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author:("Cui, daxing")
1.  Surface Functionalization of Chemically Reduced Graphene Oxide for Targeted Photodynamic Therapy 
In this study, using chemically reduced graphene oxide (GO) as a model nanocarbon, we successfully developed a facile surface-functionalization strategy of nanocarbons to allow both biocompatibility and receptor targeted drug delivery. Polyvinylpyrrolidone (PVP) coating improves aqueous dispersibility and biocompatibility of GO, and provides anchoring sites for ACDCRGDCFCG peptide (RGD4C). Aromatic photosensitizer chlorin e6 (Ce6) can be effectively loaded into the rGO-PVP-RGD system via hydrophobic interactions and π-π stacking. The nanodelivery system can significantly increase the accumulation of Ce6 in tumor cells and lead to an improved photodynamic therapy (PDT) efficacy as compared to Ce6 alone. The facile surface functionalization strategy can be applied to other nanomaterials such as carbon nanotubes, and inorganic nanomaterials.
Graphical Abstract
PMCID: PMC5218590  PMID: 26301305
Graphene Oxide; Polyvinylpyrrolidone; Chlorin e6; RGD; Photodynamic Therapy
2.  Contactless Measurement of Magnetic Nanoparticles on Lateral Flow Strips Using Tunneling Magnetoresistance (TMR) Sensors in Differential Configuration 
Sensors (Basel, Switzerland)  2016;16(12):2130.
Magnetic nanoparticles (MNPs) are commonly used in biomedical detection due to their capability to bind with some specific antibodies. Quantification of biological entities could be realized by measuring the magnetic response of MNPs after the binding process. This paper presents a contactless scanning prototype based on tunneling magnetoresistance (TMR) sensors for quantification of MNPs present in lateral flow strips (LFSs). The sensing unit of the prototype composes of two active TMR elements, which are parallel and closely arranged to form a differential sensing configuration in a perpendicular magnetic field. Geometrical parameters of the configuration are optimized according to theoretical analysis of the stray magnetic field produced by the test line (T-line) while strips being scanned. A brief description of our prototype and the sample preparation is presented. Experimental results show that the prototype exhibits the performance of high sensitivity and strong anti-interference ability. Meanwhile, the detection speed has been improved compared with existing similar techniques. The proposed prototype demonstrates a good sensitivity for detecting samples containing human chorionic gonadotropin (hCG) at a concentration of 25 mIU/mL. The T-line produced by the sample with low concentration is almost beyond the visual limit and produces a maximum stray magnetic field some 0.247 mOe at the sensor in the x direction.
doi:10.3390/s16122130
PMCID: PMC5191110  PMID: 27983659
magnetic nanoparticles; tunneling magnetoresistance (TMR) sensor; differential sensing; lateral flow strip (LFS); magnetic biosensor
3.  Superparamagnetic Fe3O4-PEG2K-FA@Ce6 Nanoprobes for in Vivo Dual-mode Imaging and Targeted Photodynamic Therapy 
Scientific Reports  2016;6:36187.
The development of targeted nanoprobes is a promising approach to cancer diagnostics and therapy. In the present work, a novel multifunctional photo/magnet-diagnostic nanoprobe (MNPs-PEG2K-FA@Ce6) has been developed. This nanoprobe is built using folic acid (FA), bifunctional polyethylene glycol (PEG2K) and photosensitizer chlorin e6 (Ce6). The MNPs-PEG2K-FA@Ce6 nanoprobes are superparamagnetic, can be synthesized on a large scale by a one-pot hydrothermal process without further surface modification and are stable in an aqueous environment for eight months. Compared with free Ce6 nanoprobes in vitro studies, the MNPs-PEG2K-FA@Ce6 nanoprobes significantly enhance cellular uptake efficiency and promote the effectiveness of photodynamic therapy (PDT) with the assistance of 633 nm laser irradiation. The unique nanoprobes show superior penetration and a retention time of more than six days with less accumulation in the liver allowing highly effective tumor recognition and monitoring. Additionally, there was little damage to healthy organs or tissues. These exciting new nanoprobes could be potential building blocks to develop new clinical therapies and translational medicine.
doi:10.1038/srep36187
PMCID: PMC5099938  PMID: 27824072
4.  Chiral Antioxidant-based Gold Nanoclusters Reprogram DNA Epigenetic Patterns 
Scientific Reports  2016;6:33436.
Epigenetic modifications sit ‘on top of’ the genome and influence DNA transcription, which can force a significant impact on cellular behavior and phenotype and, consequently human development and disease. Conventional methods for evaluating epigenetic modifications have inherent limitations and, hence, new methods based on nanoscale devices are needed. Here, we found that antioxidant (glutathione) chiral gold nanoclusters induce a decrease of 5-hydroxymethylcytosine (5hmC), which is an important epigenetic marker that associates with gene transcription regulation. This epigenetic change was triggered partially through ROS activation and oxidation generated by the treatment with glutathione chiral gold nanoclusters, which may inhibit the activity of TET proteins catalyzing the conversion of 5-methylcytosine (5mC) to 5hmC. In addition, these chiral gold nanoclusters can downregulate TET1 and TET2 mRNA expression. Alteration of TET-5hmC signaling will then affect several downstream targets and be involved in many aspects of cell behavior. We demonstrate for the first time that antioxidant-based chiral gold nanomaterials have a direct effect on epigenetic process of TET-5hmC pathways and reveal critical DNA demethylation patterns.
doi:10.1038/srep33436
PMCID: PMC5025748  PMID: 27633378
5.  Dual targeted immunotherapy via in vivo delivery of biohybrid RNAi-peptide nanoparticles to tumour-associated macrophages and cancer cells 
Advanced functional materials  2015;25(27):4183-4194.
