker detectable sensor, which allows for the effective detection of proteolytic activity about MT1-MMP extracted from invasive cancer cells.

Biomarker-specific photothermal nanoparticles that can efficiently sense the markers, which are overexpressed in distinguished adenocarcinomas, has attracted much interest in an aspect of efficacy increase of cancer treatment. In this study, we demonstrated a promising prospect of smart photothermal therapy agent employing anti-epidermal growth factor receptor aptamer (Apt EGFR )-conjugated polyethylene glycol (PEG)layted gold nanorods (Apt EGFR -PGNRs). The cetyltrimethylammonium bromide bilayer on GNRs was replaced with heterobifunctional polyethylene glycol (COOHPEG- SH) not only to serve as a biocompatible stabilizer and but also to conjugate Apt EGFR . Subsequently, to direct photothermal therapy agent toward epithelial cancer cells, the carboxylated PEGylated GNRs (PGNRs) were further functionalized with Apt EGFR using carbodiimide chemistry. And then, to assess the potential as biomarker-specific photothermal therapy agent of synthesized Apt EGFR -PGNRs, the optical properties, biocompatibility, colloidal stability, binding affinity and epicellial cancer cell killing efficacy in vitro/in vivo under NIR laser irradiation were investigated. As a results, Apt EGFR -PGNRs exhibit excellent tumor targeting ability and feasibility of effective photothermal ablation cancer therapy.

Biomarker-specific photothermal nanoparticles that can efficiently sense markers that are overexpressed in distinguished adenocarcinomas have attracted much interest in an aspect of efficacy increase of cancer treat- ment. We demonstrated a promising prospect of a smart photothermal therapy agent employing anti-epidermal growth factor receptor aptamer (Apt EGFR )-conjugated polyethylene glycol (PEG) layted gold nanorods (Apt EGFR - PGNRs). The cetyltrimethylammonium bromide bilayer on GNRs was replaced with heterobifunctional PEG (COOH-PEG-SH) not only to serve as a biocompatible stabilizer and but also to conjugate Apt EGFR . Subsequently, to direct photothermal therapy agent toward epithelial cancer cells, the carboxylated PEGylated GNRs (PGNRs) were further functionalized with Apt EGFR using carbodiimide chemistry. Then, to assess the potential as biomarker-specific photothermal therapy agent of synthesized AptEGFR-PGNRs, the optical properties, bio- compatibility, colloidal stability, binding affinity, and epicellial cancer cell killing efficacy in vitro/in vivo under near-infrared laser irradiation were investigated. As a result, AptEGFR-PGNRs exhibit excellent tumor target- ing ability and feasibility of effective photothermal ablation cancer therapy. © 2014 Society of Photo-Optical Instrumentation

Nanoparticles are attractive drug carriers that can combine drug molecules and targeting moieties in order to improve treatment efficacy and reduce unwanted side effects. In addition, activatable nanoparticles may enable drug release in the target sites at accurate timings or conditions, in which drug discharge can be controlled by specific stimuli. Especially, gold nanoparticles provide a great opportunity as drug carriers because of the following advantageous features: i) simple formulation with various sizes and shapes and non-toxicity; ii) easy incorporation of targeting molecules, drugs or other therapeutic molecules on them; iii) triggered drug release by means of external or internal stimuli. In this chapter, we describe relevant examples of the preparation techniques and the performance of various types of gold nanoparticles for drug delivery as well as theranostics.

Targeted molecular imaging with hyaluronic acid (HA) has been highlighted in the diagnosis and treatment of CD44-overexpressing cancer. CD44, a receptor for HA, is closely related to the growth of cancer including proliferation, metastasis, invasion, and angiogenesis. For the efficient detection of CD44, we fabricated a few kinds of HA-modified MnFe2O4 nanocrystals (MNCs) to serve as specific magnetic resonance (MR) contrast agents (HA-MRCAs) and compared physicochemical properties, biocompatibility, and the CD44 targeting efficiency. Hydrophobic MNCs were efficiently phase-transferred using aminated polysorbate 80 (P80) synthesized by introducing spermine molecules on the hydroxyl groups of P80. Subsequently, a few kinds of HA-MRCAs were fabricated, conjugating different ratios of HA on the equal amount of phase-transferred MNCs. The optimized conjugation ratio of HA against magnetic content was identified to exhibit not only effective CD44 finding ability but also high cell viability through in vitro experiments. The results of this study demonstrate that the suggested HA-MRCA shows strong potential to be used for accurate tumor diagnosis.

