PMCC PMCC

Search tips
Search criteria

Advanced
Results 1-25 (117)
 

Clipboard (0)
None

Select a Filter Below

Journals
more »
Year of Publication
1.  A symmetrical fluorous dendron-cyanine dye conjugated bimodal nanoprobe for quantitative 19F MRI and NIR fluorescence bioimaging 
Advanced healthcare materials  2014;3(8):1326-1333.
19F MRI and optical imaging are two powerful non-invasive molecular imaging modalities in biomedical applications. 19F MRI has great potential for high resolution in vivo imaging, while fluorescent probes enable ultracontrast cellular/tissue imaging with high accuracy and sensitivity. We, thus, developed a bimodal nanoprobe integrating the merits of 19F MRI and fluorescence imaging into a single synthetic molecule, which was further engineered into nanoprobe, by addressing shortcomings of conventional contrast agents to explore the quantitative 19F MRI and fluorescence imaging and cell tracking. Results showed that this bimodal imaging nanoprobe presented high correlation of 19F MR signal and NIR fluorescence intensity in vitro and in vivo. Additionally, this nanoprobe enabled quantitative 19F MR analysis, confirmed by complementary fluorescence analysis. This unique feature can hardly be obtained by traditional 19F MRI contrast agents. We envision that this nanoprobe would hold great potential for quantitative and sensitive multi-modal molecular imaging.
doi:10.1002/adhm.201400088
PMCID: PMC4134706  PMID: 24789108
19F MRI; fluorescence imaging; nanoparticles; stem cells; biodegradable polymer
2.  Differentiation between Solitary Cerebral Metastasis and Astrocytoma on the Basis of Subventricular Zone Involvement on Magnetic Resonance Imaging 
PLoS ONE  2015;10(7):e0133480.
Purpose
To determine the relationship between the subventricular zone (SVZ) and astrocytoma based on magnetic resonance imaging (MRI) and whether SVZ involvement can be used to distinguish solitary cerebral metastases (SCMs) from astrocytomas.
Methods
This retrospective study involved 154 patients with solitary low-grade astrocytoma (LGA), high-grade astrocytoma (HGA), and SCM, who underwent T1-weighted imaging (T1WI), Gd-DTPA–enhanced T1WI, and T2-weighted imaging (T2WI) or fluid-attenuated inversion recovery (FLAIR) T2WI. The spatial relationship between the tumor and SVZ was classified as “involvement” or “segregation” on contrast-enhanced T1WI for enhanced tumors and T2WI/FLAIR T2WI for non-enhanced tumors. Patient-based SVZ-contact rates were compared between the LGA, HGA, and SCM groups. The frequencies of involvement of various lateral ventricle regions by astrocytoma were compared. The correlation between SVZ involvement and tumor necrosis was analyzed.
Results
Patient-based SVZ-contact rates in SCM, LGA, and HGA were 24.1%, 68.8%, and 85.4%, respectively. Univariate analysis showed that the SVZ-contact rate was significantly different between SCM and astrocytoma (24.1% vs. 75.2% P < 0.001), also between LGA and HGA (68.1% vs. 85.4% P=0.037). After the tumor volume was adjusted as a covariate, SVZ-contact rates still differed between SCMs and astrocytomas (Odds ratio [OR]: 4.58, 95% Confidence interval [CI]: 1.65 to 12.8, P=0.004). Tumor volume differed between LGA and HGA (P< 0.001), and influenced the association between SVZ involvement and astrocytoma grade (P = 0.05). Among the lateral ventricle regions, the frontal horn was the most frequently involved by astrocytomas. SVZ-contact rates were higher in necrosis group compared with non-necrosis groups (83.9% vs. 50.0%, P < 0.001) among astrocytoma patients. Necrosis positively correlated with SVZ involvement in astrocytomas (rs = 0.342, P < 0.001), but did not correlate with SVZ involvement in SCMs (P = 0.193).
Conclusions
Compared to SCMs, solitary cerebral astrocytomas exhibited spatial proximity to the SVZ, which might distinguish the supratentorial astrocytomas from SCMs.
doi:10.1371/journal.pone.0133480
PMCID: PMC4510882  PMID: 26197398
3.  Chelator-Free 64Cu-Integrated Gold Nanomaterials for Positron Emission Tomography Imaging Guided Photothermal Cancer Therapy 
ACS Nano  2014;8(8):8438-8446.