Lung cancer is associated with very poor prognosis and considered one of the leading causes of death worldwide. Here, we present highly potent and selective bio-hybrid RNAi-peptide nanoparticles that can induce specific and long-lasting gene therapy in inflammatory tumour associated macrophages (TAMs), via an immune modulation of the tumour milieu combined with tumour suppressor effects. Our data prove that passive gene silencing can be achieved in cancer cells using regular RNAi NPs. When combined with M2 peptide-based targeted immunotherapy that immuno-modulates TAMs cell-population, a synergistic effect and long-lived tumour eradication can be observed along with increased mice survival. Treatment with low doses of siRNA (ED50 0.0025-0.01 mg/kg) in a multi and long-term dosing system substantially reduced the recruitment of inflammatory TAMs in lung tumour tissue, reduced tumour size (∼95%) and increased animal survival (∼75%) in mice. Our results suggest that it is likely that the combination of silencing important genes in tumour cells and in their supporting immune cells in the tumour microenvironment, such as TAMs, will greatly improve cancer clinical outcomes.
Graphical abstract
doi:10.1002/adfm.201501283
PMCID: PMC4914053  PMID: 27340392
tumour-associated macrophages; RNAi; tumour targeting; nanoparticles; lung cancer
6.  Persisting and Increasing Neutrophil Infiltration Associates with Gastric Carcinogenesis and E-cadherin Downregulation 
Scientific Reports  2016;6:29762.
H. pylori-induced chronic inflammation is considered the most important cause of gastric cancer. The actual process how chronic inflammation triggers gastric carcinogenesis is still not clear. In this study, neutrophils and relative markers in gastric cancer development were examined with immunohistochemistry and fluorescence RNA in situ hybridization methods. On average, 24 times more neutrophils were found in gastric cancer tissues and about 9 times more neutrophils were found in gastric intestinal metaplasia tissues comparing to normal gastric tissue controls. CagA+ H. pylori infection in cancer adjacent tissues or EBV infection in cancer tissues did not increase neutrophil infiltration into gastric cancer tissues significantly. Neutrophil density was positively correlated with cell proliferation while negatively correlated with E-cadherin intensity. E-cadherin is also transcriptionally downregulated in gastric cancer tissues comparing to adjacent tissue controls. The increased neutrophils in the gastric cancer tissues appear to be related to increased chemoattractant IL-8 levels. In gastric cancers, neutrophil numbers were higher comparing to cancer adjacent tissues and not associated with patient ages, tumor invasion depth, tumor staging, metastasis or cancer types. The conclusion is that persisting and increasing neutrophil infiltration is associated with E-cadherin downregulation, cell proliferation and gastric carcinogenesis.
doi:10.1038/srep29762
PMCID: PMC4944193  PMID: 27412620
7.  Birth of MTH1 as a therapeutic target for glioblastoma: MTH1 is indispensable for gliomatumorigenesis 
Malignant glioma is the most common primary tumor of the central nervous system. Chemotherapy and radiotherapy are the most common therapeutic approaches in glioma therapy. Both processes mainly kill cancer cells through generating high Reactive Oxygen Species (ROS) and lead to oxidative DNA damage. However, tumor resistance to ROS is always a challenge for cancer treatment. Human Mut T homolog 1 (MTH1, also known as NUDT1) is regarded as a protector of nucleotides against oxidization. Recent reports have verified that overexpression of MTH1 could remove oxidized dNTP pools. Here, we find that MTH1 is overexpressed both at mRNA and protein levels in GBM. MTH1 silencing inhibits colony formation; tumor spheres formation and xenograft tumor growth, and more importantly, the viability of glioma cells is significantly decreased in H2O2 after MTH1 was knocked down in glioma. PI staining show that H2O2 cause more glioma cell death after MTH1 silencing. So we speculate that overexpression of MTH1 is crucial for glioma survival, suppression of its expression can inhibit cancer cell survival in vitro and in vivo, MTH1 may be a potential target for human glioma therapy in future.
