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1.  Enhanced Fluorescence Imaging Guided Photodynamic Therapy of Sinoporphyrin Sodium Loaded Graphene Oxide 
Biomaterials  2014;42:94-102.
Extensive research indicates that graphene oxide (GO) can effectively deliver photosensitives (PSs) by π-π stacking for photodynamic therapy (PDT). However, due to the tight complexes of GO and PSs, the fluorescence of PSs are often drastically quenched via an energy/charge transfer process, which limits this GO-PS system for photodiagnostics especially in fluorescence imaging. To solve this problem, we herein strategically designed and prepared a novel photo-theranostic agent based on sinoporphyrin sodium (DVDMS) loaded PEGylated GO (GO-PEG-DVDMS) with improved fluorescence property for enhanced optical imaging guided PDT. The fluorescence of loaded DVDMS is drastically enhanced via intramolecular charge transfer. Meanwhile, the GO-PEG vehicles can significantly increase the tumor accumulation efficiency of DVDMS and lead to an improved photodynamic therapy (PDT) efficacy as compared to DVDMS alone. The cancer theranostic capability of the as-prepared GO-PEG-DVDMS was carefully investigated both in vitro and in vivo. Most intriguingly, 100% in vivo tumor elimination was achieved by intravenous injection of GO-PEG-DVDMS (2 mg/kg of DVDMS, 50 J) without tumor recurrence, loss of body weight or other noticeable toxicity. This novel GO-PEG-DVDMS theranostics is well suited for enhanced fluorescence imaging guided PDT.
doi:10.1016/j.biomaterials.2014.11.040
PMCID: PMC4280503  PMID: 25542797
photosensitizer; sinoporphyrin sodium (DVDMS); PEGylated grapheme oxide (GO); photodynamic therapy; near-infrared fluorescence imaging
2.  Biomimetic RNA Silencing Nanocomplexes Overcome Multidrug Resistance in Cancer Cells** 
RNA interference (RNAi) is an RNA-dependent gene silencing approach controlled by RNA-induced silencing complex (RISC). Here we represent a synthetic RISC-mimic nanocomplex, which can actively cleave its target RNA in a sequence-specific manner. With high enzymatic stability and efficient self-delivery to target cells, the designed nanocomplex can selectively and potently induce gene silencing without cytokine activation. The nanocomplexes targeting to multidrug resistance are able to not only bypass P-glycoprotein (Pgp) transporter due to their nano-size effect, but also effectively suppress the Pgp expression, thus resulting in successful restoration of drug sensitivity of OVCAR8/ADR cells to Pgp-transportable cytotoxic agents. This nanocomplex approach has the potential for both functional genomics and cancer therapy.
doi:10.1002/anie.201309985
PMCID: PMC4709245  PMID: 24446433
Nanocomplex; Biomimetic; Gene regulation; Multidrug resistance; Gold nanoparticle
3.  Clinical Application of Radiolabeled RGD Peptides for PET Imaging of Integrin αvβ3 
Theranostics  2016;6(1):78-92.
Molecular imaging for non-invasive assessment of angiogenesisis is of great interest for clinicians because of the wide-spread application of anti-angiogenic cancer therapeutics. Besides, many other interventions that involve the change of blood vessel/tumor microenvironment would also benefit from such imaging strategies. Of the imaging techniques that target angiogenesis, radiolabeled Arg-Gly-Asp (RGD) peptides have been a major focus because of their high affinity and selectivity for integrin αvβ3--one of the most extensively examined target of angiogenesis. Since the level of integrin αvβ3 expression has been established as a surrogate marker of angiogenic activity, imaging αvβ3 expression can potentially be used as an early indicator of effectiveness of antiangiogenic therapy at the molecular level. In this review, we summarize RGD-based PET tracers that have already been used in clinical trials and intercompared them in terms of radiosynthesis, dosimetry, pharmacokinetics and clinical applications. A perspective of their future use in the clinic is also provided.
doi:10.7150/thno.13242
PMCID: PMC4679356  PMID: 26722375
Angiogenesis; RGD; PET; clinical translation
4.  Chemical Conjugation of Evans Blue Derivative: A Strategy to Develop Long-Acting Therapeutics through Albumin Binding 
Theranostics  2016;6(2):243-253.
