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author:("Huang, xingu")
1.  Differentiation of Reactive and Tumor Metastatic Lymph Nodes with Diffusion-weighted and SPIO Enhanced MRI 
Objectives
Determination of lymphatic metastasis is of great importance for both treatment planning and patient prognosis. We aim to distinguish tumor metastatic lymph nodes (TLNs) and reactive lymph nodes (RLNs) with diffusion-weighted and superparamagnetic iron oxide (SPIO) enhanced magnetic resonance imaging (MRI).
Materials and methods
Ipsilateral popliteal lymph node metastasis or lymphadenitis model was established by hock injection of either luciferase-expressing 4T1 murine breast cancer cells or Complete Freund Adjuvant (CFA) in male Balb/C mice. At different time points after inoculation, bioluminescence imaging, T2-weighted, diffusion-weighted and SPIO enhanced MRI were performed. Imaging findings were confirmed by histopathological staining.
Results
Size enlargement was observed in both TLNs and RLNs. At day 28, TLNs showed strong bioluminescence signal and bigger size than RLNs (p < 0.01). At early stages up to day 21, both TLNs and RLNs appeared homogeneous on diffusion-weighted imaging (DWI). At day 28, TLNs showed heterogeneous apparent diffusion coefficient (ADC) map with significantly higher average ADC value of 0.41 ± 0.03 × 10−3 mm2/s than that of RLNs (0.34 ± 0.02 10−3 mm2/s, p < 0.05). On SPIO enhanced MRI, both TLNs and RLNs showed distinct T2 signal reduction at day 21 after inoculation. At day 28, TLNs demonstrated partial uptake of the iron oxide particles, which was confirmed by Prussian blue staining.
Conclusions
Both diffusion-weighted and SPIO enhanced MRI can distinguish tumor metastatic lymph nodes from reactive lymph nodes. However, neither method is able to detect tumor metastasis to the draining lymph nodes at early stages.
doi:10.1007/s11307-012-0562-2
PMCID: PMC3460060  PMID: 22588595
Lymph node metastasis; diffusion-weighted imaging (DWI); superparamagnetic iron oxide (SPIO); magnetic resonance imaging (MRI); apparent diffusion coefficient (ADC) map
2.  Mesenchymal stem cell-based cell engineering with multifunctional mesoporous silica nanoparticles for tumor delivery 
Biomaterials  2012;34(7):1772-1780.
Stem cell engineering, the manipulation and control of cells, harnesses tremendous potential for diagnosis and therapy of disease; however, it is still challenging to impart multifunctionalization onto stem cells to achieve both. Here we describe a mesenchymal stem cell (MSC)-based multifunctional platform to target orthotopic glioblastoma by integrating the tumor targeted delivery of mesenchymal stem cells and the multimodal imaging advantage of mesoporous silica nanoparticles (MSNs). Rapid cellular uptake, long retention time and stability of particles exemplify the potential that the combination of MSNs and MSCs has as a stem cell-based multifunctional platform. Using such a platform, we verified tumor-targeted delivery of MSCs by in vivo multimodal imaging in an orthotopic U87MG glioblastoma model, displaying higher tumor uptake than particles without MSCs. As a proof-of-concept, this MSC platform opens a new vision for multifunctional applications of cell products by combining the superiority of stem cells and nanoparticles for actively targeted delivery.
doi:10.1016/j.biomaterials.2012.11.032
PMCID: PMC3538138  PMID: 23228423
Mesenchymal stem cells (MSCs); mesoporous silica nanoparticles (MSNs); cell engineering; multimodal imaging; targeted delivery
3.  A Highly Robust, Recyclable Displacement Assay for Mercuric Ions in Aqueous Solutions and Living Cells 
ACS nano  2012;6(12):10999-11008.
We designed a recyclable Hg2+ probe based on Rhodamine B isothiocyanate (RBITC) - poly (ethylene glycol) (PEG)-co-modified gold nanoparticles (AuNPs) with excellent robustness, selectivity and sensitivity. Based on a rational design, only Hg2+ can displace RBITC from the AuNP surfaces, resulting in a remarkable enhancement of RBITC fluorescence initially quenched by AuNPs. To maintain stability and monodispersity of AuNPs in real samples, thiol-terminated PEG was employed to bind with the remaining active sites of AuNPs. Besides, this displacement assay can be regenerated by resupplying free RBITC into the AuNPs solutions that were already used for detecting Hg2+. Importantly, the detection limit of this assay for Hg2+ (2.3 nM) was lower than the maximum limits guided by the United States Environmental Protection Agency as well as that permitted by the World Health Organization. The efficiency of this probe was demonstrated in monitoring Hg2+ in complex samples such as river water and living cells.