PMCID: PMC4931174  PMID: 27398163
GBM; MTH1; reactive oxygen species; viability; stemness
8.  Human CIK Cells Loaded with Au Nanorods as a Theranostic Platform for Targeted Photoacoustic Imaging and Enhanced Immunotherapy and Photothermal Therapy 
How to realize targeted photoacoustic imaging, enhanced immunotherapy, and photothermal therapy of gastric cancer has become a great challenge. Herein, we reported for the first time that human cytokine-induced killer cells (CIK) loaded with gold nanorods were used for targeted photoacoustic imaging, enhanced immunotherapy, and photothermal therapy of gastric cancer. Silica-modified gold nanorods were prepared; then incubated with human cytokine-induced killer cells (CIK), resultant human CIK cells loaded with Au nanorods were evaluated for their cytotoxicity, targeted ability of gastric cancer in vitro and in vivo, immunotherapy, and photothermal therapy efficacy. In vitro cell experiment shows that human CIK cells labeled with gold nanorods actively target gastric cancer MGC803 cells, inhibit growth of MGC803 cells by inducing cell apoptosis, and kill MGC803 cells under low power density near-infrared (NIR) laser treatment (808-nm continuous wave laser, 1.5 W/cm2, 3 min). In vivo experiment results showed that human CIK cells labeled with gold nanorods could target actively and image subcutaneous gastric cancer vessels via photoacoustic imaging at 4 h post-injection, could enhance immunotherapy efficacy by up-regulating cytokines such as IL-1, IL-12, IL-2, IL-4, IL-17, and IFN-γ, and kill gastric cancer tissues by photothermal therapy via direct injection into tumor site under near-infrared (NIR) laser irradiation. High-performance human CIK cells labeled with Au nanorods are a good novel theranostic platform to exhibit great potential in applications such as tumor-targeted photoacoustic imaging, enhanced immunotherapy, and photothermal therapy in the near future.
doi:10.1186/s11671-016-1468-8
PMCID: PMC4894853  PMID: 27271853
Human CIK cell; Gold nanorods; Gastric cancer cell; Immunotherapy; Photothermal therapy; Photoacoustic imaging
9.  CdSe/ZnS Quantum Dot-Labeled Lateral Flow Strips for Rapid and Quantitative Detection of Gastric Cancer Carbohydrate Antigen 72-4 
Carbohydrate antigen 72-4 (CA72-4) is an important biomarker associated closely with diagnosis and prognosis of early gastric cancer. How to realize quick, sensitive, specific, and quantitative detection of CA72-4 in clinical specimens has become a great requirement. Herein, we reported a CdSe/ZnS quantum dot-labeled lateral flow test strip combined with a charge-coupled device (CCD)-based reader was developed for rapid, sensitive, and quantitative detection of CA72-4. Two mouse monoclonal antibodies (mAbs) against CA72-4 were employed. One of them was coated as a test line, while another mAb was labeled with quantum dots and coated onto conjugate pad. The goat anti-mouse IgG was immobilized as a control line. After sample was added, a sandwich structure was formed with CA72-4 and these two mAbs. The fluorescent signal from quantum dots (QD)-labeled mAb in sandwich structure was related to the amount of detected CA72-4. A CCD-based reader was used to realize quantitative detection of CA72-4. Results showed that developed QD-labeled lateral flow strips to detect CA72-4 biomarker with the sensitivity of 2 IU/mL and 10 min detection time. One hundred sera samples from clinical patients with gastric cancer and healthy people were used to confirm specificity of this strip method; results showed that established strip method own 100 % reproducibility and 100 % specificity compared with Roche electrochemiluminescence assay results. In conclusion, CdSe/ZnS quantum dot-labeled lateral flow strips for detection of CA72-4 could realize rapid, sensitive, and specific detection of clinical samples and could own great potential in clinical translation in near future.
doi:10.1186/s11671-016-1355-3
PMCID: PMC4788655  PMID: 26969591
Gastric cancer; CA72-4; CdSe/ZnS quantum dots; Lateral flow strip
10.  Co-delivery of VEGF and bFGF via a PLGA nanoparticle-modified BAM for effective contracture inhibition of regenerated bladder tissue in rabbits 
Scientific Reports  2016;6:20784.
Graft contracture is a common problem associated with the regeneration processes of tissue-engineered bladders. Currently, most strategies used for incorporating bioactive molecules into biomaterial designs do not work during all phases of tissue regeneration. In this study, we used a growth factor-PLGA nanoparticle thermo-sensitive gel system (i.e., BAM with incorporated VEGF and bFGF-loaded PLGA nanoparticles and mixed with a hydrophilic gel) to promote bladder tissue regeneration in a rabbit model. At 4 and 12 weeks after surgery, contracture rate assessment and histological examination were conducted to evaluate bladder tissue regeneration. The results indicated that the functional composite scaffold continuously and effectively released VEGF and bFGF and promoted bladder reconstruction with a significant decrease in graft contracture. In addition, the number and arrangement of regenerated urothelial cells and smooth muscle cells as well as microvascular density and maturity were improved in the VEGF/bFGF nanoparticle group compared with the single factor VEGF or bFGF nanoparticle group and BAM alone. The nanoparticle thermo-sensitive gel system, which exhibited favourable performance, may effectively inhibit graft contracture and promote bladder tissue regeneration in rabbits.
doi:10.1038/srep20784
PMCID: PMC4745101  PMID: 26854200
11.  Simultaneous Quantitative Detection of Helicobacter Pylori Based on a Rapid and Sensitive Testing Platform using Quantum Dots-Labeled Immunochromatiographic Test Strips 
Quantum dots-labeled urea-enzyme antibody-based rapid immunochromatographic test strips have been developed as quantitative fluorescence point-of-care tests (POCTs) to detect helicobacter pylori. Presented in this study is a new test strip reader designed to run on tablet personal computers (PCs), which is portable for outdoor detection even without an alternating current (AC) power supply. A Wi-Fi module was integrated into the reader to improve its portability. Patient information was loaded by a barcode scanner, and an application designed to run on tablet PCs was developed to handle the acquired images. A vision algorithm called Kmeans was used for picture processing. Different concentrations of various human blood samples were tested to evaluate the stability and accuracy of the fabricated device. Results demonstrate that the reader can provide an easy, rapid, simultaneous, quantitative detection for helicobacter pylori. The proposed test strip reader has a lighter weight than existing detection readers, and it can run for long durations without an AC power supply, thus verifying that it possesses advantages for outdoor detection. Given its fast detection speed and high accuracy, the proposed reader combined with quantum dots-labeled test strips is suitable for POCTs and owns great potential in applications such as screening patients with infection of helicobacter pylori, etc. in near future.