The efficacy of therapeutic drugs is highly dependent on their optimal in vivo pharmacokinetics. Albumin conjugation is considered to be one of the most effective means of protracting the short lifespan of peptides and proteins. In this study, we proposed a novel platform for developing long lasting therapeutics by conjugating a small molecular albumin binding moiety, truncated Evans blue, to either peptides or proteins. Using the anti-diabetic peptide drug Exendin-4 as a model peptide, we synthesized a new long-acting Exendin-4 derivative (denoted as Abextide). Through complexation with albumin in situ, the biological half-life of Abextide was significantly extended. The hypoglycemic effect of Abextide was also improved remarkably over Exendin-4. Thus, Abextide has considerable potential to treat type 2 diabetes. This strategy as a general technology platform can be applied to other small molecules and biologics for the development of long-acting therapeutic drugs.
doi:10.7150/thno.14322
PMCID: PMC4729772  PMID: 26877782
Exendin-4; Evans blue; Albumin-binding; PET; Abextide
5.  Intrinsically Radioactive [64Cu]CuInS/ZnS Quantum Dots for PET and Optical Imaging: Improved Radiochemical Stability and Controllable Cerenkov Luminescence 
ACS Nano  2014;9(1):488-495.
Functionalized quantum dots (QDs) have been widely explored for multimodality bioimaging and proven to be versatile agents. Attaching positron-emitting radioisotopes onto QDs not only endows their positron emission tomography (PET) functionality, but also results in self-illuminating QDs, with no need for an external light source, by Cerenkov resonance energy transfer (CRET). Traditional chelation methods have been used to incorporate the radionuclide, but these methods are compromised by the potential for loss of radionuclide due to cleavage of the linker between particle and chelator, decomplexation of the metal, and possible altered pharmacokinetics of nanomaterials. Herein, we described a straightforward synthesis of intrinsically radioactive [64Cu]CuInS/ZnS QDs by directly incorporating 64Cu into CuInS/ZnS nanostructure with 64CuCl2 as synthesis precursor. The [64Cu]CuInS/ZnS QDs demonstrated excellent radiochemical stability with less than 3% free 64Cu detected even after exposure to serum containing EDTA (5 mM) for 24 h. PEGylation can be achieved in situ during synthesis, and the PEGylated radioactive QDs showed high tumor uptake (10.8% ID/g) in a U87MG mouse xenograft model. CRET efficiency was studied as a function of concentration and 64Cu radioactivity concentration. These [64Cu]CuInS/ZnS QDs were successfully applied as an efficient PET/self-illuminating luminescence in vivo imaging agents.
doi:10.1021/nn505660r
PMCID: PMC4310640  PMID: 25549258
quantum dots; CRET; CuInS/ZnS; PET imaging; dual-modality imaging
6.  Engineering interface-type resistive switching in BiFeO3 thin film switches by Ti implantation of bottom electrodes 
Scientific Reports  2015;5:18623.
BiFeO3 based MIM structures with Ti-implanted Pt bottom electrodes and Au top electrodes have been fabricated on Sapphire substrates. The resulting metal-insulator-metal (MIM) structures show bipolar resistive switching without an electroforming process. It is evidenced that during the BiFeO3 thin film growth Ti diffuses into the BiFeO3 layer. The diffused Ti effectively traps and releases oxygen vacancies and consequently stabilizes the resistive switching in BiFeO3 MIM structures. Therefore, using Ti implantation of the bottom electrode, the retention performance can be greatly improved with increasing Ti fluence. For the used raster-scanned Ti implantation the lateral Ti distribution is not homogeneous enough and endurance slightly degrades with Ti fluence. The local resistive switching investigated by current sensing atomic force microscopy suggests the capability of down-scaling the resistive switching cell to one BiFeO3 grain size by local Ti implantation of the bottom electrode.
doi:10.1038/srep18623
PMCID: PMC4686890  PMID: 26692104
7.  Bioinspired Nanocomplex for Spatiotemporal Imaging of Sequential mRNA Expression in Differentiating Neural Stem Cells 
ACS Nano  2014;8(12):12386-12396.