doi:10.1021/nn3046192
PMCID: PMC3528810  PMID: 23121626
gold nanoparticles; sensitivity; selectivity; recyclable detection; Rhodamine B isothiocyanate
4.  Real-time monitoring of caspase cascade activation in living cells 
We introduce a simple, versatile and robust one-step technique that enables real-time imaging of multiple intracellular caspase activities in living cells without the need for complicated synthetic protocols. Conventional fluorogenic probes or recently reported activatable probes have been designed to target various proteases but are limited to extracellular molecules. Only a few have been applied to image intracellular proteases in living cells because most of these probes have limited cell-permeability. Our platform does not need complicated synthetic processes; instead it involves a straightforward peptide synthesis and a simple mixing step with a commercial transfection agent. The transfection agent efficiently delivered the highly quenched fluorogenic probes, comprised of distinctive pairs of dyes and quenchers, to the initiator caspase-8 and the effector caspase-3 in MDA-MB-435 cells, allowing dual-imaging of the activities of both caspases during the apoptotic process induced by TNF-related apoptosis induced ligand (TRAIL). With the combination of multiple fluorogenic probes, this simple platform can be applied to multiplexed imaging of selected intracellular proteases to study apoptotic processes in pathologies or for cell-based high throughput screening systems for drug discovery.
doi:10.1016/j.jconrel.2012.05.044
PMCID: PMC3462246  PMID: 22664474
caspase; activatable probe; fluorescence imaging; peptide; transfection agent
5.  Synergistic Enhancement of Iron Oxide Nanoparticle and Gadolinium for Dual-Contrast MRI 
Purpose
The use of MR contrast agents allows accurate diagnosis by exerting an influence on the longitudinal (T1) or transverse (T2) relaxation time of the surrounding tissue. In this study, we combined the use of iron oxide (IO) particles and nonspecific extracellular gadolinium chelate (Gd) in order to further improve the sensitivity and specificity of lesion detection.
Procedures
With a 7-Tesla scanner, pre-contrasted, IO-enhanced and dual contrast agent enhanced MRIs were performed in phantom, normal animals, and animal models of lymph node tumor metastases and orthotopic brain tumor. For the dual-contrast (DC) MRI, we focused on the evaluation of T2 weighted DC MRI with IO administered first, then followed by the injection of a bolus of gadolinium diethylenetriamine pentaacetic acid (Gd-DTPA).
Results
Quantified with C/N ratios and MRI relaxometry, the synergistic effect of coordinated administration of Gd-DTPA and IO was observed and confirmed in phantom, normal liver and tumor models. At 30 min after administration of Feridex, Gd-DTPA further decreased T2 relaxation in liver immediately after the injection. Additional administration of Gd-DTPA also immediately increased the signal contrast between tumor and brain parenchyma and maximized the C/N ratio to −4.12 ± 0.71. Dual contrast MRI also enhanced the delineation of tumor borders and small lesions.
Conclusions
DC-MRI will be helpful to improve diagnostic accuracy and decrease the threshold size for lesion detection.
doi:10.1016/j.bbrc.2012.07.168
PMCID: PMC3438351  PMID: 22898051
MRI; Gd-DTPA; Iron oxide; RGD; Dual Contrast
6.  Long-term multimodal imaging of tumor draining sentinel lymph nodes using mesoporous silica-based nanoprobes 
Biomaterials  2012;33(17):4370-4378.
The imaging of sentinel lymph nodes (SLNs), the first defense against primary tumor metastasis, has been considered as an important strategy for noninvasive tracking tumor metastasis in clinics. In this study, we report the development and application of mesoporous silica-based triple-modal nanoprobes that integrate multiple functional moieties to facilitate near-infrared optical, magnetic resonance (MR) and positron emission tomography (PET) imaging. After embedding near-infrared dye ZW800, the nanoprobe was labeled with T1 contrast agent Gd3+ and radionuclide 64Cu through chelating reactions. High stability and long intracellular retention time of the nanoprobes was confirmed by in vitro characterization, which facilitate long-term in vivo imaging. Longitudinal multimodal imaging was subsequently achieved to visualize tumor draining SLNs up to 3 weeks in a 4T1 tumor metastatic model. Obvious differences in uptake rate, amount of particles, and contrast between metastatic and contralateral sentinel lymph nodes were observed. These findings provide very helpful guidance for the design of robust multifunctional nanomaterials in SLNs’ mapping and tumor metastasis diagnosis.
doi:10.1016/j.biomaterials.2012.02.060
PMCID: PMC3758914  PMID: 22425023
Mesoporous silica nanoparticles; Multimodality imaging; Tumor metastasis; Magnetic resonance imaging; Positron emission tomography; Near-infrared fluorescence imaging
7.  A Facile, One-Step Nanocarbon Functionalization for Biomedical Applications 
Nano Letters  2012;12(7):3613-3620.