doi:10.1186/s11671-016-1254-7
PMCID: PMC4740476  PMID: 26842795
Test strip reader; CMOS; Wi-Fi transmission; Kmeans algorithm; Urea enzymes; QD test strips
12.  A Nanomedicine Approach to Effectively Inhibit Contracture During Bladder Acellular Matrix Allograft-Induced Bladder Regeneration by Sustained Delivery of Vascular Endothelial Growth Factor 
Tissue Engineering. Part A  2014;21(1-2):45-52.
Macroscopic evidence of contracture has been identified as a major issue during the regeneration process. We hypothesize that lack of angiogenesis is the primary cause of contracture and explore a nanomedicine approach to achieve sustained release of vascular endothelial growth factor (VEGF) to stimulate angiogenesis. We evaluate the efficacy of poly(lactic-co-glycolic acid) (PLGA) nanoparticles (NPs) for long-term (3 months) sustained release of VEGF in bladder acellular matrix allografts (BAMA) in a swine model. We anticipate that the sustained release of VEGF could stimulate angiogenesis along the regeneration process and thereby inhibit contracture. Bladder was replaced with BAMA (5×5 cm), modified with PLGA NPs encapsulated with VEGF in a pig model. The time points chosen for sampling were 1, 2, 4, and 12 weeks. The regenerated areas were then measured to obtain the contracture rate, and the extent of revascularization was calculated using histological and morphological features. In the control group of animals, the bladder was replaced with only BAMA. The in vivo release of VEGF was evident for ∼3 months, achieving the goal of long-acting sustained release, and successfully promoted the regeneration of blood vessels and smooth muscle fibers. In addition, less collagen deposition was observed in the experimental group compared with control. Most importantly, the inhibition of contracture was highly significant, and the ultimate contracture rate decreased by ∼57% in the experimental group compared with control. In isolated strips analysis, there were no significant differences between BAMA-regenerated (either VEGF added or not) and autogenous bladder. BAMA modified with VEGF-loaded PLGA-NPs can sustainably release VEGF in vivo (>3 months) to stimulate angiogenesis leading to the inhibition of contracture. This is the first study to report a viable nanomedicine-based strategy to overcome contracture during bladder regeneration induced by BAMA. Furthermore, this study also confirms that insufficient angiogenesis plays a crucial role in the onset of contracture.
doi:10.1089/ten.tea.2013.0671
PMCID: PMC4293130  PMID: 24947133
13.  Near-Infrared Light Triggered ROS-activated Theranostic Platform based on Ce6-CPT-UCNPs for Simultaneous Fluorescence Imaging and Chemo-Photodynamic Combined Therapy 
Theranostics  2016;6(4):456-469.
Many drug controlled release methods have been integrated in multifunctional nanoparticles, such as pH-, redox-, temperature-, enzyme-, and light-responsive release. However, few report is associated with the ROS responsive drug controlled release. Herein, a thioketal linker-based ROS responsive drug (camptothecin conjugated with thioketal linker, abbreviated as TL-CPT) was prepared and the thioketal linker could be cleaved by ROS(reactive oxygen species). To achieve cancer simultaneous optical imaging, photodynamic therapy and chemotherapy, the photosensitizer Chlorin e6(Ce6), TL-CPT and carboxyl-mPEG were loaded on the upconversion nanoparticles (UCNPs), which were named as Ce6-CPT-UCNPs. Under 980 nm laser irradiation, Ce6-CPT-UCNPs emitted a narrow emission band at 645-675 nm which was overlapped with Ce6 absorption peak. Ce6 absorbed the light to produce ROS, which was used for photodynamic therapy and to cleave the thioketal linker in Ce6-CPT-UCNPs to release camptothecin for chemotherapy. Meanwhile, Ce6 absorbed the light, was used for near-infrared fluorescence imaging. The in vivo biodistribution studies showed that the prepared nanoparticles had high orthotopic lung cancer targeting efficiency. The in vivo therapeutic results demonstrated that NCI-H460 lung cancers could be completely eliminated by combining chemo- and photodynamic therapy under 980 nm laser irradiation. The prepared multifunctional Ce6-CPT-UCNPs have great potential in applications such as cancer targeted fluorescent imaging, simultaneous ROS activated chemo- and photodynamic therapy in near future.
doi:10.7150/thno.14101
PMCID: PMC4775857  PMID: 26941840
ROS-sensitive nanoparticles; photodynamic therapy; Camptothecin; UCNPs; orthotopic lung cancer.
14.  ROS-Responsive Mitochondria-Targeting Blended Nanoparticles: Chemo- and Photodynamic Synergistic Therapy for Lung Cancer with On-Demand Drug Release upon Irradiation with a Single Light Source 
Theranostics  2016;6(13):2352-2366.