We describe a near-infrared-sensitive molecular imaging probe based on hydrogel complexes that can target a stem-like gastric cancer cell marker (CD44, a marker that often correlates with a poor prognosis in patients). Thus, CD44-targetable and near-infrared-sensitive supramolecular hydrogels (NIRSHs, Cy5.5-conjugated polyethyleneimine/hyaluronic acid polyplexes) were fabricated by polyplexing in an aqueous medium. NIRSHs demonstrated good water-stability, biocompatibility, and specificity to CD44-expressing stem-like gastric cancer cells. Furthermore, NIR-sensitive in vivo imaging potentials of CD44-targetable NIRSHs for heterotopic/orthotopic xenograft mouse models were investigated.

We have developed a nanovector consisting of hyaluronic acid (HA) and poly-L-lysine-graft-imidazole (PLI)-based polyplexes containing Bcl-xL-specific shRNA-encoding plasmid DNA (HA/PLI/pDNA) for CD44 targeted gastric cancer therapy. The prepared ternary polyplexes have a negative surface charge of -24 mV and a size of approximately 100 nm at an N/P ratio of 5 with HA/PLI molar ratio of 0.03. Gel electrophoresis and cell viability experiments demonstrated that the ternary polyplexes showed high stability and no cytotoxicity due to the anchored HA molecules on the surface of PLI/pDNA binary polyplexes. Selective cancer cell death was achieved by CD44-mediated gene delivery and the internalized gene was effectively escaped from endosomes due to the buffering capacity of imidazole groups in an acidic environment. These nanovectors may be highly efficient gene delivery tools that allow the selective destruction of metastatic gastric cancer cells.

The presence of glioma stromal mesenchymal stem‑like cells (GS-MSLCs) in tumors from glioma patients has been previously reported. The mechanisms through which these cells function as a part of the glioma microenvironment, however, remain incompletely understood. We investigated the biological effects of GS-MSLCs on glioma cancer stem cells (gCSCs), testing the hypothesis that GS-MSLCs alter the biological characteristics of gCSCs. GS-MSLCs and gCSCs were isolated from different glioblastoma (GBM) specimens obtained from patients. In in vitro experiments, gCSCs were cultured alone or co-cultured with GS-MSLCs, and gCSCs cell counts were compared between the two groups. In addition, two groups of orthotopic GBM xenografts in mice were created, one using gCSCs from the monoculture group and one using gCSCs isolated from the co-culture group, and tumor volume and survival were analyzed. Furthermore, in vivo proliferation, apoptosis and vessel formation were examined using immunohistochemical analyses. In vitro cell counts for gCSCs co-cultured with GS-MSLCs increased 3-fold compared to gCSCs cultured alone. In orthotopic xenograft experiments, mice injected with gCSCs isolated from the co-culture group had significantly larger tumor volume, measured on day 40 after injection, and their survival times were shorter. Immunohistochemical analysis showed increased tumor expression of CD31, indicative of enhanced microvessel formation in mice injected with gCSCs co-cultured with GS-MSLCs compared to mice injected with gCSCs cultured alone. However, proliferation (PCNA) and apoptosis (TUNEL) markers showed no significant difference between the two groups. In conclusion, GS-MSLCs may influence the biological properties of gCSCs, shifting them towards a more aggressive status; moreover, increased angiogenesis may be a critical component of this mechanism.

