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author:("Chen, xiaoyan")
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.  Carbon dots based two-photon visible nanocarriers for safe and highly efficient delivery of siRNA and DNA 
Advanced healthcare materials  2014;3(8):1203-1209.
The emergence of photoluminescent carbon-based nanomaterials offers great potential for a wide variety of biomedical applications such as fluorescence imaging and cellular labeling. This report illustrates a novel photonic carbon dot (Cdots) based nanocarrier by using low molecular weight amphiphilic PEI (Alkyl-PEI2k) for surface passivation. The resulting water-dispersible Alkyl-PEI2k-Cdot nanocarrier possesses good stability, monodispersity with narrow size distribution and fluorescence properties. In addition, Alkyl-PEI2k-Cdot nanocarrier has a markedly low toxicity and good gene transfection effect in vitro and in vivo. Considering its low cytotoxicity, high gene delivery efficiency and fluorescence performance, Alkyl-PEI2k-Cdots could serve as a novel imaging-trackable gene-delivery nanocarrier promising for gene therapy and optical molecular imaging.
doi:10.1002/adhm.201300611
PMCID: PMC4134771  PMID: 24692418
Carbon dots; gene delivery; polyethylenimine; RNA interference; plasmid DNA
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.  Rigid nanoparticle-baseddelivery of anti-cancer siRNA: challenges and opportunities 
Biotechnology advances  2013;32(4):831-843.
Gene therapy is a promising strategy to treat various genetic and acquired diseases. Small interfering RNA (siRNA) is a revolutionary tool for gene therapy and the analysis of gene function. However, the development of a safe, efficient, and targetable non-viral siRNA delivery system remains a major challenge in gene therapy. An ideal delivery system should be able to encapsulate and protect the siRNA cargo from serum proteins, exhibit target tissue and cell specificity, penetrate the cell membrane, and release its cargo in the desired intracellular compartment. Nanomedicine has the potential to deal with these challenges faced by siRNA delivery. The unique characteristics of rigid nanoparticles mostly inorganic nanoparticles and allotropes of carbon nanomaterials, including high surface area, facile surface modification, controllable size, and excellent magnetic/optical/electrical properties, make them promising candidates for targeted siRNA delivery. In this review, recent progresses on rigid nanoparticle-based siRNA delivery systems will be summarized.
doi:10.1016/j.biotechadv.2013.08.020
PMCID: PMC3947394  PMID: 24013011
Gene therapy; RNA interference (RNAi); small-interfering RNA (siRNA); Gene delivery; Nanoparticles
5.  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.  Role of Albumin in the Formation and Stabilization of Nanoparticle Aggregates in Serum Studied by Continuous Photon Correlation Spectroscopy and Multiscale Computer Simulations 
Recently, small (<5 nm diameter) nanoparticles (NPs) have shown improved in vivo biocompatibility compared to that of larger (>10 nm) NPs. However, the fate of small NPs under physiological conditions is poorly understood and remains unexplored. Here, the long-term aggregation behavior of gold nanoparticles (AuNPs) exposed to serum proteins in a near-physiological setup is studied using continuous photon correlation spectroscopy and computer simulations. It is found that the medium, temperature, and NP concentration affect the aggregation of AuNPs, but the observed aggregates are much smaller than previously reported. Simulations show that a single layer of albumin is deposited on the NP surface, but the properties of the aggregates (size, shape, and internal structure) depend critically on the charge distribution on the proteins, which changes with the conditions of the solution. These results explain the seemingly conflicting data reported in the literature regarding the size of aggregates and the morphology of the albumin corona. The simulations suggest that controlling the concentration of NPs as well as the pH and ionic strength of the solution prior to intravenous administration may help to preserve properties of the functionalized NPs in the bloodstream.
doi:10.1021/jp5034068
PMCID: PMC4159775  PMID: 25221633
8.  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
9.  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
10.  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
11.  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
12.  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
13.  Versatile RNA Interference Nanoplatform for Systemic Delivery of RNAs 
ACS Nano  2014;8(5):4559-4570.