Mitochondria in cancer cells maintain a more negative membrane potential than normal cells. Mitochondria are the primary source of cellular reactive oxygen species (ROS), which are necessary for photodynamic therapy. Thus, the strategy of targeting mitochondria can maximize the photodynamic therapeutic efficiency for cancer. Here we report, for the first time, synthesis of a new mitochondria-targeting drug delivery system, ZnPc/CPT-TPPNPs. To synthesize this novel compound, polyethylene glycol was functionalized with thioketal linker-modified camptothecin (TL-CPT) and triphenylphosphonium to form the block copolymer, TL-CPT-PEG1K-TPP. The ZnPc/CPT-TPPNPs was constructed for delivery of the photosensitizer Zinc phthalocyanine (ZnPc) by blending the block copolymer TL-CPT-PEG1K-TPP with 1, 2-distearoyl-sn-glycero-3-phosphoethanolamine-N-[methoxy (polyethylene glycol)] (DSPE-PEG).Triphenylphosphine can accumulate selectively several hundred-fold within mitochondria. The thioketal linker is ROS-responsive and CPT can be released upon ROS cleavage. We also show that the ZnPc loaded in ZnPc/CPT-TPPNPs absorbed the 633 nm laser to produce ROS, which could be utilized both in photodynamic therapy and to cleave the thioketal linker thereby releasing camptothecin for chemotherapy. Thus, the mitochondria-targeting nanoparticles could elevate photodynamic therapeutic efficacy. Our results showed that surface modification of the nanoparticles with triphenylphosphine cations facilitated efficient subcellular delivery of the photosensitizer to mitochondria. The nanoparticles had a good ROS-responsive effect to release CPT, which could transfer to the nucleus and interfere with DNA replication as a topoisomeraseⅠinhibitor. Thus, the blended nanoparticles provide a new promising approach as a mitochondria-targeting ROS-activated chemo- and photodynamic therapy with a single light source for lung cancer.
doi:10.7150/thno.15433
PMCID: PMC5118600  PMID: 27877240
mitochondria-targeting nanoparticles; ROS-responsive; Zinc phthalocyanine; photodynamic therapy; camptothecin.
15.  A Novel Electrochemical Microfluidic Chip Combined with Multiple Biomarkers for Early Diagnosis of Gastric Cancer 
Early diagnosis is very important to improve the survival rate of patients with gastric cancer and to understand the biology of cancer. In order to meet the clinical demands for early diagnosis of gastric cancer, we developed a disposable easy-to-use electrochemical microfluidic chip combined with multiple antibodies against six kinds of biomarkers (carcinoembryonic antigen (CEA), carbohydrate antigen 19-9 (CA19-9), Helicobacter pylori CagA protein (H.P.), P53oncoprotein (P53), pepsinogen I (PG I), and PG-II). The six kinds of biomarkers related to gastric cancer can be detected sensitively and synchronously in a short time. The specially designed three electrodes system enables cross-contamination to be avoided effectively. The linear ranges of detection of the electrochemical microfluidic chip were as follows: 0.37–90 ng mL−1 for CEA, 10.75–172 U mL−1 for CA19-9, 10–160 U L−1 for H.P., 35–560 ng mL−1 for P53, 37.5–600 ng mL−1 for PG I, and 2.5–80 ng mL−1for PG II. This method owns better sensitivity compared with enzyme-linked immunosorbent assay (ELISA) results of 394 specimens of gastric cancer sera. Furthermore, we established a multi-index prediction model based on the six kinds of biomarkers for predicting risk of gastric cancer. In conclusion, the electrochemical microfluidic chip for detecting multiple biomarkers has great potential in applications such as early screening of gastric cancer patients, and therapeutic evaluation, and real-time dynamic monitoring the progress of gastric cancer in near future.
doi:10.1186/s11671-015-1153-3
PMCID: PMC4675772  PMID: 26659608
Electrochemical; Microfluidic chip; Multiple biomarkers; Early diagnosis; Gastric cancer
16.  Ultrafine ferroferric oxide nanoparticles embedded into mesoporous carbon nanotubes for lithium ion batteries 
Scientific Reports  2015;5:17553.
An effective one-pot hydrothermal method for in situ filling of multi-wall carbon nanotubes (CNT, diameter of 20–40 nm, length of 30–100 μm) with ultrafine ferroferric oxide (Fe3O4) nanoparticles (8–10 nm) has been demonstrated. The synthesized Fe3O4@CNT exhibited a mesoporous texture with a specific surface area of 109.4 m2 g−1. The loading of CNT, in terms of the weight ratio of Fe3O4 nanoparticles, can reach as high as 66.5 wt%. Compared to the conventional method of using a Al2O3 membrane as template to fill CNT with iron oxides nanoparticles, our strategy is facile, effective, low cost and easy to scale up to large scale production (~1.42 g per one-pot). When evaluated for lithium storage at 1.0 C (1 C = 928 mA g−1), the mesoporous Fe3O4@CNT can retain at 358.9 mAh g−1 after 60 cycles. Even when cycled at high rate of 20 C, high capacity of 275.2 mAh g−1 could still be achieved. At high rate (10 C) and long life cycling (500 cycles), the cells still exhibit a good capacity of 137.5 mAhg−1.
doi:10.1038/srep17553
PMCID: PMC4668383  PMID: 26631536
17.  Bioresponsive antisense DNA gold nanobeacons as a hybrid in vivo theranostics platform for the inhibition of cancer cells and metastasis 
Scientific Reports  2015;5:12297.