Amphiphilic surfactants have been used to disperse magnetic nanoparticles in biological media, because they exhibit a dual hydrophobic/hydrophilic affinity that facilitates the formation of a nanoemulsion, within which nanoparticle surfaces can be modified to achieve different physicochemical properties. For the investigation of the interactions of cells with charged magnetic nanoparticles in a biological medium, we selected the nanoemulsion method to prepare water-soluble magnetic nanoparticles using amphiphilic surfactant (polysorbate 80). The hydroxyl groups of polysorbate 80 were modified to carboxyl or amine groups. The chemical structures of carboxylated and aminated polysorbate 80 were confirmed, and water-soluble manganese ferrite nanoparticles (MFNPs) were synthesized with three types of polysorbate 80. Colloidal size, morphology, monodispersity, solubility and T2 relaxivity were found to be similar between the three types of MFNP. However, cationic MFNPs exhibited greater cytotoxicity in macrophages (RAW264.7 cells) and lower cellular membrane effective stiffness than anionic and non-ionic MFNPs. Moreover, cationic MFNPs exhibited large uptake efficiency for RAW264.7 cells compared with anionic or non-ionic MFNPs under the same conditions. Therefore, we propose that surface charge should be a key consideration factor in the design of magnetic nanoparticles for theragnostic applications.

It was presented that mesenchymal stem cells (MSCs) can be isolated from western glioma specimens. However, whether MSCs exist in glioma specimens of different ethnicities is unknown. To verify the existence of MSCs in an independent cohort, we undertook studies to isolate MSCs from a group of Korean patients. We hypothesized that cells resembling MSCs that were deemed mesenchymal stemlike cells (MSLCs) exist in an independent cohort of Korean gliomas.We cultured fresh glioma specimens using the protocols used for culturing MSCs. The cultured cells were analyzed with fluorescence-activated cell sorting (FACS) for surface markers associated with MSCs. Cultured cells were exposed to mesenchymal differentiation conditions. To presume possible locations of MSLCs in the glioma, sections of glioma were analyzed by immunofluorescent labeling for CD105, CD31, and NG2.From nine of 31 glioma specimens, we isolated cells resembling MSCs, which were deemed Korean glioma stroma MSLCs (KGS-MSLCs). KGS-MSLCs were spindle shaped and adherent to plastic. KGS-MSLCs had similar surface markers to MSCs (CD105(+), CD90(+), CD73(+), and CD45(-)). KGS-MSLCs were capable of mesenchymal differentiation and might be located around endothelial cells, pericytes, and in a disorganized perivascular area inside glioma stroma.We found that cells resembling MSCs indeed exist in an independent cohort of glioma patients, as presented in western populations. We could presume that the possible location of KGS-MSLCs was in perivascular area or in glioma stroma that was a disorganized vascular niche. It might be possible that KGS-MSLCs could be one of constituent of stroma of glioma microenvironment.

Hybrid organic-inorganic near-infrared responsive magnetic nanoparticles were synthesized for theragnosis combined with localized therapy. In detail, inorganic super-paramagnetic nanoparticles were embedded inside organic polyaniline matrix, which enables localized photothermal therapy upon NIR illumination under intracellular acidic/oxidative condition. In this structure, super-paramagnetic nanoparticle works as MRI contrast agent, that enables the visualization of a tumor and polyaniline works for near-infrared responsive tumor ablation.

The ultrasensitive and selective diagnosis along with efficient therapy in earliest stage of cancer has been enormously highlighted by a better means to treat the cancer. Herein, Gd (III) chelated polyaniline nanoparticles (GPNPs) was synthesized to be served as a highly T 1 enhanced contrast agents and Near-Infrared photothermal therapy probes. In addition, therapeutic antibody was conjugated on the surface of GPNPs for the targeted theragnosis. Fabricated GPNPs significantly reduced the T 1 of water protons with as well as represented photothermal ability. The physicochemical properties and biocompatibilities of GNPSs were fully characterized and GPNPs exhibited excellent tumor targeting ability. Consequently, GPNPs exhibited strong potential for efficient diagnosis of cancer in MR imaging and photothermal ablation of epithelial cancer cells.

Here we introduce a new class of smart imaging probes hybridizing polysorbate 80 coated-magnetic nanoparticles with vascular endothelial growth factor receptor 2 (VEGFR2)-targetable aptamer for specific magnetic resonance (MR) imaging of angiogenesis from glioblastoma.

