Search

We have synthesized water-stable polyaniline nanoparticles coated with triarmed polyethylene glycol chains using a solvent-shift method and confirmed their colloidal size and aqueous solubility. Furthermore, we have demonstrated that the polyaniline nanoparticles can be doped with biological dopants to produce distinct color changes allowing the detection of live cancer cells.

It has been of high significance to devise a biochemical analytical tool kit enabling the detection of few circulating tumor cells (CTCs) for early diagnosis of cancer. Despite recent effort made to detect few CTCs, it is still challenging to sense such cells with their low concentration and/or the minute amount of marker proteins expressed on few CTCs. In this work, we report the label-free recognition of carcinoembryonic antigens (CEAs) expressed on few CTCs by using a carbon nanotube (CNT) sensor coupled with scanning probe microscopy imaging for cancer diagnosis. It is shown that a CNT-patterned surface is able to specifically capture the CEA molecules in the whole cell lysate of CTCs with their concentration even up to 10(-3) cells/mL. Our work sheds light on our bioassay based on a CNT-patterned surface for highly sensitive, label-free detection of marker proteins expressed on few tumor cells, which may open a new avenue in early diagnosis of cancer by providing a novel biochemical analysis tool kit.

An electrohydrodynamic atomization (EHDA) system that generates an electrospray can achieve particle formation and encapsulation by accumulating an electric charge on liquid flowing out from the nozzle. A novel coaxial EHDA system for continuous fabrication of water-stable magnetic nanoparticles (MNPs) is established, based on a cone-jet mode of electrospraying. Systemic variables, such as flow rates from dual nozzles and inducing voltages, are controlled to enable the preparation of water-soluble MNPs coated by polysorbate 80. The PEGylated MNPs exhibit water stability. The magnetic resonance imaging potential of these MNPs is confirmed by in vivo imaging using a gastric cancer xenograft mouse model. Thus, this advanced coaxial EHDA system demonstrates remarkable capabilities for the continuous encapsulation of MNPs to render them water-stable while preserving their properties as imaging agents.

Magnetic nanoparticles offer potential advances in cancer treatment. One example is cancer theranostics, which refers to the combination of a diagnostic tool, i.e., magnetic resonance (MR) imaging, and therapeutic entities such as drugs, oligonucleotides, antibodies, and peptides. They can be conjugated with bioactive molecules and have the ability to form a magnetic field gradient under an external magnetic field. They can offer a variety of active drug delivery and imaging strategies along with modalities such as magnetic hyperthermia. Imaging with magnetic nanoparticles can facilitate more effective cancer therapy through more well informed decision-making. In this article, we review notable progress in magnetic particle design, including surface modifications and multi-functionalization, and we discuss the recent bioapplications of magnetic nanoparticles in simultaneous cancer imaging and therapy.

Nanomedicine has seen a significant increase in research on stimuli-responsive activatable nanoprobes for tumor-specific delivery and diagnosis. The tumor microenvironment has particular characteristics that can be exploited to implement therapeutic strategies based on disparities between normal tissues and tumor tissues, including differences in pH, oxygenation, enzymatic expression, gene activation/inactivation, and vasculature. The nanocarriers of activatable nanoparticles maintain their structure while circulating in the body and, upon reaching the tumor site, are altered by unique tumoral stimuli, leading to the release of a drug or other agent. This review demonstrates the latest achievements in the use of internal stimuli-responsive, activatable nanoparticles with respect to unique design strategies and applications.

Background: A trend of stage-by-stage increase in tumorsphere (TS) formation from glioma samples has been reported. Despite this trend, not all surgical specimens give rise to TSs, even World Health Organization (WHO) grade IV gliomas. Furthermore, it has been reported that differences in overall survival of primary glioblastoma patients depends on the propensity of their tumors to form TSs. However, the weights of fresh specimens vary from one surgical isolate to the next. Methods: Accordingly, we evaluated the relationship between the weights of surgical specimens in WHO grade IV gliomas with the capacity to isolate TSs. Thirty-five fresh WHO grade IV glioma specimens were separated into two groups, based on whether they were positive or negative for TS isolation, and the relationship between TS isolation and weight of surgical specimens was assessed. Results: We observed no significant difference in the weights of surgical samples in the two groups, and found that the optimal weight of specimens for TSs isolation was 500 mg. Conclusion: Thus, contrary to our expectations, the ability to isolate TSs from WHO grade IV glioma specimens was not related to the weight of fresh specimens.

Background Deprivation of tumor bioenergetics by inhibition of multiple energy pathways has been suggested as an effective therapeutic approach for various human tumors. However, this idea has not been evaluated in glioblastoma (GBM). We hypothesized that dual inhibition of glycolysis and oxidative phosphorylation could effectively suppress GBM tumorspheres (TS). Methods Effects of 2-deoxyglucose (2DG) and metformin, alone and in combination, on GBM-TS were evaluated. Viability, cellular energy metabolism status, stemness, invasive properties, and GBM-TS transcriptomes were examined. In vivo efficacy was tested in a mouse orthotopic xenograft model. Results GBM-TS viability was decreased by the combination of 2DG and metformin. ATP assay and PET showed that cellular energy metabolism was also decreased by this combination. Sphere formation, expression of stemness-related proteins, and invasive capacity of GBM-TS were also significantly suppressed by combined treatment with 2DG and metformin. A transcriptome analysis showed that the expression levels of stemness- and epithelial mesenchymal transition-related genes were also significantly downregulated by combination of 2DG and metformin. Combination treatment also prolonged survival of tumor-bearing mice and decreased invasiveness of GBM-TS. Conclusion The combination of 2DG and metformin effectively decreased the stemness and invasive properties of GBM-TS and showed a potential survival benefit in a mouse orthotopic xenograft model. Our findings suggest that targeting TS-forming cells by this dual inhibition of cellular bioenergetics warrants expedited clinical evaluation for the treatment of GBM.