Messenger RNA plays a pivotal role in regulating cellular activities. The expression dynamics of specific mRNA contains substantial information on the intracellular milieu. Unlike the imaging of stationary mRNAs, real-time intracellular imaging of the dynamics of mRNA expression is of great value for investigating mRNA biology and exploring specific cellular cascades. In addition to advanced imaging methods, timely extracellular stimulation is another key factor in regulating the mRNA expression repertoire. The integration of effective stimulation and imaging into a single robust system would significantly improve stimulation efficiency and imaging accuracy, producing fewer unwanted artifacts. In this study, we developed a multifunctional nanocomplex to enable self-activating and spatiotemporal imaging of the dynamics of mRNA sequential expression during the neural stem cell differentiation process. This nanocomplex showed improved enzymatic stability, fast recognition kinetics, and high specificity. With a mechanism regulated by endogenous cell machinery, this nanocomplex realized the successive stimulating motif release and the dynamic imaging of chronological mRNA expression during neural stem cell differentiation without the use of transgenetic manipulation. The dynamic imaging montage of mRNA expression ultimately facilitated genetic heterogeneity analysis. In vivo lateral ventricle injection of this nanocomplex enabled endogenous neural stem cell activation and labeling at their specific differentiation stages. This nanocomplex is highly amenable as an alternative tool to explore the dynamics of intricate mRNA activities in various physiological and pathological conditions.
doi:10.1021/nn505047n
PMCID: PMC4278684  PMID: 25494492
mRNA; imaging; gold nanoparticle; drug delivery; neural stem cell
8.  PET and NIR Optical Imaging Using Self-Illuminating 64Cu-Doped Chelator-Free Gold Nanoclusters 
Biomaterials  2014;35(37):9868-9876.
Self-illuminating fluorescence imaging without autofluorescence background interference has recently aroused more research interests in molecular imaging. Currently, only a few self-illuminating probes were developed, based mainly on toxic quantum dots such as CdSe, CdTe. Herein, we report a novel design of nontoxic self-illuminating gold nanocluster (64Cu-doped AuNCs) for dual-modality positron emission tomography (PET) and near-infrared (NIR) fluorescence imaging based on Cerenkov resonance energy transfer (CRET). PET radionuclide 64Cu was introduced by a chelator-free doping method, which played dual roles as the energy donor and the PET imaging source. Meanwhile, AuNCs acted as the energy acceptor for NIR fluorescence imaging. 64Cu-doped AuNCs exhibited efficient CRET-NIR and PET imaging both in vitro and in vivo. In a U87MG glioblastoma xenograft model, 64Cu-doped AuNCs showed high tumor uptake (14.9%ID/g at 18 h) and produced satisfactory tumor self-illuminating NIR images in the absence of external excitation. This self-illuminating nanocluster with non-toxicity and good biocompatibility can be employed as a novel imaging contrast agent for biomedical applications, especially for molecular imaging.
doi:10.1016/j.biomaterials.2014.08.038
PMCID: PMC4180787  PMID: 25224367
9.  Early-Stage Imaging of Nanocarrier-Enhanced Chemotherapy Response in Living Subjects by Scalable Photoacoustic Microscopy 
ACS Nano  2014;8(12):12141-12150.
Conventional evaluation methods of chemotherapeutic efficacy such as tissue biopsy and anatomical measurement are either invasive with potential complications or dilatory to capture the rapid pathological changes. Here, a sensitive and resolution-scalable photoacoustic microscopy (PAM) with theranostic nanoformulation was developed to noninvasively monitor the therapy response in a timely manner. Ultrasmall graphene oxide nanosheets were designed as both drug-loading vehicle and photoacoustic signal amplifier to the tumor. With the signal enhancement by the injected contrast agents, the subtle microvascular changes of the chemotherapy response in tumor were advantagely revealed by our PAM system, which was much earlier than the morphological measurement by standard imaging techniques. High tumor uptake of the enhanced nanodrug with Cy5.5 labeling was validated by fluorescence imaging. At different observation scales, PAM offered unprecedented sensitivity of optical absorption and high spatial resolution over optical imaging. Our studies demonstrate the PAM system with synergistic theranostic strategy to be a multiplexing platform for tumor diagnosis, drug delivery, and chemotherapy response monitoring at a very early stage and in an effective way.
doi:10.1021/nn505989e
PMCID: PMC4278693  PMID: 25406986
early prediction; chemotherapy response; nanocarrier; photoacoustic microscopy; scalable imaging; graphene oxide; signal amplification
10.  VEGF-loaded graphene oxide as theranostics for multi-modality imaging-monitored targeting therapeutic angiogenesis of ischemic muscle† 
Nanoscale  2013;5(15):6857-6866.