Using positron emission tomography (PET) imaging to monitor and quantitatively analyze the delivery and localization of Au nanomaterials (NMs), a widely used photothermal agent, is essential to optimize therapeutic protocols to achieve individualized medicine and avoid side effects. Coupling radiometals to Au NMs via a chelator faces the challenges of possible detachment of the radiometals as well as surface property changes of the NMs. In this study, we reported a simple and general chelator-free 64Cu radiolabeling method by chemically reducing 64Cu on the surface of polyethylene glycol (PEG)-stabilized Au NMs regardless of their shape and size. Our 64Cu-integrated NMs are proved to be radiochemically stable and can provide an accurate and sensitive localization of NMs through noninvasive PET imaging. We further integrated 64Cu onto arginine-glycine-aspartic acid (RGD) peptide modified Au nanorods (NRs) for tumor theranostic application. These NRs showed high tumor targeting ability in a U87MG glioblastoma xenograft model and were successfully used for PET image-guided photothermal therapy.
doi:10.1021/nn502950t
PMCID: PMC4148157  PMID: 25019252
64Cu labeling; chelator free; PET; image-guided photothermal therapy
4.  PET imaging of neuroinflammation in a rat traumatic brain injury model with radiolabeled TSPO ligand DPA-714 
Purpose
Inflammatory response in injured brain parenchyma after traumatic brain injury (TBI) is crucial to its pathologic process. In order to follow the microglia activation and neuroinflammation after TBI, herein, we performed PET imaging in a rat TBI model using 18F-labeled DPA-714, a ligand of 18 KDa translocator protein (TSPO).
Methods
TBI was induced in male SD rats by controlled cortical impact (CCI). The success of the TBI model was confirmed by magnetic resonance imaging (MRI). Automated synthesis of [18F]DPA-714 was carried out using a slightly modified TRACERLab FX-FN module. In vivo PET imaging was performed at different time points after surgery by an Inveon small animal PET scanner. The specificity of [18F]DPA-714 was confirmed by displacement study with an unlabeled competitive TSPO ligand, PK11195. Ex vivo autoradiography as well as immunofluorescence staining was carried out to confirm the in vivo PET results.
Results
Both in vivo T2-weighted MR images and ex vivo TTC staining results revealed successful establishment of the TBI model. Compared with the sham group, [18F]DPA-714 uptake was significantly higher in the injured brain area on PET images. Increased lesion-to-normal brain ratio of [18F]DPA-714 in TBI rats was observed at day 2 after surgery, peaked around day 6 (2.65 ± 0.36) and then decreased gradually to nearly normal level at day 28. Displacement study using PK11195 confirmed the specific binding of [18F]DPA-714 to TSPO. Ex vivo autoradiography was consistent with in vivo PET results. The immunofluorescence staining showed a time course of TSPO expression after TBI and the temporal and spatial distribution of microglia in damaged brain area.
Conclusion
TSPO targeted PET using [18F]DPA-714 as the imaging probe can be used to dynamically monitor inflammatory response after TBI in a non-invasive manner. This method will not only facilitate a better understanding of inflammation process after traumatic brain injury, but also provide a useful in vivo monitoring strategy for anti-inflammation therapy of TBI.
doi:10.1007/s00259-014-2727-5
PMCID: PMC4055510  PMID: 24615467
Traumatic brain injury (TBI); Translocator protein (TSPO); [18F]DPA-714; PET; molecular imaging
6.  Exposure of Tumor-Associated Macrophages to Apoptotic MCF-7 Cells Promotes Breast Cancer Growth and Metastasis 
Tumor-associated macrophages (TAMs) have been found to be associated with the progression and metastasis of breast cancer. To clarify the mechanisms underlying the crosstalk between TAMs and cancer stem cells (CSCs) in breast cancer recurrence and metastasis, we used a co-culture model of macrophages and apoptotic human breast cancer cell line MCF-7 cells to investigate the effects of TAMs on MCF-7 in vitro and in vivo. Macrophages co-cultured with apoptotic MCF-7 had increased tumor growth and metastatic ability in a nude mouse transplantation assay. The macrophages exposed to apoptotic cells also induce an increase in the proportion of CD44+/CD24− cancer stem-like cells, as well as their proliferative ability accompanied with an increase in mucin1 (MUC1) expression. During this process, macrophages secreted increased amounts of interleukin 6 (IL-6) leading to increased phosphorylation of signal transducers and activators of transcription 3 (STAT3), which likely explains the increased transcription of STAT3 target genes such as TGF-β1 and HIF-1α. Our results indicate that when cancer cells endure chemotherapy induced apoptosis, macrophages in their microenvironment can then activate cancer stem cells to promote cancer growth and metastasis by secreting IL-6, which activates STAT3 phosphorylation to regulate the transcription of its downstream target genes.
doi:10.3390/ijms160611966
PMCID: PMC4490423  PMID: 26016502
cancer stem cells; apoptosis; TAMs; metastasis; IL-6; STAT3
7.  Glucose Oxidase-Catalyzed Growth of Gold Nanoparticles Enables Quantitative Detection of Attomolar Cancer Biomarkers 
Analytical Chemistry  2014;86(12):5800-5806.