Gross total resection (GTR) of glioma is critical for improving the survival rate of glioma patients. One of the greatest challenges for achieving GTR is the difficulty in discriminating low grade tumor or peritumor regions that have an intact blood brain barrier (BBB) from normal brain tissues and delineating glioma margins during surgery. Here we present a highly sensitive, label-free terahertz reflectometry imaging (TRI) that overcomes current key limitations for intraoperative detection of World Health Organization (WHO) grade II (low grade), and grade III and IV (high grade) gliomas. We demonstrate that TRI provides tumor discrimination and delineation of tumor margins in brain tissues with high sensitivity on the basis of Hematoxylin and eosin (H&E) stained image. TRI may help neurosurgeons to remove gliomas completely by providing visualization of tumor margins in WHO grade II, III, and IV gliomas without contrast agents, and hence, improve patient outcomes.

// Junjeong Choi 1, 2, * , Ji-Hyun Lee 3, * , Ilkyoo Koh 4, * , Jin-Kyoung Shim 3 , Junseong Park 3 , Jeong Yong Jeon 5 , Mijin Yun 5 , Se Hoon Kim 6 , Jong In Yook 7 , Eui Hyun Kim 3 , Jong Hee Chang 3 , Sun Ho Kim 3 , Yong Min Huh 8 , Su Jae Lee 9 , Michael Pollak 10 , Pilnam Kim 4 , Seok-Gu Kang 3 , Jae-Ho Cheong 11 1 Department of Pharmacy, College of Pharmacy, Yonsei Institute of Pharmaceutical Sciences, Yonsei University, Incheon, Republic of Korea 2 Brain Korea 21 Plus Project for Medical Science, Yonsei University, Seoul, Republic of Korea 3 Departments of Neurosurgery, Brain Tumor Center, Severance Hospital, Yonsei University College of Medicine, Seoul, Republic of Korea 4 Department of Bio and Brain Engineering, Korea Advanced Institute of Science and Technology, Daejeon, Republic of Korea 5 Departments of Nuclear Medicine, Severance Hospital, Yonsei University College of Medicine, Seoul, Republic of Korea 6 Departments of Pathology, Severance Hospital, Yonsei University College of Medicine, Seoul, Republic of Korea 7 Department of Oral Pathology, Yonsei University College of Dentistry, Seoul, Republic of Korea 8 Departments of Radiology, Severance Hospital, Yonsei University College of Medicine, Seoul, Republic of Korea 9 Department of Life Science, Research Institute for Natural Sciences, Hanyang University, Seoul, Republic of Korea 10 Department of Oncology and Medicine, McGill University, Gerald Bronfman Centre, Montreal, Quebec, Canada 11 Department of Surgery, Severance Hospital, Yonsei University College of Medicine, Seoul, Republic of Korea * These authors have contributed equally to this work Correspondence to: Pilnam Kim, email: pkim@kaist.ac.kr Seok-Gu Kang, email: seokgu9@gmail.com Keywords: biguanide, glioblastoma, HL156A, invasion, tumorsphere Received: January 26, 2016 Accepted: August 13, 2016 Published: August 25, 2016 ABSTRACT Studies have investigated biguanide-derived agents for the treatment of cancers and have reported their effects against tumorspheres (TSs). The purpose of this study was determining the effects of HL156A, a newly designed biguanide with improved pharmacokinetics, on glioblastoma TSs (GMB TSs) and assess the feasibility of this drug as a new line of therapy against glioblastoma, alone or combined with a conventional therapeutic agent, temozolomide(TMZ). The effects of HL156A, alone and combined with TMZ, on the stemness and invasive properties of GBM TSs and survival of orthotopic xenograft animals were assessed. HL156A, combined with TMZ, inhibited the stemness of GBM TSs, proven by neurosphere formation assay and marker expression. Three-dimensional collagen matrix invasion assays provided evidence that combined treatment inhibited invasive properties, compared with control and TMZ-alone treatment groups. TMZ alone and combined treatment repressed the expression of epithelial-mesenchymal transition-related genes. A gene ontology comparison of TMZ and combination-treatment groups revealed altered expression of genes encoding proteins involved in cellular adhesion and migration. Combined treatment with HL156A and TMZ showed survival benefits in an orthotopic xenograft mouse model. The inhibitory effect of combination treatment on the stemness and invasive properties of GBM TSs suggest the potential usage of this regimen as a novel strategy for the treatment of GBM.

We designed and fabricated a novel terahertz (THz) otoscope to help physicians to diagnose otitis media (OM) with both THz diagnostics and conventional optical diagnostics. We verified the potential of this tool for diagnosing OM using mouse skin tissue and a human tympanic membrane samples prior to clinical application. (C) 2016 Optical Society of America

The isolation from brain tumors of tumor mesenchymal stem-like cells (tMSLCs) suggests that these cells play a role in creating a microenvironment for tumor initiation and progression. The clinical characteristics of patients with primary glioblastoma (pGBM) positive for tMSLCs have not been determined. This study analyzed samples from 82 patients with pGBM who had undergone tumor removal, pathological diagnosis, and isolation of tMSLC from April 2009 to October 2014. Survival, extent of resection, molecular markers, and tMSLC culture results were statistically evaluated. Median overall survival was 18.6 months, 15.0 months in tMSLC-positive patients and 29.5 months in tMSLC-negative patients (P=0.014). Multivariate cox regression model showed isolation of tMSLC (OR = 2.5, 95% CI = 1.1~5.6,P=0.021) showed poor outcome while larger extent of resection (OR = 0.5, 95% CI = 0.2~0.8,P=0.011) has association with better outcome. The presence of tMSLCs isolated from the specimen of pGBM is associated with the survival of patient.