Gold nanobeacons can be used as a powerful tool for cancer theranostics. Here, we proposed a nanomaterial platform based on gold nanobeacons to detect, target and inhibit the expression of a mutant Kras gene in an in vivo murine gastric cancer model. The conjugation of fluorescently-labeled antisense DNA hairpin oligonucleotides to the surface of gold nanoparticles enables using their localized surface plasmon resonance properties to directly track the delivery to the primary gastric tumor and to lung metastatic sites. The fluorescently labeled nanobeacons reports on the interaction with the target as the fluorescent Cy3 signal is quenched by the gold nanoparticle and only emit light following conjugation to the Kras target owing to reorganization and opening of the nanobeacons, thus increasing the distance between the dye and the quencher. The systemic administration of the anti-Kras nanobeacons resulted in approximately 60% tumor size reduction and a 90% reduction in tumor vascularization. More important, the inhibition of the Kras gene expression in gastric tumors prevents the occurrence of metastasis to lung (80% reduction), increasing mice survival in more than 85%. Our developed platform can be easily adjusted to hybridize with any specific target and provide facile diagnosis and treatment for neoplastic diseases.
doi:10.1038/srep12297
PMCID: PMC4507177  PMID: 26189409
18.  Regression of Gastric Cancer by Systemic Injection of RNA Nanoparticles Carrying both Ligand and siRNA 
Scientific Reports  2015;5:10726.
Gastric cancer is the second leading cause of cancer-related death worldwide. RNA nanotechnology has recently emerged as an important field due to recent finding of its high thermodynamic stability, favorable and distinctive in vivo attributes. Here we reported the use of the thermostable three-way junction (3WJ) of bacteriophage phi29 motor pRNA to escort folic acid, a fluorescent image marker and BRCAA1 siRNA for targeting, imaging, delivery, gene silencing and regression of gastric cancer in animal models. In vitro assay revealed that the RNA nanoparticles specifically bind to gastric cancer cells, and knock-down the BRCAA1 gene. Apoptosis of gastric cancer cells was observed. Animal trials confirmed that these RNA nanoparticles could be used to image gastric cancer in vivo, while showing little accumulation in crucial organs and tissues. The volume of gastric tumors noticeably decreased during the course of treatment. No damage to important organs by RNA nanoparticles was detectible. All the results indicated that this novel RNA nanotechnology can overcome conventional cancer therapeutic limitations and opens new opportunities for specific delivery of therapeutics to stomach cancer without damaging normal cells and tissues, reduce the toxicity and side effect, improve the therapeutic effect, and exhibit great potential in clinical tumor therapy.
doi:10.1038/srep10726
PMCID: PMC4490273  PMID: 26137913
19.  CdSe/ZnS Quantum Dots-Labeled Mesenchymal Stem Cells for Targeted Fluorescence Imaging of Pancreas Tissues and Therapy of Type 1 Diabetic Rats 
Mesenchymal stem cells (MSCs) have been used for therapy of type 1 diabetes mellitus. However, the in vivo distribution and therapeutic effects of transplanted MSCs are not clarified well. Herein, we reported that CdSe/ZnS quantum dots-labeled MSCs were prepared for targeted fluorescence imaging and therapy of pancreas tissues in rat models with type 1 diabetes. CdSe/ZnS quantum dots were synthesized, their biocompatibility was evaluated, and then, the appropriate concentration of quantum dots was selected to label MSCs. CdSe/ZnS quantum dots-labeled MSCs were injected into mouse models with type 1 diabetes via tail vessel and then were observed by using the Bruker In-Vivo F PRO system, and the blood glucose levels were monitored for 8 weeks. Results showed that prepared CdSe/ZnS quantum dots owned good biocompatibility. Significant differences existed in distribution of quantum dots-labeled MSCs between normal control rats and diabetic rats (p < 0.05). The ratios of the fluorescence intensity (RFI) analysis showed an accumulation rate of MSCs in the pancreas of rats in the diabetes group, and was about 32 %, while that in the normal control group rats was about 18 %. The blood glucose levels were also monitored for 8 weeks after quantum dots-labeled MSC injection. Statistical differences existed between the blood glucose levels of the diabetic rat control group and MSC-injected diabetic rat group (p < 0.01), and the MSC-injected diabetic rat group displayed lower blood glucose levels. In conclusion, CdSe/ZnS-labeled MSCs can target in vivo pancreas tissues in diabetic rats, and significantly reduce the blood glucose levels in diabetic rats, and own potential application in therapy of diabetic patients in the near future.