Ultrasensitive and quantitative detection of cancer biomarkers is an unmet challenge because of their ultralow concentrations in clinical samples. Although gold nanoparticle (AuNP)-based immunoassays offer high sensitivity, they were unable to quantitatively detect targets of interest most likely due to their very narrow linear ranges. This article describes a quantitative colorimetric immunoassay based on glucose oxidase (GOx)-catalyzed growth of 5 nm AuNPs that can detect cancer biomarkers from attomolar to picomolar levels. In addition, the limit of detection (LOD) of prostate-specific antigen (PSA) of this approach (93 aM) exceeds that of commercial enzyme-linked immunosorbent assay (ELISA) (6.3 pM) by more than 4 orders of magnitude. The emergence of red or purple color based on enzyme-catalyzed growth of 5 nm AuNPs in the presence of target antigen is particularly suitable for point-of-care (POC) diagnostics in both resource-rich and resource-limited settings.
doi:10.1021/ac500478g
PMCID: PMC4066917  PMID: 24896231
8.  Triphase Interface Synthesis of Plasmonic Gold Bellflowers as Near-Infrared Light Mediated Acoustic and Thermal Theranostics 
We present a novel gold bellflower (GBF) platform with multiple-branched petals, prepared by a liquid–liquid–gas triphase interface system, for photoacoustic imaging (PAI)-guided photothermal therapy (PTT). Upon near-infrared (NIR) laser irradiation, the GBFs, with strong NIR absorption, showed very strong PA response and an ultrahigh photothermal conversion efficiency (η, ∼74%) among the reported photothermal conversion agents. The excellent performance in PAI and PTT is mainly attributed to the unique features of the GBFs: (i) multiple-branched petals with an enhanced local electromagnetic field, (ii) long narrow gaps between adjacent petals that induce a strong plasmonic coupling effect, and (iii) a bell-shaped nanostructure that can effectively amplify the acoustic signals during the acoustic propagation. Besides the notable PTT and an excellent PAI effect, the NIR-absorbing GBFs may also find applications in NIR light-triggered drug delivery, catalysis, surface enhanced Raman scattering, stealth, antireflection, IR sensors, telecommunications, and the like.
doi:10.1021/ja503115n
PMCID: PMC4227821  PMID: 24842342
9.  Tumor Vasculature Targeted Photodynamic Therapy for Enhanced Delivery of Nanoparticles 
ACS Nano  2014;8(6):6004-6013.
Delivery of nanoparticle drugs to tumors relies heavily on the enhanced permeability and retention (EPR) effect. While many consider the effect to be equally effective on all tumors, it varies drastically among the tumors’ origins, stages, and organs, owing much to differences in vessel leakiness. Suboptimal EPR effect represents a major problem in the translation of nanomedicine to the clinic. In the present study, we introduce a photodynamic therapy (PDT)-based EPR enhancement technology. The method uses RGD-modified ferritin (RFRT) as “smart” carriers that site-specifically deliver 1O2 to the tumor endothelium. The photodynamic stimulus can cause permeabilized tumor vessels that facilitate extravasation of nanoparticles at the sites. The method has proven to be safe, selective, and effective. Increased tumor uptake was observed with a wide range of nanoparticles by as much as 20.08-fold. It is expected that the methodology can find wide applications in the area of nanomedicine.
doi:10.1021/nn501134q
PMCID: PMC4076019  PMID: 24806291
photodynamic therapy; EPR; ferritin; nanoparticles; drug delivery; integrin αvβ3
10.  Pharmacodynamics, Tissue Distribution, Toxicity Studies and Antitumor Efficacy of the Vascular Targeting Fusion Toxin VEGF121/rGel 
Biochemical pharmacology  2012;84(11):1534-1540.
As a part of an ongoing assessment of its mechanism of action, we evaluated the in vivo pharmacokinetics, tissue distribution, toxicity and antitumor efficacy of VEGF121/rGel, a novel fusion protein. Pharmacokinetic studies showed that VEGF121/rGel cleared from the circulation in a biphasic manner with calculated half-lives of 0.3 and 6 hours for the alpha and beta phases, respectively. Pharmacokinetic evaluation of 64Cu-DOTA-VEGF121/rGel showed relatively high blood retention 30 min after injection (26.6 ± 1.73 %ID/g), dropping to 11.8 ± 2.83 % and 0.82 ± 0.11 % ID/g at 60 and 240 minutes post injection, respectively. Tissue uptake studies showed that kidneys, liver and tumor had the highest drug concentrations 48 hrs after administration. The maximum tolerated dose (MTD), based on a QOD X5 i.v. administration schedule, was found to be 18 mg/kg with an LD50 of 25 mg/kg. Treatment of BALB/c mice with VEGF121/rGel at doses up to the MTD caused no alterations in hematologic parameters. However, AST and ALT parameters increased in a dose-related manner. The no-observable-adverse-effect-level (NOAEL) was determined to be 20% of the MTD (3.6 mg/kg). VEGF121/rGel treatment of mice bearing orthotopically-placed MDA-MB-231 breast tumors caused increased vascular permeability of tumor tissue by 53% compared to saline-treated controls. Immunohistochemical analysis showed significant tumor hypoxia and necrosis as a consequence of vascular damage. In summary, VEGF121/rGel appears to be an effective therapeutic agent causing focused damage to tumor vasculature with minimal toxic effects to normal organs. This agent appears to be an excellent candidate for further clinical development.
Graphical Abstract (for review)
doi:10.1016/j.bcp.2012.09.017
PMCID: PMC4423739  PMID: 23022224
Angiogenesis; Necrosis; Pharmacokinetics; Toxicology; VEGF; Vascular permeability
11.  One-Pot Two-Step Radiosynthesis of a New 18F-Labeled Thiol Reactive Prosthetic Group and Its Conjugate for Insulinoma Imaging 
Molecular Pharmaceutics  2014;11(11):3875-3884.