Carboxymethyl-dextran (CM-dextran) replaced the hydrophobic oleylamine ligands on the surfaces of MnO nanoparticles, rendering them highly water-soluble by allowing direct contact with excited water protons. Solution MRI studies of the two types of nanoparticles, exchanged and bilayered, with different core sizes have shown that the exchanged ligand structure exhibits significantly enhanced longitudinal relaxation. The modification with dextran converted the nanoparticles into effective T1 MRI contrast agents, as well as promoting strong interactions with macrophages. Thus, it is a potential MR contrast agent for visualizing inflammatory macrophages.

We report smart nanoprobe, hyaluronic acid (HA)-based nanocontainers containing miR-34a beacons (bHNCs), for the intracellular recognition of miR-34a levels in metastatic breast cancer cells, which is distinct from the imaging of biomarkers such of cell membrane receptors such as HER2. In this study, we demonstrate that a nanoscale vesicle that couples a targeting endocytic route, CD44, and a molecular imaging probe enables the efficient detection of specific miRNAs. Furthermore, bHNCs showed no cytotoxicity and high stability due to the anchored HA molecules on the surface of nanocontainers, and enables the targeted delivery of beacons via CD44 receptor-mediated endocytosis. In vitro and in vivo optical imaging using bHNCs also allow the measurement of miR-34a expression levels due to the selective recognition of the beacons released from the internalized bHNCs. We believe that the technique described herein can be further developed as a cancer diagnostic as well as a miRNA-based therapy of metastatic cancer.

…(MMPs;greenmissilesinthepicture)expressedonacancercellsurfacecanbesensedby a resonant cantilever device (satellite arm in the picture), as J. Yang, D. S. Yoon, T.Kwon et al. report in their Communication on page 5837 ff. Active MMPs attack thepeptide sequence that is immobilized on the cantilever surface. The peptide cleavageleads to an increase in the resonant frequency of the cantilever, owing to a decrease inthe mass of immobilized peptide.

Well-designed nanoparticle-mediated, image-guided cancer therapy has attracted interest for increasing the efficacy of cancer treatment. A new class of smart theragnostic nanoprobes employing cetuximab (CET)-conjugated polyethylene glycol (PEG)ylated gold nanorods (CET-PGNRs) is presented; these nanoprobes target epithelial cancer cells using near-infrared light. The cetyltrimethylammonium bromide bilayer on GNRs is replaced with heterobifunctional PEG (COOH-PEG-SH) to serve as a biocompatible stabilizer and to increase specificity. The carboxylated GNRs are further functionalized with CET using 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide/N-hydroxysuccinimide (EDC-NHS) chemistry. To assess the potential of such GNRs, their optical properties, biocompatibility, colloidal stability, in vitro/in vivo binding affinities for cancer cells, absorption imaging, and photothermal therapy effects are investigated. CET-PGNRs exhibit excellent tumor targeting ability and strong potential for simultaneous absorption imaging and photothermal ablation of epithelial cancer cells.

We estimated the photothermal transduction efficiency of gold nanorod (GNR) solutions for different GNR concentrations and irradiation laser power. In particular, we verified that the degree of cell death area could be modulated by GNR concentration and irradiation laser power. The efficacy of GNR-produced photothermal ablation of cancer cells was evaluated by irradiating GNRs in the presence of MDA-MB-231 breast cancer cells with a near-infrared (NIR) laser at different laser power densities and irradiation times. GNR-induced photothermal ablation was applied successfully to cancer cells at various NIR laser power densities and irradiation times and was characterized with live-dead cell staining. Through these techniques, we established the system for not only verification of induced photothermal effect using NIR laser and thermocouple, but also identification of uptake efficiency for GNRs and cell viability using dark field and fluorescence imaging, respectively.

Herein, we describe the development of a bimodalimaging probe enabling precise recognition of the expressionof MT1-MMP anchored on invasive cancer cells and itsprotease activity simultaneously. MT1-MMP may be atargetable biomarker for a specific delivery and possessesproteolytic activity for certain substrates.

Well-designed photothermal nanostructures have attracted many scientists pursuing a better means to accurately diagnose cancer and assess the efficacy of treatment. Recently, gold-based nanostructures (nanoshells, nanorods and nanocages) have enabled photothermal ablation of cancer cells with near-infrared (NIR) light without damaging normal human tissues and in particular, animal studies and early clinical testing showed the great promise for these materials. In this review article, we first discuss the mechanism of the cellular death signaling by thermal stress and introduce the intrinsic properties of gold nanostructures as photothermal agent for cancer treatment. Then the overview follows for evolving researches for the synthesis of various types of gold nanostructures and for their biomedical applications. Finally we introduce the optimized therapeutic strategies involving nanoparticle surface modification and laser operation method for an enhanced accumulation of gold nanostructures to the target cancer as well as for an effective cancer cell ablation.