doi:10.1186/s11671-015-0959-3
PMCID: PMC4469594  PMID: 26078050
Mesenchymal stem cell; CdSe/ZnS quantum dots; Fluorescence imaging; Cell labeling; Type 1 diabetes mellitus; Rat model
20.  The Influence of PSCA Gene Variation on Its Expression and Gastric Adenocarcinoma Susceptibility in the Northwest Chinese Population 
Gastric adenocarcinoma (GAC) imposes a considerable health burden around the world. Gene variation in prostate stem cell antigen gene (PSCA) has been identified to be associated with GAC risk, while the results showed regional variation. To explore the influence of PSCA gene variation on its expression and GAC risk in the Northwest Chinese population, four single nucleotide polymorphisms (SNPs) of PSCA were genotyped in 476 GAC cases and 481 controls using MassARRAY system. Two SNPs of rs2294008 (C>T) and rs2976392 (G>A) were identified to be associated with GAC risk. rs2294008, rs2976392 and rs10216533 made up two statistically significant haplotypes (Hap-CGG and Hap-TAG). Additionally, PSCA expression was analyzed by quantitative real time PCR, immunohistochemistry and tissue microarray. The results showed that PSCA expression was decreased in GAC tissues compared with adjacent normal tissues. For normal tissues, PSCA expression was higher with Hap-TA than that with Hap-CG. For GAC tissues, the differentiation degree of Hap-TA was higher than that of Hap-CG. The expression distribution of PSCA in multiple human organs showed disparity. These results suggest that PSCA gene variation has a potential effect on its expression and GAC risk in the Northwest Chinese population.
doi:10.3390/ijms160511648
PMCID: PMC4463721  PMID: 26006239
prostate stem cell antigen (PSCA); gastric adenocarcinoma; single nucleotide polymorphism (SNP); haplotype; gene expression
21.  Insights into the Distinguishing Stress-induced Cytotoxicity of Chiral Gold Nanoclusters and the Relationship with GSTP1 
Theranostics  2015;5(2):134-149.
Chiral gold nanoclusters (Au NCs) exhibit attracting properties owing to their unique physical and chemical properties. Herein we report for the first time chiral gold nanoclusters' cytotoxicity and potential molecular mechanism. The L-glutathione (i.e. L-GSH) and D-glutathione (i.e. D-GSH)-capped Au NCs were prepared and characterized by HRTEM, UV-vis, photoluminescence and circular dichroism (CD) spectroscopy. Results showed that the CD spectra of L-glutathione (i.e. L-GSH) and D-glutathione (i.e. D-GSH)-capped Au NCs exhibited multiple bands which were identically mirror-imaged, demonstrating that the chirality of GSH-capped NCs had contributions from both the metal core and the ligand. The effects of AuNCs@L-GSH and AuNCs@D-GSH on cells were similar based on the cell physiology related cytotoxicity, although the effects became more prominent in AuNCs@D-GSH treated cells, including ROS generation, mitochondrial membrane depolarization, cell cycle arrest and apoptosis. Global gene expression and pathway analysis displayed that both AuNCs@L-GSH and AuNCs@D-GSH caused the up-regulation of genes involved in cellular rescue and stress response, while AuNCs@D-GSH individually induced up-regulation of transcripts involved in some metabolic- and biosynthetic-related response. MGC-803 cells were more sensitive to the oxidative stress damage induced by chiral Au NCs than GES-1 cells, which was associated with GSTP1 hypermethylation. In conclusion, chiral gold nanoclusters exhibit this chirality-associated regulation of cytotoxicity, different gene expression profiling and epigenetic changes should be responsible for observed phenomena. Our study highlights the importance of the interplays between chiral materials and biological system at sub-nano level.
doi:10.7150/thno.10363
PMCID: PMC4279000  PMID: 25553104
gold nanocluster; chirality; cytotoxicity; ROS; methylation; epigenetic analysis.
22.  An Anion-Induced Hydrothermal Oriented-Explosive Strategy for the Synthesis of Porous Upconversion Nanocrystals 
Theranostics  2015;5(5):456-468.
Rare-earth (RE)-doped upconversion nanocrystals (UCNCs) are deemed as the promising candidates of luminescent nanoprobe for biological imaging and labeling. A number of methods have been used for the fabrication of UCNCs, but their assembly into porous architectures with desired size, shape and crystallographic phase remains a long-term challenging task. Here we report a facile, anion-induced hydrothermal oriented-explosive method to simultaneously control size, shape and phase of porous UCNCs. Our results confirmed the anion-induced hydrothermal oriented-explosion porous structure, size and phase transition for the cubic/hexagonal phase of NaLuF4 and NaGdF4 nanocrystals with various sizes and shapes. This general method is very important not only for successfully preparing lanthanide doped porous UCNCs, but also for clarifying the formation process of porous UCNCs in the hydrothermal system. The synthesized UCNCs were used for in vitro and in vivo CT imaging, and could be acted as the potential CT contrast agents.
doi:10.7150/thno.10946
PMCID: PMC4350008  PMID: 25767613
Hydrothermal; Anion-induced; Upconversion nanocrystals; Porous
23.  Circulating MiR-16-5p and MiR-19b-3p as Two Novel Potential Biomarkers to Indicate Progression of Gastric Cancer 
Theranostics  2015;5(7):733-745.