Despite their immense potential in biomedicine, carbon nanomaterials suffer from inefficient dispersion and biological activity in vivo. Here we utilize a single, yet multifunctional, hyaluronic acid-based biosurfactant to simultaneously disperse nanocarbons and target single-walled carbon nanotubes (SWCNTs) to CD44 receptor positive tumor cells with prompt uptake. Cellular uptake was monitored by intracellular enzyme-activated fluorescence and localization of SWCNTs within cells was further confirmed by Raman mapping. In vivo photoacoustic, fluorescence and positron emission tomography imaging of coated SWCNTs display high tumor targeting capability while providing long-term, fluorescence molecular imaging of targeted enzyme events. By utilizing a single biomaterial surfactant for SWCNT dispersion without additional bioconjugation, we designed a facile technique that brings nanocarbons closer to their biomedical potential.
doi:10.1021/nl301309g
PMCID: PMC3405986  PMID: 22694219
Carbon nanomaterials; one-step functionalization; hyaluronic acid; nanotubes; molecular
8.  Noninvasive monitoring of orthotopic glioblastoma therapy response using RGD-conjugated iron oxide nanoparticles 
Biomaterials  2012;33(21):5414-5422.
Noninvasive imaging techniques have been considered important strategies in the clinic to monitor tumor early response to therapy. In the present study, we applied RGD peptides conjugated to iron oxide nanoparticles (IONP-RGD) as contrast agents in magnetic resonance imaging (MRI) to noninvasively monitor the response of a vascular disrupting agent VEGF121/rGel in an orthotopic glioblastoma model. RGD peptides were firstly coupled to IONPs coated with a crosslinked PEGylated amphiphilic triblock copolymer. In vitro binding assays confirmed that cellular uptake of particles was mainly dependent on the interaction between RGD and integrin αvβ3 of human umbilical vein endothelial cells (HUVEC). The tumor targeting of IONP-RGD was observed in an orthotopic U87 glioblastoma model. Finally, noninvasive monitoring of the tumor response to VEGF121/rGel therapy at early stages of treatment was successfully accomplished using IONP-RGD as a contrast agent for MRI, a superior method over common anatomical approaches which are based on tumor size measurements. This preclinical study can accelerate anticancer drug development and promote clinical translation of nanoprobes.
doi:10.1016/j.biomaterials.2012.04.032
PMCID: PMC3577933  PMID: 22560667
Magnetic resonance imaging (MRI); Iron oxide nanoparticles (IONPs); RGD peptides; Tumor targeting; Therapy response
9.  Multiplex Imaging of an Intracellular Proteolytic Cascade by using a Broad-Spectrum Nanoquencher** 
doi:10.1002/anie.201107795
PMCID: PMC3622558  PMID: 22213412
caspases; fluorescence; imaging agents; nanoparticles; proteolysis
10.  Polyaspartic acid coated manganese oxide nanoparticles for efficient liver MRI† 
Nanoscale  2011;3(12):4943-4945.
We report in this communication a simple, facile surface modification strategy to transfer hydrophobic manganese oxide nanoparticles (MONPs) into water by using polyaspartic acid (PASP). We systematically investigated the effect of the size of PASP-MONPs on MRI of normal liver and found that the particles with a core size of 10 nm exhibited greater enhancement than those with larger core sizes.
doi:10.1039/c1nr11242b
PMCID: PMC3617494  PMID: 22064945
11.  Design of “smart” probes for optical imaging of apoptosis 
Apoptosis is a mode of programmed cell death in multicellular organisms and plays a central role in controlling embryonic development, growth and differentiation and monitoring the induction of tumor cell death through anticancer therapy. Since the most effective chemotherapeutics rely on apoptosis, imaging apoptotic processes can be an invaluable tool to monitor therapeutic intervention and discover new drugs modulating apoptosis. The most attractive target for developing specific apoptosis imaging probes is caspases, crucial mediators of apoptosis. Up to now, various optical imaging strategies for apoptosis have been developed as an easy and economical modality. However, current optical applications are limited by poor sensitivity and specificity. A subset of molecular imaging contrast agents known as “activatable” or “smart” molecular probes allow for very high signal-to-background ratios compared to conventional targeted contrast agents and open up the possibility of imaging intracellular targets. In this review, we will discuss the unique design strategies and applications of activatable probes recently developed for fluorescence and bioluminescence imaging of caspase activity.