We obtained the diagnostic images of cancerous tumors by employing the THz molecular imaging (TMI) technique which measured the THz response change by surface plasmon resonance induced on the surface of nanoparticles with a irradiation of near-infrared (NIR) beam. To demonstrate the principle of the TMI technique, THz images of tissues with nanoprobes were observed and compared with THz only images. The sensitivity of TMI was further enhanced by adopting a THz differential measurement technique, which was realized by modulating the NIR beams. By employing this differential TMI technique, the diagnostic images of cancerous tumors were obtained ex vivo and in vivo in the preclinical stage. These images indicated the feasibility of applying the differential TMI technique in the clinical stage.

We fabricated hyaluronan-modified magnetic nanoclusters (HA-MNCs) for detection of CD44-overexpressing breast cancer using magnetic resonance (MR) imaging. CD44 is closely associated with cancer growth, including proliferation, metastasis, invasion, and angiogenesis. Hence, pyrenyl hyaluronan (Py-HA) conjugates were synthesized as CD44-targetable surfactants with hyaluronan (HA) and 1-pyrenylbutyric acid (Py) to modify hyaluronan on hydrophobic magnetic nanocrystals. Subsequently, HA-MNCs were fabricated using the nano-emulsion method; magnetic nanocrystals were simultaneously self-assembled with Py-HA conjugates, and their physical and magnetic properties depended on the degree of substitution (DS) of Py in Py-HA conjugates. HA-MNCs exhibited superior targeting efficiency with MR sensitivity as well as excellent biocompatibility through in vitro/in vivo studies. This suggests that HA-MNCs can be a potent cancer specific molecular imaging agent via targeted detection of CD44 with MR imaging.

The synchronization of gene expression and cell trafficking in transfected stem cells is crucial for augmentation of stem cell functions (differentiation and neurotropic factor secretion) and real time in vivo monitoring. We report a magnetic nanoparticle-based gene delivery system that can ensure simultaneous gene delivery and in vivo cell trafficking by high resolution MR imaging. The polar aprotic solvent soluble MnFe₂O₄ nanoparticles were enveloped using cationic polymers (branched polyethyleneimine, PEI) by the solvent shifting method for a gene loading. Using our magnetic nanovector system (PEI-coated MnFe₂O₄ nanoparticles), thus, we synchronized stem cell migration and its gene expression in a rat stroke model.

We report the scanning probe microscope (SPM)-based single-molecule recognition of biomolecular interactions between protein kinase and small ligands (i.e., ATP and Imatinib). In general, it is difficult to sense and detect the small ligands bound to protein kinase (at single-molecule resolution) using a conventional atomic force microscope (AFM) due to the limited resolution of conventional AFM for detecting the miniscule changes in molecular size driven by ligand binding. In this study, we have demonstrated that Kelvin probe force microscopy (KPFM) is able to articulate the surface potential of biomolecules interacting with ligands (i.e., the protein kinase-ATP interactions and inhibition phenomena induced by antagonistic molecules) in a label-free manner. Furthermore, measured surface potentials for biomolecular interactions enable quantitative descriptions on the ability of protein kinase to interact with small ligands such as ATP or antagonistic molecules. Our study sheds light on KPFM that allows the precise recognition of single-molecule interactions, which opens a new avenue for the design and development of novel molecular therapeutics.

High-grade gliomas are closely related to the mesenchymal phenotype which might be explained by unorthodox differentiation of glioma cancer stem cells (gCSCs). We reasoned that other non-neural stem cells, especially mesenchymal stem cells (MSCs), might play a role in expressing mesenchymal phenotype of high-grade gliomas. Thus we hypothesized that cells resembling MSCs exist in glioma specimens.We created a mouse (m) orthotopic glioma model using human gCSCs. Single-cell suspensions were isolated from glioma specimens and cultured according to the methods for mMSCs or gliomaspheres. These cells were analyzed by fluorescence-activated cell sorting (FACS) for surface markers associated with mMSCs or gCSCs. Glioma stroma (GS)-MSCs were exposed to mesenchymal differentiation conditions. To decide the location of GS-MSCs, sections of orthotopic glioma models were analyzed by immunofluorescent labeling.GS-MSCs were isolated which were morphologically similar to mMSCs. FACS analysis showed that the GS-MSCs had similar surface markers to mMSCs (stem cell antigen-1 [Sca-1](+), CD9(+), CD45(-), CD11b(-), CD31(-), and nerve/glial antigen 2 [NG2](-)). GS-MSCs were capable of mesenchymal differentiation. Immunofluorescent labeling indicated that GS-MSCs are located around blood vessels, are distinct from endothelial cells, and have features that partially overlap with vascular pericytes.Our results indicate that cells similar to mMSCs exist in glioma specimens. The GS-MSCs might be located around vessels, which suggests that GS-MSCs may provide the mesenchymal elements of the vascular niche. GS-MSCs may represent non-neural stem cells that act as an important source of mesenchymal elements, particularly during the growth of gliomas.

Well-designed photothermal nanomaterials have attractedthe interest of many scientists pursuing a better means toaccurately diagnose cancer and assess the efficacy of treat-ment, because these materials enable therapies in which thetumor region is pin-pointed with a laser-guided light sourcewithout surgical intervention.