Gastric cancer (GC) is the second most common cancer in China and the second leading cause of cancer-related death in the world. Identifying circulating biomarkers is helpful to improve theranostics of gastric cancer. Herein, we are for the first time to report miR-16-5p and miR-19b-3p were identified to be the novel potential plasma biomarkers to detect gastric cancer. Differentially expressed miRNAs were initially screened out by genome-wide miRNA profiling microarrays between 16 plasma samples of gastric cancer and 18 matched normal controls, and then were quantified and validated by quantitative reverse transcription-PCR method between 155 gastric cancer cases and 111 normal controls. Additionally, 30 plasma samples from precancerous lesions and 18 paired samples from gastric cancer patients with gastrectomy were further detected. Results showed that based on two normalization methods, miR-16-5p and miR-19b-3p in plasma were found to be capable of distinguishing normal population from GC cases with different TNM stages and differentiation grades, particularly including the early cancer cases (P<0.05). And the two miRNAs were down-regulated in GC cases (FC<0.5). Especially, the down-regulation degree was correlated with the progression of the GC cases from the early stage to the advanced stage (0.2< rs<0.3, P<0.01). And the same weak down-regulation of the two biomarkers as the early GC occurred initially in the precancerous diseases (P<0.05). The corresponding performance of the two miRNAs to detect GC in ROC analysis gradually performed better with the disease progression from the earlier stages or lower grades to the advanced stages (TNM Ⅳ stage: AUC=0.832 for miR-16-5p; TNM Ⅲ stage: AUC=0.822 for miR-19b-3p) or high grade (Poorly differentiated: AUC=0.801, 0.791 respectively for miR-16-5p and miR-19b-3p). Additionally, miR-19b-3p remained down-regulated in patient plasma within 9 days after gastrectomy. In conclusion, miR-19b-3p and miR-16-5p maybe prospective biomarkers to detect gastric cancer and indicate its progression, and thus may own great potential in applications such as early screening and progression evaluation of gastric cancer in the near future.
doi:10.7150/thno.10305
PMCID: PMC4402497  PMID: 25897338
miR-16-5p; miR-19b-3p; circulating microRNA biomarker; gastric cancer; miRNA profiling microarray; quantitative reverse transcription-PCR
24.  CD44v6 Monoclonal Antibody-Conjugated Gold Nanostars for Targeted Photoacoustic Imaging and Plasmonic Photothermal Therapy of Gastric Cancer Stem-like Cells 
Theranostics  2015;5(9):970-984.
Developing safe and effective nanoprobes for targeted imaging and selective therapy of gastric cancer stem cells (GCSCs) has become one of the most promising anticancer strategies. Herein, gold nanostars-based PEGylated multifunctional nanoprobes were prepared with conjugated CD44v6 monoclonal antibodies (CD44v6-GNS) as the targeting ligands. It was observed that the prepared nanoprobes had high affinity towards GCSC spheroid colonies and destroyed them completely with a low power density upon near-infrared (NIR) laser treatment (790 nm, 1.5 W/cm2, 5 min) in vitro experiment. Orthotopic and subcutaneous xenografted nude mice models of human gastric cancer were established. Subsequently, biodistribution and photothermal therapeutic effects after being intravenously injected with the prepared nanoprobes were assessed. Photoacoustic imaging revealed that CD44v6-GNS nanoprobes could target the gastric cancer vascular system actively at 4 h post-injection, while the probes inhibited tumor growth remarkably upon NIR laser irradiation, and even extended survivability of the gastric cancer-bearing mice. The CD44v6-GNS nanoprobes exhibited great potential for applications of gastric cancer targeted imaging and photothermal therapy in the near future.
doi:10.7150/thno.11632
PMCID: PMC4493535  PMID: 26155313
gold nanostars; CD44v6 monoclonal antibody; gastric cancer stem cells (GCSCs); photoacoustic imaging; photothermal therapy
25.  Fluorescent carbon dots as an efficient siRNA nanocarrier for its interference therapy in gastric cancer cells 
Background
Fluorescent carbon dots (Cdots) have attracted increasing attention due to their potential applications in sensing, catalysis, and biomedicine. Currently, intensive research has been concentrated on the synthesis and imaging-guided therapy of these benign photoluminescent materials. Meanwhile, Cdots have been explored as nonviral vector for nucleic acid or drug delivery by chemical modification on purpose.
Results
We have developed a microwave assisted one-step synthesis of Cdots with citric acid as carbon source and tryptophan (Trp) as both nitrogen source and passivation agent. The Cdots with uniform size show superior water solubility, excellent biocompatibility, and high quantum yield. Afterwards, the PEI (polyethylenimine)-adsorbed Cdots nanoparticles (Cdots@PEI) were applied to deliver Survivin siRNA into human gastric cancer cell line MGC-803. The results have confirmed the nanocarrier exhibited excellent biocompatibility and a significant increase in cellular delivery of siRNA, inducing efficient knockdown for Survivin protein to 6.1%. In addition, PEI@Cdots complexes mediated Survivin silencing, the arrested cell cycle progression in G1 phase as well as cell apoptosis was observed.
Conclusion
The Cdots-based and PEI-adsorbed complexes both as imaging agents and siRNA nanocarriers have been developed for Survivin siRNA delivery. And the results indicate that Cdots-based nanocarriers could be utilized in a broad range of siRNA delivery systems for cancer therapy.
Electronic supplementary material
The online version of this article (doi:10.1186/s12951-014-0058-0) contains supplementary material, which is available to authorized users.
doi:10.1186/s12951-014-0058-0
PMCID: PMC4304159  PMID: 25547381
Carbon dots; siRNA interference therapy; Gastric cancer; Nanocarriers

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