Herein we report the design and synthesis of multifunctional VEGF-loaded IR800-conjugated graphene oxide (GO-IR800-VEGF) for multi-modality imaging-monitored therapeutic angiogenesis of ischemic muscle. The as-prepared GO-IR800-VEGF positively targets VEGF receptors, maintains an elevated level of VEGF in ischemic tissues for a prolonged time, and finally leads to remarkable therapeutic angiogenesis of ischemic muscle. Although more efforts are required to further understand the in vivo behaviors and the long-term toxicology of GO, our work demonstrates the success of using GO for efficient VEGF delivery in vivo by intravenous administration and suggests the great promise of using graphene oxide in theranostic applications for treating ischemic disease.
doi:10.1039/c3nr01573d
PMCID: PMC4607062  PMID: 23770832
11.  Protein-Based Photothermal Theranostics for Imaging-Guided Cancer Therapy 
Nanoscale  2015;7(39):16330-16336.
Development of imageable photothermal theranostics has attracted considerable attention for imaging guided photothermal therapy (PTT) with high tumor ablation accuracy. In this study, we strategically constructed a near-infrared (NIR) cyanine dye by introducing a rigid cyclohexenyl ring to the heptamethine chain to obtain a heptamethine dye CySCOOH with high fluorescence intensity and good stability. By covalent conjugation of CySCOOH onto human serum albumin (HSA), the as-prepared HSA@CySCOOH nanoplatform is highly efficient for NIR fluorescence/photoacoustic/thermal multimodality imaging and photothermal tumor ablation. The theranostic capability of HSA@CySCOOH was systematically evaluated both in vitro and in vivo. Most intriguingly, complete tumor elimination was achieved by intravenous injection of HSA@CySCOOH (CySCOOH, 1 mg/kg; 808 nm, 1.0 W/cm2 for 5 min) on 4T1 tumor-bearing mice, with no weight loss, noticeable toxicity, or tumor recurrence being observed. This as-prepared protein-based nanotheranostics exhibits high water dispersibility, no off target cytotoxicity, good biodegradability and biocompatibility, thus facilitating its clinical translation for cancer photothermal theranostics.
doi:10.1039/c5nr04428f
PMCID: PMC4599582  PMID: 26382146
12.  Dye Loaded Ferritin Nanocages for Multimodal Imaging and Photothermal Therapy 
doi:10.1002/adma.201400914
PMCID: PMC4215197  PMID: 25123089
Theranostics; ferritin; IR820; ICG; fluorescence imaging; photoacoustic imaging; photothermal therapy
13.  Novel 19F Activatable Probe for the Detection of Matrix Metalloprotease-2 Activity by MRI/MRS 
Molecular Pharmaceutics  2014;11(11):4208-4217.
Matrix metalloproteases (MMPs) have been found to be highly expressed in a variety of malignant tumor tissues. Noninvasive visualization of MMP activity may play an important role in the diagnosis of MMP associated diseases. Here we report the design and synthesis of a set of fluorine-19 dendron-based magnetic resonance imaging (MRI) probes for real-time imaging of MMP-2 activity. The probes have the following features: (a) symmetrical fluorine atoms; (b) the number of fluorine atoms can be increased through facile chemical modification; (c) readily accessible peptide sequence as the MMP-2 substrate; (d) activatable 19F signal (off/on mode) via paramagnetic metal ion incorporation. Following optimization for water solubility, one of the probes was selected to evaluate MMP-2 activity by 19F magnetic resonance spectroscopy (MRS). Our results showed that the fluorine signal increased by 8.5-fold in the presence of MMP-2. The specific cleavage site was verified by mass spectrometry. The selected probe was further applied to detect secreted MMP-2 activity of living SCC7 squamous cell carcinoma cells. The fluorine signal was increased by 4.8-fold by MRS analysis after 24 h incubation with SCC7 cells. This type of fluorine probe can be applied to evaluate other enzyme activities by simply tuning the substrate structures. This symmetrical fluorine dendron-based probe design extends the scope of the existing 19F MRI agents and provides a simple but robust method for real-time 19F MRI application.