Human bone marrow mesenchymal stromal cells (hBM-MSCs) are a promising tools for cell therapy. However, the poor viability of the transplanted cells is a major limiting factor. Human erythropoietin (hEPO) has been extensively studied in non-hematopoietic tissues for its neurotrophic, anti-oxidant, antiapoptotic, and anti-inflammatory effects. In this study, we evaluate whether transduction of the hEPO gene into MSCs provides protection and affects their migration. hBM-MSCs transduced with the hEPO gene (EPO-MSCs) stably secreted high levels of hEPO (10 IU/ml) with no alteration of their mesenchymal phenotype. MSCs were also treated with 10 IU rhEPO, an amount similar to what was secreted by EPO-MSCs, to generate 10U-MSCs. Protection against H2O2-induced oxidative stress and staurosporine-induced apoptosis was registered for both EPO-MSCs and 10U-MSCs, but the protective effects were higher for the EPO-MSCs than for the 10U-MSCs. EPO-MSCs had significantly higher migration rates compared to MSCs and 10U-MSCs. We confirmed that the intracellular signaling of ERK1/2 was higher in the EPO-MSCs than 10U-MSCs. This data demonstrates that the endogenous expression of EPO may efficiently initiate the ERK1/2 signaling pathway, resulting in synergistic effects on the production of neurotrophic factors. Thus, EPO-MSCs are a good candidate for cell therapy in ischemic and neurodegenerative diseases.

We investigated the synergism between shRNAs against Bcl-xL and doxorubicin (DOX) using aptamer-conjugated polyplexes (APs) in combination cancer therapy. Synergistic and selective cancer cell death was achieved by AP-mediated co-delivery of very small amounts of DOX and Bcl-xL-specific shRNA, which simultaneously activated an intrinsic apoptotic pathway. A branched polyethyleneimine (PEI) was grafted to polyethylene glycol (PEI-PEG) to serve as a vehicle for shRNA delivery, and its surface was further conjugated with an anti-PSMA aptamer (APT) for the selective delivery of APs to prostate cancer cells that express prostate-specific membrane antigens (PSMA) on their cell surface. The APs were finally obtained after intercalation of DOX to form shRNA/PEI-PEG-APT/DOX conjugates. Cell viability assays and FACS analysis of GFP expression against PC3 (PSMA deficient) and LNCaP (PSMA overexpressed) cells demonstrated that the synthesized APs inhibited the growth of PSMA-abundant prostate cancer cells with strong cell selectivity. Consequently, IC(50) values of APs loaded with both DOX and shRNA were approximately 17-fold less than those for the simple mixture of shRNA plus drug (shRNA/Lipofectamine + DOX). These results suggest that AP-mediated co-delivery of an anti-cancer drug and shRNA against Bcl-xL may widen the therapeutic window and allow for the selective destruction of cancer cells.

Purpose The modification of the cancer classification system aimed to improve the classical anatomy-based tumor, node, metastasis (TNM) staging by considering tumor biology, which is associated with patient prognosis, because such information provides additional precision and flexibility. Materials and Methods We previously developed an mRNA expression-based single patient classifier (SPC) algorithm that could predict the prognosis of patients with stage II/III gastric cancer. We also validated its utilization in clinical settings. The prognostic single patient classifier (pSPC) differentiates based on 3 prognostic groups (low-, intermediate-, and high-risk), and these groups were considered as independent prognostic factors along with TNM stages. We evaluated whether the modified TNM staging system based on the pSPC has a better prognostic performance than the TNM 8th edition staging system. The data of 652 patients who underwent gastrectomy with curative intent for gastric cancer between 2000 and 2004 were evaluated. Furthermore, 2 other cohorts (n=307 and 625) from a previous study were assessed. Thus, 1,584 patients were included in the analysis. To modify the TNM staging system, one-grade down-staging was applied to low-risk patients according to the pSPC in the TNM 8th edition staging system; for intermediate- and high-risk groups, the modified TNM and TNM 8th edition staging systems were identical. Results Among the 1,584 patients, 187 (11.8%), 664 (41.9%), and 733 (46.3%) were classified into the low-, intermediate-, and high-risk groups, respectively, according to the pSPC. pSPC prognoses and survival curves of the overall population were well stratified, and the TNM stage-adjusted hazard ratios of the intermediate- and high-risk groups were 1.96 (95% confidence interval [CI], 1.41–2.72; P

For efficient labeling and tracking via magnetic resonance (MR) imaging of human mesenchymal stem cells (h-MSCs), magnetic labeling agents must be responsive to an external magnetic field. Thus, we developed ultrasensitive magnetoplex as a magnetic labeling agent composed of PEGylated MnFe2O4 nanocrystals (PMNCs) and polycationics (poly-l-lysine, PLL) for efficient labeling of the h-MSCs and monitoring of the transplanted h-MSCs for a long term. PMNCs were prepared by nanoemulsion methods composed of MnFe2O4 nanocrystals (MNCs) and amphiphilic polymers (mPEG–dodecanoic acid). The prepared PMNCs exhibited excellent biocompatibility and their polycationic complexes (PMNCs/PLL) demonstrated remarkable sensitivity compared with magnetic iron oxide nanoparticles (MION)/PLL or Ferumoxides/PLL. Furthermore, PMNCs demonstrated the potentials for novel diagnostic and therapeutic strategies with potential applications in various biomedical fields.

Novel bifunctional fluorescent magneto polymeric nanoprobes (FMPNs) were synthesized to provide simultaneous diagnostic information via magnetic resonance imaging (MRI) and optical imaging. FMPNs consist of ultra-sensitive magnetic nanocrystals that function as MR probes combined with Nile Red, which functions as a fluorescent probe. FMPNs were encapsulated by a nano-emulsion method in polyvinyl alcohol (PVA, 87-89% hydrolyzed) through a matrix of polymethyl methacrylate (PMMA). FMPNs exhibited excellent colloidal stability and monodispersity. The production of MR and optical images demonstrated that FMPNs have potential as dual-mode imaging agents.