Development of nontoxic, tumor-targetable, and potent in vivo RNA delivery systems remains an arduous challenge for clinical application of RNAi therapeutics. Herein, we report a versatile RNAi nanoplatform based on tumor-targeted and pH-responsive nanoformulas (NFs). The NF was engineered by combination of an artificial RNA receptor, Zn(II)-DPA, with a tumor-targetable and drug-loadable hyaluronic acid nanoparticle, which was further modified with a calcium phosphate (CaP) coating by in situ mineralization. The NF can encapsulate small-molecule drugs within its hydrophobic inner core and strongly secure various RNA molecules (siRNAs, miRNAs, and oligonucleotides) by utilizing Zn(II)-DPA and a robust CaP coating. We substantiated the versatility of the RNAi nanoplatform by demonstrating effective delivery of siRNA and miRNA for gene silencing or miRNA replacement into different human types of cancer cells in vitro and into tumor-bearing mice in vivo by intravenous administration. The therapeutic potential of NFs coloaded with an anticancer drug doxorubicin (Dox) and multidrug resistance 1 gene target siRNA (siMDR) was also demonstrated in this study. NFs loaded with Dox and siMDR could successfully sensitize drug-resistant OVCAR8/ADR cells to Dox and suppress OVCAR8/ADR tumor cell proliferation in vitro and tumor growth in vivo. This gene/drug delivery system appears to be a highly effective nonviral method to deliver chemo- and RNAi therapeutics into host cells.
doi:10.1021/nn500085k
PMCID: PMC4046792  PMID: 24779637
RNAi; nanomedicine; gene and drug delivery; hyaluronic acid; cancer therapy
14.  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
15.  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)
17.  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
18.  Stability Analysis of Glutamic Acid Linked Peptides Coupled to NOTA through Different Chemical Linkages 
Molecular Pharmaceutics  2014;11(11):3867-3874.
Glutamic acid is a commonly used linker to form dimeric peptides with enhanced binding affinity than their corresponding monomeric counterparts. We have previously labeled NOTA-Bn-NCS-PEG3-E[c(RGDyK)]2 (NOTA-PRGD2) [1] with [18F]AlF and 68Ga for imaging tumor angiogenesis. The p-SCN-Bn-NOTA was attached to E[c(RGDyK)]2 [2] through a mini-PEG with a thiourea linkage, and the product [1] was stable at radiolabeling condition of 100 °C and pH 4.0 acetate buffer. However, when the same p-SCN-Bn-NOTA was directly attached to the α-amine of E[c(RGDfK)]2 [3], the product NOTA-Bn-NCS-E[c(RGDfK)]2 [4] became unstable under similar conditions and the release of monomeric c(RGDfK) [5] was observed. The purpose of this work was to use HPLC and LC-MS to monitor the decomposition of glutamic acid linked dimeric peptides and their NOTA derivatives. A c(RGDyK) [6] and bombesin (BBN) [7] heterodimer c(RGDyK)-E-BBN [8], and a dimeric bombesin E(BBN)2 [9], both with a glutamic acid as the linker, along with a model compound PhSCN-E[c(RGDfK)] [10] were also studied. All the compounds were dissolved in 0.5 M pH 4.0 acetate buffer at the concentration of 1 mg/mL, and 0.1 mL of each sample was heated at 100 °C for 10 min and the more stable compounds were heated for another 30 min. The samples at both time points were analyzed with analytical HPLC to monitor the decomposition of the heated samples. The samples with decomposition were further analyzed by LC-MS to determine the mass of products from the decomposition for possible structure elucidation. After 10 min heating, the obvious release of c(RGDfK) [5] was observed for NOTA-Bn-NCS-E[c(RGDfK)]2 [4] and Ph-SCN-E[c(RGDfK)] [10]. Little or no release of monomers was observed for the remaining samples at this time point. After further heating, the release of monomers was clearly observed for E[c(RGDyK)]2 [2], E[c(RGDfK)]2 [3], c(RGDyK)-E-BBN [8], and E(BBN)2 [9]. No decomposition or little decomposition was observed for NOTA-Bn-NCS-PEG3-E[c(RGDyK)]2 [1], PEG3-E[c(RGDyK)]2 [11], NOTA-E[c(RGDyK)]2 [12], and NOTA-PEG3-E[c(RGDyK)]2 [13]. The glutamic acid linked dimeric peptides with a free α-amine are labile due to the neighboring amine participation in the hydrolysis. The stability of peptides could be increased by converting the free amine into amide. The instability of thiourea derivatives formed from α-amine was caused by participation of thiol group derived from thiourea.