N-(2-(2,5-dioxo-2,5-dihydro-1H-pyrrol-1-yl)ethyl)-6-fluoronicotinamide ([18F]FNEM), a novel prosthetic agent that is thiol-specific, was synthesized using a one-pot two-step strategy: (1) 18F incorporation by a nucleophilic displacement of trimethylammonium substrate under mild conditions; (2) amidation of the resulting 6-[18F]fluoronicotinic acid 2,3,5,6-tetrafluorophenyl ester with N-(2-aminoethyl)maleimide trifluoroacetate salt. The radiosynthesis of the maleimide tracer was completed in 75 min from [18F]fluoride with 26 ± 5% decay uncorrected radiochemical yield, and specific activity of 19–88 GBq/μmol (decay uncorrected). The in vitro cell uptake, in vivo biodistribution, and positron emission tomography (PET) imaging properties of its conjugation product with [Cys40]-exendin-4 were described. [18F]FNEM-Cys40-exendin-4 showed specific targeting of glucagon-like peptide 1 receptor (GLP-1R) positive insulinomas and comparable imaging results to our recently reported [18F]FPenM-Cys40-exendin-4.
doi:10.1021/mp5001857
PMCID: PMC4224565  PMID: 24798315
fluorine-18; thiol reactive prosthetic group; insulinoma imaging
12.  Design Considerations of Iron-Based Nanoclusters for Noninvasive Tracking of Mesenchymal Stem Cell Homing 
ACS Nano  2014;8(5):4403-4414.
Stem-cell-based therapies have attracted considerable interest in regenerative medicine and oncological research. However, a major limitation of systemic delivery of stem cells is the low homing efficiency to the target site. Here, we report a serendipitous finding that various iron-based magnetic nanoparticles (MNPs) actively augment chemokine receptor CXCR4 expression of bone-marrow-derived mesenchymal stem cells (MSCs). On the basis of this observation, we designed an iron-based nanocluster that can effectively label MSCs, improve cell homing efficiency, and track the fate of the cells in vivo. Using this nanocluster, the labeled MSCs were accurately monitored by magnetic resonance imaging and improved the homing to both traumatic brain injury and glioblastoma models as compared to unlabeled MSCs. Our findings provide a simple and safe method for imaging and targeted delivery of stem cells and extend the potential applications of iron-based MNPs in regenerative medicine and oncology.
doi:10.1021/nn4062726
PMCID: PMC4046801  PMID: 24754735
mesenchymal stem cell; homing; iron oxide nanoparticle; magnetic resonance imaging; CXCR4/SDF-1α
13.  Targeted Therapeutic Nanotubes Influence the Viscoelasticity of Cancer Cells to Overcome Drug Resistance 
ACS Nano  2014;8(5):4177-4189.
Resistance to chemotherapy is the primary cause of treatment failure in over 90% of cancer patients in the clinic. Research in nanotechnology-based therapeutic alternatives has helped provide innovative and promising strategies to overcome multidrug resistance (MDR). By targeting CD44-overexpressing MDR cancer cells, we have developed in a single-step a self-assembled, self-targetable, therapeutic semiconducting single-walled carbon nanotube (sSWCNT) drug delivery system that can deliver chemotherapeutic agents to both drug-sensitive OVCAR8 and resistant OVCAR8/ADR cancer cells. The novel nanoformula with a cholanic acid-derivatized hyaluronic acid (CAHA) biopolymer wrapped around a sSWCNT and loaded with doxorubicin (DOX), CAHA-sSWCNT-DOX, is much more effective in killing drug-resistant cancer cells compared to the free DOX and phospholipid PEG (PL-PEG)-modified sSWCNT formula, PEG-sSWCNT-DOX. The CAHA-sSWCNT-DOX affects the viscoelastic property more than free DOX and PL-PEG-sSWCNT-DOX, which in turn allows more drug molecules to be internalized. Intravenous injection of CAHA-sSWCNT-DOX (12 mg/kg DOX equivalent) followed by 808 nm laser irradiation (1 W/cm2, 90 s) led to complete tumor eradication in a subcutaneous OVCAR8/ADR drug-resistant xenograft model, while free DOX alone failed to delay tumor growth. Our newly developed CAHA-sSWCNT-DOX nanoformula, which delivers therapeutics and acts as a sensitizer to influence drug uptake and induce apoptosis with minimal resistance factor, provides a novel effective means of counteracting the phenomenon of multidrug resistance.