doi:10.1021/mp500443x
PMCID: PMC4224523  PMID: 25271556
19F magnetic resonance imaging; 19F magnetic resonance spectroscopy; activatable probe; matrix metalloproteases
14.  The Role of Molecular Imaging in Drug Delivery 
The parallel development of molecular imaging and drug delivery allows the combination of therapeutic agents with imaging moieties, which facilitates visualisation of the drug delivery process and provides a realtime readout on the in vivo efficacy of a therapeutic agent. Although challenging, it is feasible to construct a highly versatile, multifunctional single ‘theranostic’ probe for quantitative molecular imaging, targeted drug delivery and controlled drug release to obtain an effective therapeutic response. Compared with conventional methods for the evaluation of pharmacokinetics/pharmacodynamics, molecular imaging has advantages such as substantially decreasing the workload and increasing the volume of more precise data with statistical relevance. More importantly, molecular imaging techniques bridge the gap between pre-clinical and clinical research to develop candidate drugs that have the optimal target specificity, pharmacodynamics and efficacy. With the advancement and integration of technology in various fields, diverse types of targeted imaging probe coupled with drug delivery potential have been developed. Preliminary data have demonstrated that it is feasible and promising to use these targeted carriers for simultaneous target imaging and drug delivery.
PMCID: PMC4589172  PMID: 26435748
Drug delivery; molecular imaging; positron emission tomography (PET); single photon emission computed tomography (SPECT); ultrasound; magnetic resonance imaging (MRI)
15.  In Vivo Labeling of Serum Albumin for PET 
The purpose of this study was to develop a novel in vivo albumin-labeling method to allow PET of cardiac function after myocardial infarction and vascular leakage and increased permeability in inflammatory diseases and malignant tumors.
Methods
To label albumin in vivo, we synthesized a NOTA (1,4,7-triazacyclononane-N,N′, N″-triacetic acid)-conjugated truncated form of Evans blue (NEB). 18F labeling was achieved by the formation of an 18F-aluminum fluoride (18F-AlF) complex, and 64Cu labeling was obtained by a standard chelation method. Sixty-minute dynamic PET imaging was performed on normal mice to evaluate the distribution of 18F-AlF-NEB, which was compared with in vitro–labeled mouse serum albumin (18F-fluorobenzyl-MSA). Electrocardiography-gated PET imaging was performed in a mouse model of myocardial infarction. Both dynamic and static PET scans were obtained in a mouse inflammation model induced by local injection of turpentine to evaluate vascular leakage. Tumor permeability was studied by dynamic and late-point static PET using 64Cu-NEB in a UM-22B xenograft model.
Results
NEB was successfully synthesized, and 18F labeling including work-up took about 20–30 min, with a radiochemical purity greater than 95% without the need for high-performance liquid chromatography purification. Most of the radioactivity was retained in the circulation system at 60 min after injection (26.35 ± 1.52 percentage injected dose per gram [%ID/g]). With electrocardiography-gated PET, ventricles of the heart and major arteries were clearly visualized. The myocardial infarction mice showed much lower left ventricular ejection fraction than the control mice. Inflammatory muscles showed significantly higher tracer accumulation than the contralateral healthy ones. UM-22B tumor uptake of 64Cu-NEB gradually increased with time (5.73 ± 1.11 %ID/g at 1 h and 8.03 ± 0.77 %ID/g at 2 h after injection).
Conclusion
The distribution and local accumulation of serum albumin can be noninvasively visualized and quantified by 18F-AlF-NEB and 64Cu-NEB PET. The simple labeling and broad applications make these imaging probes attractive for clinical translation.
doi:10.2967/jnumed.114.139642
PMCID: PMC4576845  PMID: 24842890
serum albumin; in vivo labeling; Evans blue; PET; vascular permeability
16.  Boramino acid as a marker for amino acid transporters 
Science Advances  2015;1(8):e1500694.
A new class of boramino acids (BAAs) has been developed as the general marker for imaging the expression of amino acid transporters.