Ligand molecules that can recognize and interact with cancer cell surface marker proteins with high affinity and specificity should greatly aid the development of novel cancer diagnostics and therapeutics. HER-2/ErbB2/Neu (HER-2), a member of the epidermal growth factor receptor family, is specifically overexpressed on the surface of breast cancer cells and serves as both a useful biomarker and a therapeutic target for breast cancer. In this study, we aimed to isolate RNA aptamers that specifically bind to a HER-2-overexpressing human breast cancer cell line, SK-BR-3, using Cell-SELEX strategy. The selected aptamers showed strong affinity to SK-BR-3, but not to MDA-MB-231, a HER-2-underexpressing breast cancer cell line. In addition, we confirmed the specific targeting of HER-2 receptor by aptamers using an unrelated mouse cell line overexpressing human HER-2 receptor. The HER-2-targeting RNA aptamers could become a useful reagent for the development of breast cancer diagnostics and therapeutics.

We fabricate the high-performance probes based on Au nanoparticles (AuNP) for detection of live cancer cell. AuNP were synthesized with narrow sized distribution (ca. 10 nm) by Au salt reduction method and deposited onto the aminated substrate as a cross-linker and hot spot. Herein, AuNP has enabled the easy and efficient immobilization of the antibody (Cetuximab), which can selectively interact with epidermal growth factor receptor (EGFR) on the surface of epidermal cancer, as detecting moiety onto the AuNP-deposited substrate without nanolithography process. After conjugation of Cetuximab with AuNP-deposited substrate, Cetuximab-conjugated probe as a live cancer cell detector (LCCD) could detect EGFR-highexpressed A431 cells related to epithelial cancer with 54-times larger specificity and sensitivity in comparison with EGFR-deficient MCF7 cells. This implies that AuNP-based probes demonstrate abundant potentials for detection and separation of small biomolecules, cells and other chemicals.

Cetuximab conjugated fluorescent magnetic nanohybrids (CET-FMNHs) were synthesized for detection of human epithelial cancer via magnetic resonance (MR) and optical imaging. Spherical FMNHs consist of MnFe 2 O 4 magnetic nanocrystals encapsulated in pyrene-labeled PCL- b -PMAA as a surfactant prepared by a nano-emulsion method. FMNHs demonstrated excellent colloidal stability and biocompatibility for biomedical application. Antibody conjugated fluorescent magnetic nanohybrids (CET-FMNHs) served as effective agents for both magnetic resonance (MR) and fluorescence optical imaging of cancer cell lines.

We report the successful fabrication of the various types of water soluble PEGylated magnetic complexes (PMCs) for magnetism-related biomedical applications. Various types of PMCs were synthesized and tested to accomplish phase transfer from organic to aqueous phase using monomethoxy polyethylene glycol (mPEG)-fatty acid amphiphilic block copolymers (PFs) through conjugation of the hydroxyl group of mPEG with the carboxyl group of fatty acids. We also carefully investigate their colloidal stabilities in aqueous phase according to the ratio of hydrophilic and hydrophobic lengths relying on different types of fatty acids. Synthesized PMCs clearly demonstrated high magnetic sensitivity under magnetic field as magnetic resonance (MR) contrast agents. Furthermore, PMCs exhibited sufficient cell viabilities and excellent cell affinities in an in vitro model. Our results demonstrated that our PMCs possessed the potential for highly efficient magnetism-related biomedical applications such as MR image agents, drug delivery and tracking of cells.

Precise diagnosis by magnetic resonance imaging (MRI) requires sensitive magnetic resonance probes to detect low concentrations of magnetic substances. Ionic magnetic clusters (IMCs) as versatile magnetic probes were successfully synthesized for enhancing the magnetic resonance (MR) contrast effect as well as ensuring high water solubility. IMCs with various sizes were prepared by assembly of MNCs using cationic cetyltrimethylammonium bromide (CTAB) and anionic sodium dodecyl sulfate (SDS). To synthesize IMCs in the aqueous phase, magnetic nanocrystals in an organic solvent were assembled with CTAB and SDS using the nanoemulsion method, to fabricate cationic magnetic clusters (CMCs) and anionic magnetic clusters (AMCs), respectively. IMCs demonstrated ultrasensitivity by MR imaging and sufficient magnetic mobility under an external magnetic field.

Novel multifunctional magnetic gold nanocomposites (MGNCs) were synthesized for synchronous cancer therapy and diagnosis via magnetic resonance imaging (MRI). The MGNCs consist of magnetic kernels (aggregates of ultra-sensitive MnFe 2 O 4 magnetic nanocrystals wrapped in polymer) as effective MR contrast agents and silica-gold nanocomposites as hyperthermal therapeutic agents. A therapeutic antibody, Erbitux (ERB), was conjugated for specific tumor cell targeting both to localize the near-IR laser beam and to image their events through MRI. ERB-conjugated MGNCs selectively recognize the target cancer cell lines. Fluorescence images and MRI analysis show that the MGNCs are effectively taken up by the cells. ERB-conjugated MGNCs have an excellent synchronous therapeutic efficacy as a result of the therapeutic antibody and near-IR laser-induced surface plasmon resonance. Consequently, MGNCs clearly demonstrate selective imaging and treatment of human epithelial cancer simultaneously.