doi:10.1021/nn501223q
PMCID: PMC4046789  PMID: 24708375
semiconducting carbon nanotube; hyaluronic acid; doxorubicin; multidrug resistance; viscoelasticity; live cell imaging; quartz-crystal microbalance with dissipation (QCM-D)
14.  Role of Glucokinase in the Subcellular Localization of Glucokinase Regulatory Protein 
Glucokinase (GCK) is the rate-limiting enzyme of liver glucose metabolism. Through protein-protein interactions, glucokinase regulatory protein (GCKR) post-transcriptionally regulates GCK function in the liver, and causes its nuclear localization. However the role of GCK in regulating GCKR localization is unknown. In the present study, using in vitro and in vivo models, we examined the levels of GCK and GCKR, and their subcellular localization. We found that total cellular levels of GCKR did not vary in the in vivo models, but its subcellular localization did. In animals with normal levels of GCK, GCKR is mainly localized to the nuclei of hepatocytes. In seven-day old rats and liver-specific Gck gene knockout mice (animals that lack or have reduced levels of GCK protein), GCKR was found primarily in the cytoplasm. The interaction of GCK with GCKR was further examined using in vitro models where we varied the levels of GCK and GCKR. Varying the level of GCK protein had no effect on total cellular GCKR protein levels. Taken together, our results indicate that GCK is important for the localization of GCKR to the nucleus and raises the possibility that GCKR may have functions in addition to those regulating GCK activity in the cytoplasm.
doi:10.3390/ijms16047377
PMCID: PMC4425023  PMID: 25849650
protein–protein interaction; glucokinase regulatory protein; glucokinase; sub-cellular localization; glucose metabolism
15.  Rational Design of Matrix Metalloproteinase-13 (MMP-13) Activatable Probes for Enhanced Specificity 
ACS chemical biology  2013;9(2):510-516.
Due to the important roles of matrix metalloproteinases (MMPs) play in tumor invasion and metastasis, various activatable optical probes have been developed to visualize MMP activities in vitro and in vivo. Our recently developed MMP-13 activatable probe, L-MMP-P12, has been successfully applied to image the expression and inhibition of MMPs in a xenografted tumor model (Zhu L et al., Theranostics. 2011;1:18–27). In this study, to further optimize the in vivo behavior of the proteinase activatable probe, we tracked and profiled the metabolites by a high resolution LC/MS system. Two major metabolites that contributed to the fluorescence recovery were identified: One was specifically cleaved between Glycine (G4) and Valine (V5) by MMP, while the other one was generated by non-specific cleavage between Glycine (G7) and Lysine (K8). In order to visualize the MMP activity more accurately and specifically, a new probe D-MMP-P12 was designed by replacing the L-lysine with D-lysine in the MMP substrate sequence. The metabolic profile of the new probe, D-MMP-P12, was further characterized by in vitro enzymatic assay and no non-specific metabolite was found by LC/MS. Our in vivo optical imaging also demonstrated that D-MMP-12 had significantly higher tumor-to-background ratio (TBR, 5.55 ± 0.75) compared with L-MMP-P12 (3.73 ± 0.31) at 2 h post-injection. The improved MMP activatable probe may have the potential for drug screening, tumor diagnosis and therapy response monitoring. Moreover, our research strategy can be further extended to study other protease activatable probes.
doi:10.1021/cb400698s
PMCID: PMC3944097  PMID: 24266806
Liquid chromatography–mass spectrometry (LC-MS); activatable probe; matrix metalloproteinases (MMPs); metabolite; near-infrared fluorescence imaging
16.  Self-Illuminating 64Cu-Doped CdSe/ZnS Nanocrystals for in Vivo Tumor Imaging 
Construction of self-illuminating semiconducting nanocrystals, also called quantum dots (QDs), has attracted much attention recently due to their potential as highly sensitive optical probes for biological imaging applications. Here we prepared a self-illuminating QD system by doping positron-emitting radionuclide 64Cu into CdSe/ZnS core/shell QDs via a cation-exchange reaction. The 64Cu-doped CdSe/ZnS QDs exhibit efficient Cerenkov resonance energy transfer (CRET). The signal of 64Cu can accurately reflect the biodistribution of the QDs during circulation with no dissociation of 64Cu from the nanoparticles. We also explored this system for in vivo tumor imaging. This nanoprobe showed high tumor-targeting ability in a U87MG glioblastoma xenograft model (12.7% ID/g at 17 h time point) and feasibility for in vivo luminescence imaging of tumor in the absence of excitation light. The availability of these self-illuminating integrated QDs provides an accurate and convenient tool for in vivo tumor imaging and detection.
doi:10.1021/ja410438n
PMCID: PMC4004262  PMID: 24401138
17.  The genotype-dependent influence of functionalized multiwalled carbon nanotubes on fetal development 
Biomaterials  2014;35(2):856-865.
In many cases cancer is caused by gene deficiency that is being passed along from generation to generation. Soluble carbon nanotubes (CNTs) have shown promising applications in the diagnosis and therapy of cancer, however, the potential relationship between cancer-prone individuals and response to CNT exposure as a prerequisite for development of personalized nanomedicine, is still poorly understood. Here we report that intravenous injections of multi-walled carbon nanotubes into p53 (a well-known cancer susceptible gene) heterozygous pregnant mice can induce p53- dependent responses in fetal development. Larger sized multi-walled carbon nanotubes moved across the blood-placenta barrier (BPB), restricted the development of fetuses, and induced brain deformity, whereas single-walled and smaller sized multi-walled carbon nanotubes showed no or less fetotoxicity. A molecular mechanism study found that multi-walled carbon nanotubes directly triggered p53-dependent apoptosis and cell cycle arrest in response to DNA damage. Based on the molecular mechanism, we also incorporated N-acetylcysteine (NAC), a FDA approved antioxidant, to prevent CNTs induced nuclear DNA damage and reduce brain development abnormalities. Our findings suggest that CNTs might have genetic background-dependent toxic effect on the normal development of the embryo, and provide new insights into protection against nanoparticle-induced toxicity in potential clinical applications.