Amino acid transporters (AATs) are a series of integral channels for uphill cellular uptake of nutrients and neurotransmitters. Abnormal expression of AATs is often associated with cancer, addiction, and multiple mental diseases. Although methods to evaluate in vivo expression of AATs would be highly useful, efforts to develop them have been hampered by a lack of appropriate tracers. We describe a new class of AA mimics—boramino acids (BAAs)—that can serve as general imaging probes for AATs. The structure of a BAA is identical to that of the corresponding natural AA, except for an exotic replacement of the carboxylate with -BF3−. Cellular studies demonstrate strong AAT-mediated cell uptake, and animal studies show high tumor-specific accumulation, suggesting that BAAs hold great promise for the development of new imaging probes and smart AAT-targeting drugs.
doi:10.1126/sciadv.1500694
PMCID: PMC4643766  PMID: 26601275
Biology; amino acids
18.  [18F]DPA-714 PET Imaging of AMD3100 Treatment in a Mouse Model of Stroke 
Molecular Pharmaceutics  2014;11(10):3463-3470.
Chemokine receptor 4 and stromal-cell-derived factor 1 have been found to be related to the initiation of neuroinflammation in ischemic brain. Herein, we aimed to monitor the changes of neuorinflammation after AMD3100 treatment using a translocator protein (TSPO) specific PET tracer in a mouse model of stroke. The transient MCAO model was established with Balb/C mice. The success of the model was confirmed by magnetic resonance imaging and FDG PET. The treatment started the same day after surgery via daily intraperitoneal injection of 1 mg of AMD3100/kg for three consecutive days. [18F]DPA-714 was used as the TSPO imaging tracer. In vivo PET was performed at different time points after surgery in both control and treated mice. Ex vivo histological and immunofluorescence staining of brain slices was performed to confirm the lesion site and inflammatory cell activation. The TSPO level was also evaluated using Western blotting. Longitudinal PET scans revealed that the level of [18F]DPA-714 uptake was significantly increased in the ischemic brain area with a peak accumulation at around day 10 after surgery, and the level of uptake remained high until day 16. The in vivo PET data were consistent with those from ex vivo immunofluorescence staining. After AMD3100 treatment, the signal intensity was significantly decreased compared with that of normal saline-treated control group. In conclusion, TSPO-targeted PET imaging using [18F]DPA-714 can be used to monitor inflammatory response after stroke and provide a useful method for evaluating the efficacy of anti-inflammation treatment.
doi:10.1021/mp500234d
PMCID: PMC4186675  PMID: 25157648
stroke; AMD3100; translocator protein (TSPO); DPA-714; PET
19.  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
20.  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
21.  Optimal cytoreductive surgery for underlying ovarian cancer associated with deep venous thrombosis without placement of inferior vena cava filter: A case report and literature review 
Oncology Letters  2015;10(4):2579-2583.
Ovarian cancer associated with deep venous thrombosis (DVT) is an uncommon, potentially life-threatening condition. The primary therapeutic strategy for the treatment of this condition is up-front primary cytoreductive surgery, with placement of an inferior vena cava (IVC) filter prior to surgery to prevent fatal pulmonary embolism. The present study describes the case of a 49-year-old female, who presented with DVT unresponsive to anticoagulant therapy in the lower extremities prior to the diagnosis of ovarian cancer. During the search for the underlying malignancy, transvaginal sonography (TVS) revealed a cystic solid mass in the pelvic cavity. Subsequently, the patient underwent up-front primary cytoreductive surgery without placement of a preoperative IVC filter, followed by six cycles of chemotherapy. The patient was diagnosed with ovarian clear cell adenocarcinoma stage IIIC, complicated by DVT, and had survived >3 years without relapse at the time of completion of the present study. The successful outcome of the present case demonstrated that occult primary cancer should be suspected in patients with DVT unresponsive to anticoagulant therapy. The present study also indicated that up-front primary cytoreductive surgery without placement of an IVC filter represents an effective potential strategy for the treatment of advanced ovarian cancer associated with DVT, as the thrombus strongly adheres to the vessel wall following organization.
doi:10.3892/ol.2015.3497
PMCID: PMC4579976  PMID: 26622893
deep venous thrombosis; inferior vena cava filter; ovarian cancer; up-front primary cytoreductive surgery
22.  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
23.  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
25.  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

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