Nanoparticles have the potential to revolutionize current bio-medical diagnostic and therapeutic methods. For example, magnetic nanoparticles with unique superparamagnetism are emerging as next-generation probes for high performance magnetic resonance (MR) imaging. Their enhanced properties and nanoscale controllability in terms of size, composition, surface states, and magnetic spin structure have allowed for the highly sensitive and target-specific MR imaging of various biological systems including cancer detection, cell trafficking, and angiogenesis. On the other hand, viruses can be utilized as excellent delivery vehicles due to their facile cellular transfection and gene expression efficacies within their target cells. Such excellent properties of viruses offer promising prospects for gene therapy of genetic diseases and cancers, as well as for the genetic engineering of cells. Despite these prospects, a lack of understanding of their biological behaviors including in vivo migration, molecular recognition, gene delivery, and ultimate fate following their desired biofunctional applications limits their further development. There have been previous studies in the development of nanoparticle probing systems for viruses including virus-gold and virus-quantum dot nanoparticle systems. However, their utilization in the probing of viral gene delivery has not been investigated so far. Recently, Gd-based MR contrast agent-coated viruses were developed, but their functional behaviors including targetrecognition, cellular transfection, and gene delivery capabilities have not been demonstrated partly due to the intrinsically low sensitivity of Gd-based MR contrast agents. Our strategy is to hybridize the virus with magnetic nanoparticles into a single nanoparticle system with the dual-functional capabilities of target-specific MR imaging and gene delivery. Specifically, we fabricate hybrid nanoparticles of “enhanced green fluorescent protein (eGFP) promoter genecontaining adenovirus” and “manganese-doped magnetism engineered iron oxide (abbreviated as MnMEIO) nanoparticle”. As the viral gene delivery vector, we selected adenoviruses. Adenoviruses are known to be highly effective for transferring double-stranded DNAs to various cell types. Along with a gene delivery capability, adenoviruses possess targetspecificity to the cells with overexpression of Coxsackievirus B adenovirus receptor (CAR) which is known to facilitate the binding and intrusion of adenoviruses to the host cells. As the magnetic nanoparticle component we selected manganese-doped magnetism-engineered iron oxide (MnFe2O4, MnMEIO) nanoparticles, since it is known that MnMEIO exhibits exceptional MR contrast effects (R2 (=1/T2) value of 358 sec mM) and therefore is advantageous as probes for ultra-sensitive MR imaging. Briefly, the thermal reaction of manganese chloride (MnCl2) and iron tris(2,4-pentadionate) in hot organic solvents containing oleic acid and oleylamine capping molecules yielded hydrophobically capped MnMEIO nanoparticles. Their water-solubility and biocompatibility were attained by introducing 2,3-dimercaptosuccinic acids to the nanoparticle surface. Nanoparticles obtained were 12 nm with a high sizemonodispersity (r < 7%) and possessed single crystallinity, and a saturation magnetization value of 110 emu g (Mn+Fe). Hybridization of adenoviruses with MnMEIO nanoparticles was performed through a slight modification of a literature method, as follows. First, the capsid lysine residues of the adenoviruses were converted to maleimide groups by reacting them with sulfo-succinimidyl(4-N-maleimidomethyl)cyclohexane-1-carboxylate (sulfo-SMCC) cross-linkers. These groups were allowed to react with a large stoichiometric amount of MnMEIO nanoparticles, which resulted in the formation of adenovirus-MnMEIO hybrid nanoparticles by way of the nucleophilic addition of a surface thiol group of MnMEIO to the C O M M U N IC A IO N

The nano-sized magnetite and the magnetic nanospheres (MNS) were synthesized for biomedical applications by co-precipitation method and emulsion solvent evaporation method, respectively. The prepared magnetite and the MNS (∼250 nm) exhibited superparamagnetic behaviors with the saturation of magnetization of 52.6 and 38.7 emu/g, respectively. The size, distribution and morphology were investigated by light scattering and electron microscopy. The motions of the MNS under the magnetic field in rectangular microchannel were investigated by using the particle tracking velocimetry (PTV) method. The particle motions due to both the fluid flow and the magnetic field were calculated and the experimentally observed data were in good agreement with theoretical model.

Diagnosis of cancer in the early stages requires sensitive magnetic resonance (MR) probes to detect low concentrations of magnetic substances. In this study, ultrasensitive magnetic resonance contrast agents (UMRCAs) composed of magnetic nanocrystals and amphiphilic block copolymers were synthesized for cancer detection using polyethylene glycol and fatty acid. The chemical structures and the compositions of PEGylated magnetic nanoparticles were analyzed. UMRCAs displayed remarkable colloidal stability and high sensitivity as MR probes. Furthermore, UMRCAs exhibited low cytotoxicity and excellent cancer detection ability in an in vivo animal model.

At magnetic resonance (MR) imaging and multidetector computed tomography (CT), artifacts arising from metallic orthopedic hardware are an obstacle to obtaining optimal images. Although various techniques for reducing such artifacts have been developed and corroborated by previous researchers, a new era of more powerful MR imaging and multidetector CT modalities has renewed the importance of a systematic consideration of methods for artifact reduction. Knowledge of the factors that contribute to artifacts, of related theories, and of artifact reduction techniques has become mandatory for radiologists. Factors that affect artifacts on MR images include the composition of the metallic hardware, the orientation of the hardware in relation to the direction of the main magnetic field, the strength of the magnetic field, the pulse sequence type, and other MR imaging parameters (mainly voxel size, which is determined by the field of view, image matrix, section thickness, and echo train length). At multidetector CT, the factors that affect artifacts include the composition of the hardware, orientation of the hardware, acquisition parameters (peak voltage, tube charge, collimation, and acquired section thickness), and reconstruction parameters (reconstructed section thickness, reconstruction algorithm used, and whether an extended CT scale was used). A comparison of images obtained with different hardware and different acquisition and reconstruction parameters facilitates an understanding of methods for reducing or overcoming artifacts related to metallic implants.