PMCID: PMC4091802  PMID: 24344357
Carbon nanotubes; nanotoxicity; genetic background; blood-placenta barrier; fetal development
18.  PEGylated Exendin-4, a Modified GLP-1 Analog Exhibits More Potent Cardioprotection than Its Unmodified Parent Molecule on a Dose to Dose Basis in a Murine Model of Myocardial Infarction 
Theranostics  2015;5(3):240-250.
A Site-specifically PEGylated exendin-4 (denoted as PEG-Ex4) is an exendin-4 (denoted as Ex4) analog we developed by site-specific PEGylation of exendin-4 with a high molecular weight trimeric poly(ethylene glycol) (tPEG). It has been shown to possess prolonged half-life in vivo with similar receptor binding affinity compared to unmodified exendin-4 by our previous work. This study is sought to test whether PEG-Ex4 is suitable for treating myocardial infarction (MI). In the MI model, PEG-Ex4 was administered every 3 days while equivalent amount of Ex4 was administered every 3 days or twice daily. Animal survival rate, heart function, remodeling and neoangiogenesis were evaluated and compared. Tube formation was examined in endothelial cells. In addition, Western blotting and histology were performed to determine the markers of cardiac hypertrophy and angiogenesis and to explore the possible molecular mechanism involved. PEG-Ex4 and Ex4 showed comparable binding affinity to GLP-1 receptor. In MI mice, PEG-Ex4 given at 3 days interval achieved similar extent of protection as Ex4 given twice daily, while Ex4 given at 3 days interval failed to produce protection. PEG-Ex4 elevated endothelial tube formation in vitro and capillary density in the border area of MI. PEG-Ex4 increased Akt activity and VEGF production in a GLP-1R dependent manner in endothelial cells and antagonism of GLP-1R, Akt or VEGF abolished the protection of PEG-Ex4 in the MI model. PEG-Ex4 is a potent long-acting GLP-1 receptor agonist for the treatment of chronic heart disease. Its protection might be attributed to enhanced angiogenesis mediated by the activation of Akt and VEGF.
doi:10.7150/thno.10226
PMCID: PMC4279188  PMID: 25553112
Exendin-4; PEGylation; cardioprotection; Angiogenesis; myocardial infarction.
19.  Lymphatic Imaging: Focus on Imaging Probes 
Theranostics  2015;5(7):686-697.
In view of the importance of sentinel lymph nodes (SLNs) in tumor staging and patient management, sensitive and accurate imaging of SLNs has been intensively explored. Along with the advance of the imaging technology, various contrast agents have been developed for lymphatic imaging. In this review, the lymph node imaging agents were summarized into three groups: tumor targeting agents, lymphatic targeting agents and lymphatic mapping agents. Tumor targeting agents are used to detect metastatic tumor tissue within LNs, lymphatic targeting agents aim to visualize lymphatic vessels and lymphangionesis, while lymphatic mapping agents are mainly for SLN detection during surgery after local administration. Coupled with various signal emitters, these imaging agents work with single or multiple imaging modalities to provide a valuable way to evaluate the location and metastatic status of SLNs.
doi:10.7150/thno.11862
PMCID: PMC4402493  PMID: 25897334
Sentinel lymph node; contrast agent; PET; MRI; fluorescence; imaging.
20.  Prospective Study of 68Ga-NOTA-NFB: Radiation Dosimetry in Healthy Volunteers and First Application in Glioma Patients 
Theranostics  2015;5(8):882-889.
Purpose: The chemokine receptor CXCR4 is overexpressed in various types of human cancers. As a specific imaging agent of CXCR4, 68Ga-NOTA-NFB was investigated in this study to assess its safety, biodistribution and dosimetry properties in healthy volunteers, and to preliminarily evaluate its application in glioma patients.
Methods: Six healthy volunteers underwent whole-body PET scans at 0, 0.5, 1, 2 and 3 h after 68Ga-NOTA-NFB injection (mean dose, 182.4 ± 3.7 MBq (4.93 ± 0.10 mCi)). For time-activity curve calculations, 1 mL blood samples were obtained at 1, 3, 5, 10, 30, 60, 90, 120, 150 and 180 min after the injection. The estimated radiation doses were calculated by OLINDA/EXM software. Eight patients with glioma were enrolled and underwent both 68Ga-NOTA-NFB and 18F-FDG PET/CT scans before surgery. The expression of CXCR4 on the resected brain tumor tissues was determined by immunohistochemical staining.