An understanding of neovascularization and/or angiogenesis in cancer is acutely required for effective cancer therapy due to concerns about tumor growth and metastasis. In particular, integrin αvβ3 is closely associated with cell migration and invasion during angiogenesis. Hence, we developed aptamer(αvβ3)-conjugated magnetic nanoparticles (Apt(αvβ3)-MNPs) to enable precise detection of integrin-expressing cancer cells using magnetic resonance imaging. Apt(αvβ3)-MNPs exhibited not only cytocompatibility, but also an efficient targeting ability with high magnetic sensitivity through in vitro/in vivo studies. The results of this study demonstrate that Apt(αvβ3)-MNPs have the potential to be used for accurate tumor diagnosis and therapy.

The existence of cancer stem cells (CSCs) in glioblastoma has been proposed. However, the unknown knowledge that is yet to be revealed is the presence of glioma CSCs (gCSCs) in correlation to each WHO grades of glioma. We approached this study with a hypothesis that specimens from high-grade gliomas would have higher isolation rate of gCSCs in comparison to those of lower-grade gliomas. The glioma specimens were obtained from patients and underwent gliomasphere assay. The gliomaspheres were chosen to be analyzed with immunocytochemisty for surface markers. Then the selected gliomaspheres were exposed to neural differentiation conditions. Lastly, we made mouse orthotopic glioma models to examine the capacity of gliomagenesis. The gliomaspheres were formed in WHO grade IV (13 of 21) and III (two of nine) gliomas. Among them, WHO grade IV (11 of 13) and III (two of two) gliomaspheres showed similar surface markers to gCSCs and were capable of neural differentiation. Lastly, among the chosen cells, 10 of 11 WHO grade IV and two of two WHO grade III gliomaspheres were capable of gliomagenesis. Thus, overall, the rates of existence of gCSCs were more prominent in high-grade gliomas: 47.6 % (10 of 21) in WHO grade IV gliomas and 22.2 % (two of nine) in WHO grade III gliomas, whereas WHO grade II and I gliomas showed virtually no gCSCs. This trend of stage-by-stage increase of gCSCs in gliomas showed statistical significance by chi-square test linear-by-linear association. We prove that the rates of existence of gCSCs increase proportionally as the WHO grades of gliomas rise.

We present the medical applications of the terahertz spectroscopic imaging technology to the brain and blood system as well as to the molecular imaging for the target specific imaging.

We present a photo-thermal therapeutics control technique using terahertz (THz) imaging technology and an optical beam intensity modulation method. The heat induced in nanoparticle probes under irradiation by a near-infrared beam was monitored using a THz imaging system and was fixed by adjusting the illumination time of the optical beam. The THz-monitored optical beam modulation technique allowed the viability of cells to be controlled.

Currently, the interaction between the niche and glioma cancer stem cells (gCSCs) is gaining attention. However, there are few studies concerned with the effects of repeated exposure to a new microenvironment on gCSCs characteristics. In this study, serial in vivo subtransplantation was performed to create a new microenvironment. We evaluated and compared the biological characteristics of gCSCs after serial in vivo subtransplantation.We cultured gCSCs from human glioma specimens according to cultured gliomasphere methods. The isolated gCSCs were termed zero-generation gCSCs (G0-gCSCs). By subsequent serial subtransplantation, we obtained first-generation gCSCs (G1-gCSCs) and second-generation gCSCs (G2-gCSCs). We evaluated and compared the biological characteristics of G0-gCSCs, G1-gCSCs, and G2-gCSCs. The in vitro characteristics included the morphology, surface marker profiles, and neural differentiation capacity and the in vivo characteristics was the survival of mice xenografts. Additionally, brain sections were analyzed using PCNA, TUNEL, and CD31 staining.We observed no significant differences in the in vitro characteristics of G0-gCSCs, G1-gCSCs, and G2-gCSCs. However, the survival time of mice glioma xenografts was significantly decreased upon serial subtransplantation. In addition, immunohistochemical analyses showed that the number of TUNEL(+) cells was significantly decreased while the number of CD31(+) cells was significantly increased with serial in vivo subtransplantation.There were significant in vivo biological changes in gCSCs upon serial in vivo subtransplantation, which were shorter xenograft survival, increased angiogenesis, and decreased apoptosis. This study suggests that the repeated exposure to new microenvironments may affect the biological changes in gCSCs in vivo.