To retrospectively determine the accuracy of coronal contrast material-enhanced fat-suppressed three-dimensional (3D) fast spoiled gradient-recalled acquisition in the steady state (SPGR) magnetic resonance (MR) imaging, as compared with that of routine transverse MR imaging, in the assessment of distal tibiofibular syndesmosis injury, with arthroscopy as the reference standard.The review board of the College of Medicine in Yonsei University approved this study; informed consent was waived. The study group comprised 45 patients (26 men, 19 women; mean age, 32.1 years; range, 18-58 years) with a chronic ankle injury who had undergone MR imaging and arthroscopic surgery. Three independent readers retrospectively reviewed the two sets of MR images (one set of gadolinium-enhanced 3D fast SPGR images and one set of routine T1-, T2-, and intermediate-weighted images). Scores from 1 to 5 in increasing order of the probability of injury were assigned to both sets. Arthroscopy was the reference standard. Syndesmotic recess height was measured on contrast-enhanced images. The two sets of images were compared for diagnostic performance with receiver operating characteristic (ROC) analysis. Dissection and histologic examination of six cadaveric ankles was performed to assess the syndesmotic area and ascertain the enhancing structure at MR imaging.At arthroscopy, syndesmotic injury was found in 24 ankles but not in 21 ankles. Areas under the ROC curve were significantly higher for the contrast-enhanced images (P.05). The contrast-enhanced set showed higher accuracy, sensitivity, and specificity compared with the routine set for the assessment of syndesmosis injury. Mean syndesmotic recess height was significantly greater (P.05) in patients with syndesmotic injury. Dissection and histologic examination revealed a highly vascular synovial fold in the syndesmotic area that is expected to enhance at MR imaging.In the assessment of chronic syndesmosis injury, coronal gadolinium-enhanced fat-suppressed 3D fast SPGR MR images were more sensitive, specific, and accurate than routine MR images.

SIMULTANEOUS functional and anatomical imaging using PET-MR system has been reported to be useful in preclinical research to investigate various in vivo biological processes [1-3]. The purpose of this study was to develop a MR compatible small animal PET insert and to evaluate the performance of the developed PET and the influence of the PET on MRI performance.

Multi-drug delivery focuses on different signaling pathways in cancer cells that have synergistic anti-proliferative effects. In this study, we developed multi-prodrug nanocarriers (MPDNCs) consisting of poly ( l -lysine)–carboxylate PTX (PLL-PTX) and hyaluronic acid-conjugated GEM (HA-GEM) for CD44-targeted synergistic biliary cancer therapy. An in vitro study of cell viability and mRNA expression levels and an in vivo study showed that MPDNCs more effectively inhibit proliferation in CD44-overexpressing cancer cells (HuCCT1) than in cells with lower CD44 expression (SCK) by synergistically inducing apoptosis. Consequently, these results demonstrate that MPDNCs are prodrugs with synergistic cancer therapeutic efficacy and effective cellular uptake at target cells compared to free drugs, indicating their strong potential as efficient multi-drug-carrying nano-platforms for cancer treatment.

We have investigated the feasibility of THz time-domain reflectometry for the discrimination of human early gastric cancer (EGC) from the normal gastric region. Eight fresh EGC tissues, which were resected by endoscopic submucosal dissection, were studied. Of them, six lesions were well discriminated on THz images and the regions well correlated with tumor regions on pathologically mapped images. Four THz parameters could be suggested for quantitative discrimination of EGCs. (C) 2015 Optical Society of America

Successful development of ultra-sensitive molecular imaging nanoprobes for the detection of targeted biological objects is a challenging task. Although magnetic nanoprobes have the potential to perform such a role, the results from probes that are currently available have been far from optimal. Here we used artificial engineering approaches to develop innovative magnetic nanoprobes, through a process that involved the systematic evaluation of the magnetic spin, size and type of spinel metal ferrites. These magnetism-engineered iron oxide (MEIO) nanoprobes, when conjugated with antibodies, showed enhanced magnetic resonance imaging (MRI) sensitivity for the detection of cancer markers compared with probes currently available. Also, we successfully visualized small tumors implanted in a mouse. Such high-performance, nanotechnology-based molecular probes could enhance the ability to visualize other biological events critical to diagnostics and therapeutics.

Current progress integrating stem cell biology and tissue engineering techniques has been invaluable to clinical applications. Prior to the application of cellular transplantation technique to patients, we need to establish techniques that can monitor their tissue biodistribution non-invasively. In this study, we proposed an imaging modality using MRI to not only monitor implanted scaffold in vivo, but also to track transplanted cells and behavior around the implant. For this purpose, human bone marrow-derived mesenchymal stem cells (hMSCs) were labeled with superparamagnetic iron oxide (Feridex) and then labeled hMSCs were cultured in a gelatin sponge used as a scaffold to support cell growth and proliferation. Histological assessment and MTT assay showed that cell labeling with MR contrast agent did not harm cell viability. Also, Feridex-labeled hMSCs showed a significant decrease in T2 signal intensity, even within the gelatin sponge in vitro. After implanting the sponge/cell complex in vivo, we could visualize cellular behavior around the implant over time using a noninvasive MRI modality and this finding was correlated with histological study, which illustrates the potential of a new approach proposed here for in vivo monitoring of implanted cell-based tissue-engineered product.