Results: 68Ga-NOTA-NFB was safe and well tolerated by all subjects. A rapid activity clearance from the blood circulation was observed. The organs with the highest absorbed doses were spleen (193.8 ± 32.5 μSv/MBq) and liver (119.3 ± 25.0 μSv/MBq). The mean effective dose was 25.4 ± 6.1 μSv/MBq. The maximum standardized uptake values (SUVmax) and the maximum target to non-target ratios (T/NTmax) of 68Ga-NOTA-NFB PET/CT in glioma tissues were 4.11 ± 2.90 (range, 0.45-8.21) and 9.21 ± 8.75 (range, 3.66-24.88), respectively, while those of 18F-FDG PET/CT were 7.34 ± 2.90 (range, 3.50-12.27) and 0.86 ± 0.41 (range, 0.35-1.59). The histopathological staining confirmed that CXCR4 was overexpressed on resected tumor tissues with prominent 68Ga-NOTA-NFB uptake.
Conclusion: With a favorable radiation dosimetry profile, 68Ga-NOTA-NFB is safe for clinical imaging. Compared to 18F-FDG PET/CT, 68Ga-NOTA-NFB PET/CT is more sensitive in detecting glioma and could have potential in diagnosing and treatment planning for CXCR4 positive patients.
doi:10.7150/thno.12303
PMCID: PMC4440444  PMID: 26000059
68Ga-NOTA-NFB; internal dosimetry; CXCR4; glioma; PET/CT
21.  Pilot Prospective Evaluation of 18F-Alfatide II for Detection of Skeletal Metastases 
Theranostics  2015;5(10):1115-1121.
This pilot prospective evaluation study is to verify the efficiency of 18F-Alfatide II, a specific PET imaging agent for integrin αvβ3, in detecting bone metastasis in human, with comparison to 18F-FDG PET. Thirty recruited patients underwent 18F-FDG and 18F-alfatide II PET/CT successively within days. The final diagnosis of bone lesions was established based on the comprehensive assessment of all available data and clinical follow-up, which fall into four groups: osteolytic, osteoblastic, mixed and bone marrow. Visual analysis and quantification of SUVmax were performed to compare the detection sensitivity of 18F-Alfatide II and 18F-FDG PET. Eleven patients were found to have a total of 126 bone metastasis lesions. 18F-Alfatide II PET can detect the bone metastatic lesions with good contrast and higher sensitivity (positive rate of 92%) than 18F-FDG PET (77%). Especially, 18F-Alfatide II PET showed superiority to 18F-FDG PET in detecting osteoblastic (70% vs. 53%) and bone marrow metastatic lesions (98% vs. 77%). In conclusion, 18F-Alfatide II PET/CT can be used to detect skeletal and bone marrow metastases, with nearly 100% sensitivity in osteolytic, mixed and bone marrow lesions. The sensitivity of 18F-Alfatide II PET/CT in osteoblastic metastases is relatively low but still significantly higher than that of 18F-FDG PET/CT. This pilot clinical study warrants the further application of 18F-Alfatide II PET/CT in metastatic lesion detection, patient management and drug therapy response monitoring.
doi:10.7150/thno.12938
PMCID: PMC4508500  PMID: 26199649
RGD peptide; Alfatide II; FDG; PET/CT; bone metastasis
22.  Acetylcholinesterase-Catalyzed Hydrolysis Allows Ultrasensitive Detection of Pathogens with the Naked Eye** 
Angewandte Chemie (International ed. in English)  2013;52(52):10.1002/anie.201307952.
This paper describes a rapid diagnostic platform for pathogen detection based on the acetylcholinesterase-catalyzed hydrolysis reaction. Owing to the signal amplification strategies, the sensitivity of this assay is comparable to that of PCR. In addition, the readout of this assay is based on the color change of solutions, which can be easily observed by the naked eye alone.
doi:10.1002/anie.201307952
PMCID: PMC3874880  PMID: 24155243
acetylcholinesterase-catalyzed hydrolysis; pathogen detection; high-sensitivity; gold nanoparticle; clinical samples
23.  Biodegradable Gold Nanovesicles with Ultra-Strong Plasmonic Coupling Effect for Photoacoustic Imaging and Photothermal Therapy** 
Hierarchical assembling of gold nanoparticles (GNPs) allows one to engineer the localized surface plasmon resonance (LSPR) peaks to the near-infrared (NIR) region for enhanced photothermal Therapy (PTT). Herein we report a novel theranostic platform based on biodegradable plasmonic gold nanovesicles for photoacoustic (PA) Imaging and PTT. The disulfide bond (S-S) termed PEG-b-PCL block copolymer graft allows dense packing of GNPs during the assembly process and induces ultra-strong plasmonic coupling effect between adjacent GNPs. The strong NIR absorption induced by plasmon coupling and very high photothermal conversion efficiency (η= 37 %) enable simultaneous thermal/PA imaging and enhanced PTT efficacy with improved clearance of the dissociated particles after the completion of PTT. These vesicle-architectures assembling of various nanocrystals with tailored optical, magnetic, and electronic properties opens new possibilities for constructing multifunctional biodegradable platforms for biomedical applications, particularly in cancer theranotics.
doi:10.1002/anie.201308986
PMCID: PMC4058316  PMID: 24318645
Theranostics; Biodegradable block co-polymer; Gold Nanovesicles; Plasmonic Coupling Effect; Photoacoustic Imaging; Photothermal Therapy
24.  18F-Alfatide II and 18F-FDG Dual Tracer Dynamic PET for Parametric, Early Prediction of Tumor Response to Therapy 
A single dynamic PET acquisition using multiple tracers administered closely in time could provide valuable complementary information about a tumor’s status under quasi-constant conditions. This study aims to investigate the utility of dual-tracer dynamic PET imaging with 18F-Alfatide II (18F-AlF-NOTA-E[PEG4-c(RGDfk)]2) and 18F-FDG for parametric monitoring of tumor responses to therapy.