Multimodal imaging systems may eliminate the disadvantages of individual imaging modality by providing complementary information about cellular and molecular activites. In this sutdy, we developed a reverse complementary multimodal imaging system to image microRNAs (miRNA, miR) during neurognesis using transferrin receptor (TfR) and a magnetic fluorescence (MF) nanoparticle-conjugated peptide targeting TfR (MF targeting TfR). Both in vitro and in vivo imaging demonstrated that, in the absence of miR9 during pre-differentiation of P19 cells, the MF targeting TfR nanoparticles greatly targeted TfR and were successfully internalized into P19 cells, resulting in high fluorescence and low MR signals. When the miR9 was highly expressed during neurogenesis of P19 cells, the MF targeting TfR nanoparticles were hardly targeted due to the miR9 function, which represses the expression and functional activity of TfR from the miRNA TfR reproter gene, resulting in low fluorescence and high MR signals. The reverse complementary multimodal miRNA imaging system may serve as a new imaging probe to montior miRNA-involved cellular developments and diseases.

Recently, the advancement of nanotechnology has had a significant impact on clinical therapeutics. Advances in biocompatible drug carriers using organic/inorganic nanoparticles have enabled safer and more efficient delivery of anti-cancer agents. In particular, nanoparticles designed and fabricated by sophisticated processes can (as drug carriers) deliver precise doses of multiple anti-cancer agents to target cancer cells, improving therapeutic efficacy and minimizing side effects. In addition, a comprehensive understanding of cancer biology, chemo-resistance, cancer relapse, and metastasis is essential for successful development of combination therapy using nanoparticles. In this review, we discuss the species of functional nanoparticles for delivery of anti-cancer agents and their potential to improve chemotherapeutic indices via combination therapy. We also discuss novel therapeutic strategies using functional nanoparticles developed through multidisciplinary collaboration for combination chemotherapy.

The sections in this article are Introduction Anatomy of Multifunctional Nanocomposites The Biomedical Payload The Carrier The Biological Surface Modifier Types of Nanomaterial Multifunctionality Multimodal Imaging Multicolor Optical Coding Optical/T1 MR Bimodal Image Probes Optical/T2 MR Bimodal Image Probes Theragnostics: Simultaneous Diagnosis and Therapy Optical Imaging/Therapy MR Imaging/Therapy Optical Coherence Tomography Imaging/Therapy Combination Therapy Therapeutic Antibodies/Chemotherapeutic Drugs Combinations of Different Chemotherapeutic Drugs Combinations of Chemotherapeutic Drugs and Genes Photothermal or Photodynamic Agents with Chemotherapeutic Drugs Activatable Smart Nanocomposites Temperature-Responsive Nanocomposites pH-Responsive Nanocomposites Enzyme-Responsive Nanocomposites Reactive Oxygen Species-Responsive Nanocomposites Conclusions and Outlook Acknowledgments Keywords: multifunctional; nanocomposite; biomedical; imaging; smart; theragnosis

Localized surface plasmon resonance (LSPR) is induced by incident light when it interacts with noble metal nanoparticles that have smaller sizes than the wavelength of the incident light. Recently, LSPR-based nanobiosensors were developed as tools for highly sensitive, label-free, and flexible sensing techniques for the detection of biomolecular interactions. In this paper, we describe the basic principles of LSPR-based nanobiosensing techniques and LSPR sensor system for biomolecule sensing. We also discuss the challenges using LSPR nanobiosensors for detection of biomolecules as a biomarker.