doi:10.1021/mp400706q
PMCID: PMC4224566  PMID: 24533430
peptide; glutamate linker; thiourea; hydrolysis; Edman degradation
19.  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
20.  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
21.  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.
22.  Kinetic Analysis of Dynamic 11C-Acetate PET/CT Imaging as a Potential Method for Differentiation of Hepatocellular Carcinoma and Benign Liver Lesions 
Theranostics  2015;5(4):371-377.
Objective: The kinetic analysis of 11C-acetate PET provides more information than routine one time-point static imaging. This study aims to investigate the potential of dynamic 11C-acetate hepatic PET imaging to improve the diagnosis of hepatocellular carcinoma (HCC) and benign liver lesions by using compartmental kinetic modeling and discriminant analysis.
Methods: Twenty-two patients were enrolled in this study, 6 cases were with well-differentiated HCCs, 7 with poorly-differentiated HCCs and 9 with benign pathologies. Following the CT scan, all patients underwent 11C-acetate dynamic PET imaging. A three-compartment irreversible dual-input model was applied to the lesion time activity curves (TACs) to estimate the kinetic rate constants K1-k3, vascular fraction (VB) and the coefficient α representing the relative hepatic artery (HA) contribution to the hepatic blood supply on lesions and non-lesion liver tissue. The parameter Ki (=K1×k3/(k2 + k3)) was calculated to evaluate the local hepatic metabolic rate of acetate (LHMAct). The lesions were further classified by discriminant analysis with all the above parameters.
Results: K1 and lesion to non-lesion standardized uptake value (SUV) ratio (T/L) were found to be the parameters best characterizing the differences among well-differentiated HCC, poorly-differentiated HCC and benign lesions in stepwise discriminant analysis. With discriminant functions consisting of these two parameters, the accuracy of lesion prediction was 87.5% for well-differentiated HCC, 50% for poorly-differentiated HCC and 66.7% for benign lesions. The classification was much better than that with SUV and T/L, where the corresponding classification accuracy of the three kinds of lesions was 57.1%, 33.3% and 44.4%.
Conclusion: 11C-acetate kinetic parameter K1 could improve the identification of HCC from benign lesions in combination with T/L in discriminant analysis. The discriminant analysis using static and kinetic parameters appears to be a very helpful method for clinical liver masses diagnosis and staging.
doi:10.7150/thno.10760
PMCID: PMC4329501  PMID: 25699097
11C-Acetate, dynamic PET; hepatocellular carcinoma; kinetic modeling; discriminant analysis
23.  Molecular Magnetic Resonance Imaging of Angiogenesis In Vivo using Polyvalent Cyclic RGD-Iron Oxide Microparticle Conjugates 
Theranostics  2015;5(5):515-529.