Methods
We administered doxorubicin to one group of athymic nude mice with U87MG tumors and Abraxane to another group of mice with MDA-MB-435 tumors. To monitor therapeutic responses, we performed dual-tracer dynamic imaging, in sessions that lasted 90 min, starting by injecting the mice via tail vein catheters with 18F-Alfatide II, followed 40 minutes later by 18F-FDG. To achieve signal separation of the two tracers, we fit a three-compartment reversible model to the time activity curve (TAC) of 18F-Alfatide II for the 40 min prior to 18F-FDG injection, and then extrapolated to 90 min. The 18F-FDG tumor TAC was isolated from the 90 min dual tracer tumor TAC by subtracting the fitted 18F-Alfatide II tumor TAC. With separated tumor TACs, the 18F-Alfatide II binding potential (Bp=k3/k4) and volume of distribution (VD), and 18F-FDG influx rate ((K1×k3)/(k2 + k3)) based on the Patlak method were calculated to validate the signal recovery in a comparison with 60-min single tracer imaging and to monitor therapeutic response.
Results
The transport and binding rate parameters K1-k3 of 18F-Alfatide II, calculated from the first 40 min of dual tracer dynamic scan, as well as Bp and VD, correlated well with the parameters from the 60 min single tracer scan (R2 > 0.95). Compared with the results of single tracer PET imaging, FDG tumor uptake and influx were recovered well from dual tracer imaging. Upon doxorubicin treatment, while no significant changes in static tracer uptake values of 18F-Alfatide II or 18F-FDG were observed, both 18F-Alfatide II Bp and 18F-FDG influx from kinetic analysis in tumors showed significant decreases. For Abraxane therapy of MDA-MB-435 tumors, significant decrease was only observed with 18F-Alfatide II Bp value from kinetic analysis but not 18F-FDG influx.
Conclusion
The parameters fitted with compartmental modeling from the dual tracer dynamic imaging are consistent with those from single tracer imaging, substantiating the feasibility of this methodology. Even though no significant differences in tumor size were found until 5 days after doxorubicin treatment started, at day 3 there were already substantial differences in 18F-Alfatide II Bp and 18F-FDG influx rate. Dual tracer imaging can measure 18F-Alfatide II Bp value and 18F-FDG influx simultaneously to evaluate tumor angiogenesis and metabolism. Such changes are known to precede anatomical changes, and thus parametric imaging may offer the promise of early prediction of therapy response.
doi:10.2967/jnumed.113.122069
PMCID: PMC4209961  PMID: 24232871
dual-tracer dynamic PET; parametric imaging; 18F-Alfatide II; 18F-FDG; therapy response
25.  Resistin disrupts glycogen synthesis under high insulin and high glucose levels by down-regulating the hepatic levels of GSK3β 
Gene  2013;529(1):50-56.
The effect of mouse resistin on hepatic insulin resistance in vivo and in vitro, and its possible molecular mechanism were examined. Focusing on liver glycogen metabolism and gluconeogenesis, which are important parts of glucose metabolism, in primary cultures of rat hepatocytes we found that glycogen content was significantly lower (P<0.05) after treatment with recombinant murine resistin only in the presence of insulin plus glucose stimulation. Protein levels of factors in the insulin signaling pathway involved in glycogen synthesis were examined by Western blot analysis, with the only significant change observed being the level of phosphorylated (at Ser 9) glycogen synthase kinase-3β (GSK-3β) (P<0.001). No differences in the protein levels for the insulin receptor β (IRβ), insulin receptor substrates (IRS1 and IRS2), phosphatidylinositol 3-kinase (PI3K), protein kinase B (Akt) or their phosphorylated forms were observed between control and resistin treated primary rat hepatocytes. In a mouse model with high liver-specific expression of resistin, fasting blood glucose levels and liver glycogen content changed. Fasting blood glucose levels were significantly higher (P<0.001) in the model mice, compared to the control mice, while the glycogen content of the liver tissue was about 60% of that of the control mice (P<0.05). The gluconeogenic response was not altered between the experimental and control mice. The level of phosphorylated GSK-3β in the liver tissue was also decreased (P<0.05) in the model mice, consistent with the results from the primary rat hepatocytes. Our results suggests that resistin reduces the levels of GSK-3β phosphorylated at Ser 9 leading to impaired hepatic insulin action in primary rat hepatocytes and in a mouse model with high liver-specific expression of resistin.
doi:10.1016/j.gene.2013.06.085
PMCID: PMC3897445  PMID: 23860320 CAMSID: cams3833
Resistin; Insulin resistance; Glycogen synthase kinase-3β (GSK-3β); Liver

Results 1-25 (117)