PMCID: PMC3327302  PMID: 22514789
Activatable probes; apoptosis; bioluminescence; caspases; optical imaging
12.  Co-encapsulation of magnetic Fe3O4 nanoparticles and doxorubicin into biodegradable PLGA nanocarriers for intratumoral drug delivery 
In this study, the authors constructed a novel PLGA [poly(D,L-lactic-co-glycolic acid)]-based polymeric nanocarrier co-encapsulated with doxorubicin (DOX) and magnetic Fe3O4 nanoparticles (MNPs) using a single emulsion evaporation method. The DOX-MNPs showed high entrapment efficiency, and they supported a sustained and steady release of DOX. Moreover, the drug release was pH sensitive, with a faster release rate in an acidic environment than in a neutral environment. In vitro, the DOX-MNPs were easily internalized into murine Lewis lung carcinoma cells and they induced apoptosis. In vivo, the DOX-MNPs showed higher antitumor activity than free DOX solution. Furthermore, the antitumor activity of the DOX-MNPs was higher with than without an external magnetic field; they were also associated with smaller tumor volume and a lower metastases incidence rate. This work may provide a new modality for developing an effective drug delivery system.
doi:10.2147/IJN.S28629
PMCID: PMC3356178  PMID: 22619520
antitumor activity; external magnetic field; intratumoral injection; apoptosis; Lewis lung carcinoma
13.  Design of “smart” probes for optical imaging of apoptosis 
Apoptosis is a mode of programmed cell death in multicellular organisms and plays a central role in controlling embryonic development, growth and differentiation and monitoring the induction of tumor cell death through anticancer therapy. Since the most effective chemotherapeutics rely on apoptosis, imaging apoptotic processes can be an invaluable tool to monitor therapeutic intervention and discover new drugs modulating apoptosis. The most attractive target for developing specific apoptosis imaging probes is caspases, crucial mediators of apoptosis. Up to now, various optical imaging strategies for apoptosis have been developed as an easy and economical modality. However, current optical applications are limited by poor sensitivity and specificity. A subset of molecular imaging contrast agents known as “activatable” or “smart” molecular probes allow for very high signal-to-background ratios compared to conventional targeted contrast agents and open up the possibility of imaging intracellular targets. In this review, we will discuss the unique design strategies and applications of activatable probes recently developed for fluorescence and bioluminescence imaging of caspase activity.
PMCID: PMC3327302  PMID: 22514789
Activatable probes; apoptosis; bioluminescence; caspases; optical imaging
14.  Synthesis of Aqueous CdTe/CdS/ZnS Core/shell/shell Quantum Dots by a Chemical Aerosol Flow Method 
Nanoscale Research Letters  2009;5(1):189-194.
This work described a continuous method to synthesize CdTe/CdS/ZnS core/shell/shell quantum dots. In an integrated system by flawlessly combining the chemical aerosol flow system working at high temperature (200–300°C) to generate CdTe/CdS intermediate products and an additional heat-up setup at relatively low temperature to overcoat the ZnS shells, the CdTe/CdS/ZnS multishell structures were realized. The as-synthesized CdTe/CdS/ZnS core/shell/shell quantum dots are characterized by photoluminescence spectra, X-ray diffraction (XRD), energy-dispersive X-ray spectra (EDS), transmission electron microscopy (TEM), and high-resolution transmission electron microscopy (HRTEM). Fluorescence and XRD results confirm that the obtained quantum dots have a core/shell/shell structure. It shows the highest quantum yield above 45% when compared to the rhodamine 6G. The core/shell/shell QDs were more stable via the oxidation experiment by H2O2.
doi:10.1007/s11671-009-9464-x
PMCID: PMC2894201  PMID: 20652095
Chemical aerosol flow; CdTe/CdS/ZnS; Aqueous; Core–shell; Quantum dot
15.  Synthesis of Aqueous CdTe/CdS/ZnS Core/shell/shell Quantum Dots by a Chemical Aerosol Flow Method 
Nanoscale Research Letters  2009;5(1):189-194.
This work described a continuous method to synthesize CdTe/CdS/ZnS core/shell/shell quantum dots. In an integrated system by flawlessly combining the chemical aerosol flow system working at high temperature (200–300°C) to generate CdTe/CdS intermediate products and an additional heat-up setup at relatively low temperature to overcoat the ZnS shells, the CdTe/CdS/ZnS multishell structures were realized. The as-synthesized CdTe/CdS/ZnS core/shell/shell quantum dots are characterized by photoluminescence spectra, X-ray diffraction (XRD), energy-dispersive X-ray spectra (EDS), transmission electron microscopy (TEM), and high-resolution transmission electron microscopy (HRTEM). Fluorescence and XRD results confirm that the obtained quantum dots have a core/shell/shell structure. It shows the highest quantum yield above 45% when compared to the rhodamine 6G. The core/shell/shell QDs were more stable via the oxidation experiment by H2O2.
doi:10.1007/s11671-009-9464-x
PMCID: PMC2894201  PMID: 20652095
Chemical aerosol flow; CdTe/CdS/ZnS; Aqueous; Core–shell; Quantum dot

Results 1-15 (15)