Angiogenesis is an essential component of tumour growth and, consequently, an important target both therapeutically and diagnostically. The cell adhesion molecule αvβ3 integrin is a specific marker of angiogenic vessels and the most prevalent vascular integrin that binds the amino acid sequence arginine-glycine-aspartic acid (RGD). Previous studies using RGD-targeted nanoparticles (20-50 nm diameter) of iron oxide (NPIO) for magnetic resonance imaging (MRI) of tumour angiogenesis, have identified a number of limitations, including non-specific extravasation, long blood half-life (reducing specific contrast) and low targeting valency. The aim of this study, therefore, was to determine whether conjugation of a cyclic RGD variant [c(RGDyK)], with enhanced affinity for αvβ3, to microparticles of iron oxide (MPIO) would provide a more sensitive contrast agent for imaging of angiogenic tumour vessels. Cyclic RGD [c(RGDyK)] and RAD [c(RADyK)] based peptides were coupled to 2.8 μm MPIO, and binding efficacy tested both in vitro and in vivo. Significantly greater specific binding of c(RGDyK)-MPIO to S-nitroso-n-acetylpenicillamine (SNAP)-stimulated human umbilical vein endothelial cells in vitro than PBS-treated cells was demonstrated under both static (14-fold increase; P < 0.001) and flow (44-fold increase; P < 0.001) conditions. Subsequently, mice bearing subcutaneous colorectal (MC38) or melanoma (B16F10) derived tumours underwent in vivo MRI pre- and post-intravenous administration of c(RGDyK)-MPIO or c(RADyK)-MPIO. A significantly greater volume of MPIO-induced hypointensities were found in c(RGDyK)-MPIO injected compared to c(RADyK)-MPIO injected mice, in both tumour models (P < 0.05). Similarly, administration of c(RGDyK)-MPIO induced a greater reduction in mean tumour T2* relaxation times than the control agent in both tumour models (melanoma P < 0.001; colorectal P < 0.0001). Correspondingly, MPIO density per tumour volume assessed immunohistochemically was significantly greater for c(RGDyK)-MPIO than c(RADyK)-MPIO injected animals, in both melanoma (P < 0.05) and colorectal (P < 0.0005) tumours. In both cases, binding of c(RGDyK)-MPIO co-localised with αvβ3 expression. Comparison of RGD-targeted and dynamic contrast enhanced (DCE) MRI assessment of tumour perfusion indicated sensitivity to different vascular features. This study demonstrates specific binding of c(RGDyK)-MPIO to αvβ3 expressing neo-vessels, with marked and quantifiable contrast and rapid clearance of unbound particles from the blood circulation compared to NPIO. Combination of this molecular MRI approach with conventional DCE MRI will enable integrated molecular, anatomical and perfusion tumour imaging.
doi:10.7150/thno.10319
PMCID: PMC4350013  PMID: 25767618
Tumour; angiogenesis; cRGDyK; microparticles; MRI; DCE.
24.  Molecular Imaging of Apoptosis: From Micro to Macro 
Theranostics  2015;5(6):559-582.
Apoptosis, or programmed cell death, is involved in numerous human conditions including neurodegenerative diseases, ischemic damage, autoimmune disorders and many types of cancer, and is often confused with other types of cell death. Therefore strategies that enable visualized detection of apoptosis would be of enormous benefit in the clinic for diagnosis, patient management, and development of new therapies. In recent years, improved understanding of the apoptotic machinery and progress in imaging modalities have provided opportunities for researchers to formulate microscopic and macroscopic imaging strategies based on well-defined molecular markers and/or physiological features. Correspondingly, a large collection of apoptosis imaging probes and approaches have been documented in preclinical and clinical studies. In this review, we mainly discuss microscopic imaging assays and macroscopic imaging probes, ranging in complexity from simple attachments of reporter moieties to proteins that interact with apoptotic biomarkers, to rationally designed probes that target biochemical changes. Their clinical translation will also be our focus.
doi:10.7150/thno.11548
PMCID: PMC4377726  PMID: 25825597
Apoptosis; Microscopic imaging assays; Macroscopic imaging probes; Clinical translation.
25.  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.

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