Bone marrow-derived mesenchymal stromal cells (MSCs) have been used successfully as a source of stem cells for treating neurodegenerative diseases. However, for reasons that are not clear, autologous MSC transplants have not yielded successful results in human trials. To test one possible reason, we compared the migratory ability of MSCs from amyotrophic lateral sclerosis (ALS) patients with those of healthy controls. We found that MSCs derived from ALS patients (ALS-MSCs) had a reduced ability to migrate, which may explain why autologous transplantation is not successful. We also found that expression of one of the intracellular factors implicated in migration, β-PIX, was significantly reduced in ALS-MSCs compared with healthy stem cells. Restoration of β-PIX expression by genetic manipulation restored the migratory ability of ALS-MSCs, and inhibition of β-PIX expression with shRNA reduced the migration of healthy MSCs. We suggest that transplantation of allogeneic or genetically modified autologous stem cells might be a more promising strategy for ALS patients than transplantation of autologous stem cells.

We determined the optical constant of whole blood and its constituents by using terahertz spectroscopy and showed that the concentration of red blood cells in whole blood could be determined using the terahertz absorption constant.

We obtained the terahertz images of fresh brains with and without tumor by using reflection type terahertz pulses imaging system.

We synthesized novel fluorescent magnetic silica nanoparticles (FMSNPs) containing large magnetic components for biomedical application. By employing assemblies of magnetic nanoparticles as kernels against FMSNPs, both the saturation of magnetization and the magnetic resonance (MR) signal intensity were significantly enhanced. Furthermore, the cellular binding of FMSNPs was improved by introducing a positive charge on the surface of the FMSNPs, and fluorescent dyes on the surface of FMSNPs enable optical imaging of sub-cellular regions.

Organic solvent-soluble nanocrystals suitable for magnetic resonance imaging are prepared by two routes, namely, a coprecipitation method and a multiple-step thermal decomposition method (seed-mediated growth). The size, shape, crystallinity, phase, and composition of the prepared nanocrystals are determined by various characterization techniques, including transmission electron microscopy, vibrating-sample magnetometer, X-ray diffraction, and inductively coupled plasma mass spectroscopy. Subsequently, the organic-soluble nanocrystals are rendered water-soluble by two methods, the microemulsion method and the ligand exchange method, for biomedical applications. Detailed protocols for the preparation of water-soluble nanocrystals, as well as procedures for drug-loading and antibody conjugation to the water-soluble nanocrystals are provided.

To investigate the efficiency of magnetic resonance imaging (MRI) contrast agents employing vascular endothelial growth factor (VEGF121)/rGel conjugated MnFe2O4 nanocrystals for imaging of neovasculature using a bladder tumor model.VEGF121/rGel was conjugated to MnFe2O4 nanoparticles (MNPs). The targeting efficiency and detection capability of the VEGF121/rGel-MNPs were investigated in both KDR-deficient (253JB-V) and KDR-overexpressing (PAE/KDR) cells using MRI. The internalization of VEGF121/rGel-MNPs into cells was confirmed by electron microscopy. Their phosphorylation ability and cytotoxicity were compared with unconjugated VEGF121/rGel. The orthotopic tumor mice were established by implanting low KDR-expressing 253JB-V cells into the bladder dome. After tail-vein injection of VEGF121/rGel-MNPs, the MR signal enhancement of intratumoral vessels by VEGF121/rGel-MNPs was observed and inhibition test using VEGF121 was also conducted. Ex vivo MR imaging of tumor tissue, and a fluorescence immunostaining study was also performed.The water-soluble VEGF121/rGel-MNPs (44.5 ± 1.2 nm) were stably suspended in the biologic media and exhibited a high relaxivity coefficient (423 mMs). They demonstrated sufficient targeting capability against KDR-overexpressing PAE/KDR cells, as confirmed by dose-dependent MR images and VEGF121 inhibition tests. The phosphorylation activity of KDR and cytotoxicity of VEGF121/rGel-MNPs were evaluated. VEGF121/rGel-MNPs successfully targeted the tumor and provided accurate anatomic details through (i) acquisition of clear neoangiogenic vascular distributions and (ii) obvious enhancement of the MR signal in T2*-weighted images. Immunostaining and blocking studies demonstrated the specific targeting ability of VEGF121/rGel-MNPs toward intratumoral angiogenesis.Synthesized VEGF121/rGel-MNPs as targeted MR imaging contrast agents can be specifically delivered to tumors and bind to KDR-expressing angiogenic tumor vessels.