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author:("Shen, mingw")
1.  Magnetic resonance imaging of glioma with novel APTS-coated superparamagnetic iron oxide nanoparticles 
Nanoscale Research Letters  2014;9(1):304.
We report in vitro and in vivo magnetic resonance (MR) imaging of C6 glioma cells with a novel acetylated 3-aminopropyltrimethoxysilane (APTS)-coated iron oxide nanoparticles (Fe3O4 NPs). In the present study, APTS-coated Fe3O4 NPs were formed via a one-step hydrothermal approach and then chemically modified with acetic anhydride to generate surface charge-neutralized NPs. Prussian blue staining and transmission electron microscopy (TEM) data showed that acetylated APTS-coated Fe3O4 NPs can be taken up by cells. Combined morphological observation, cell viability, and flow cytometric analysis of the cell cycle indicated that the acetylated APTS-coated Fe3O4 NPs did not significantly affect cell morphology, viability, or cell cycle, indicating their good biocompatibility. Finally, the acetylated APTS-coated Fe3O4 nanoparticles were used in magnetic resonance imaging of C6 glioma. Our results showed that the developed acetylated APTS-coated Fe3O4 NPs can be used as an effective labeling agent to detect C6 glioma cells in vitro and in vivo for MR imaging. The results from the present study indicate that the developed acetylated APTS-coated Fe3O4 NPs have a potential application in MR imaging.
PMCID: PMC4067370  PMID: 24994959
Iron oxide nanoparticles; 3-Aminopropyltrimethoxysilane; Magnetic resonance imaging; Tumor cells; Glioma
2.  Hyaluronic Acid-Modified Magnetic Iron Oxide Nanoparticles for MR Imaging of Surgically Induced Endometriosis Model in Rats 
PLoS ONE  2014;9(4):e94718.
Endometriosis is defined as the presence of endometrial tissue outside the uterine, which may affect nearly 60% of women in reproductive age. Deep infiltrating endometriosis (DIE) defined as an endometriotic lesion penetrating into the retroperitoneal space or the wall of the pelvic organs to a depth of at least 5 mm represents the most diagnostic challenge. Herein, we reported the use of hyaluronic acid (HA)-modified magnetic iron oxide nanoparticles (HA-Fe3O4 NPs) for magnetic resonance (MR) imaging of endometriotic lesions in the rodent model. Sixteen endometriotic lesions were surgically induced in eight rats by autologous transplantation. Four weeks after lesion induction, three rats were scanned via MR imaging after tail vein injection of the HA-Fe3O4 NPs. Accordingly, the remaining five mice were sacrificed in the corresponding time points. The ectopic uterine tissues (EUTs) were confirmed by histological analysis. Quantification of Fe in the EUT was also performed by inductively coupled plasma-optical emission spectroscopy. Our results showed that by using the HA-Fe3O4 NPs, the EUTs were able to be visualized via T2-weighted MR imaging at 2 hours post injection, corroborating the Prussian blue staining results. The developed HA-Fe3O4 NPs could be used as negative contrast agents for sensitively detecting endometriosis in a mouse model and may be applied for future hyperthermia treatment of endometriosis.
PMCID: PMC3983238  PMID: 24722347
3.  Neighborhood health-promoting resources and obesity risk (the Multi-Ethnic Study of Atherosclerosis) 
Obesity (Silver Spring, Md.)  2013;21(3):10.1002/oby.20255.
While behavioral change is necessary to reverse the obesity epidemic, it can be difficult to achieve and sustain in unsupportive residential environments. This study hypothesized that environmental resources supporting walking and a healthy diet are associated with reduced obesity incidence. Data came from 4008 adults aged 45–84 at baseline who participated in a neighborhood ancillary study of the Multi-Ethnic Study of Atherosclerosis. Participants were enrolled at 6 study sites at baseline (2000–2002) and neighborhood scales were derived from a supplementary survey that asked community residents to rate availability of healthy foods and walking environments for a one-mile buffer area. Obesity was defined as body mass index (BMI) >=30 kg/m2. Associations between incident obesity and neighborhood exposure were examined using proportional hazards and generalized linear regression. Among 4008 non-obese participants, 406 new obesity cases occurred during 5 years of follow-up. Neighborhood healthy food environment was associated with 10% lower obesity incidence per standard deviation increase neighborhood score. The association persisted after adjustment for baseline BMI and individual level covariates (HR 0.88, 95% CI: 0.79, 0.97), and for correlated features of the walking environment but confidence intervals widened to include the null (HR 0.89, 95% CI: 0.77, 1.03). Associations between neighborhood walking environment and lower obesity were weaker and did not persist after adjustment for correlated neighborhood healthy eating amenities (HR 0.98, 95% CI 0.84, 1.15). Altering the residential environment so that healthier behaviors and lifestyles can be easily chosen may be a pre-condition for sustaining existing healthy behaviors and for adopting new healthy behaviors.
PMCID: PMC3511654  PMID: 23592671
Adult; Health Behavior; Obesity/*epidemiology; Residence Characteristics; Longitudinal Studies; Geographic Information Systems; Environment Design; Public Health; Risk Factors
4.  Multifunctional dendrimer-based nanoparticles for in vivo MR/CT dual-modal molecular imaging of breast cancer 
Development of dual-mode or multi-mode imaging contrast agents is important for accurate and self-confirmatory diagnosis of cancer. We report a new multifunctional, dendrimer-based gold nanoparticle (AuNP) as a dual-modality contrast agent for magnetic resonance (MR)/computed tomography (CT) imaging of breast cancer cells in vitro and in vivo. In this study, amine-terminated generation 5 poly(amidoamine) dendrimers modified with gadolinium chelate (DOTA-NHS) and polyethylene glycol monomethyl ether were used as templates to synthesize AuNPs, followed by Gd(III) chelation and acetylation of the remaining dendrimer terminal amine groups; multifunctional dendrimer-entrapped AuNPs (Gd-Au DENPs) were formed. The formed Gd-Au DENPs were used for both in vitro and in vivo MR/CT imaging of human MCF-7 cancer cells. Both MR and CT images demonstrate that MCF-7 cells and the xenograft tumor model can be effectively imaged. The Gd-Au DENPs uptake, mainly in the cell cytoplasm, was confirmed by transmission electron microscopy. The cell cytotoxicity assay, cell morphology observation, and flow cytometry show that the developed Gd-Au DENPs have good biocompatibility in the given concentration range. Our results clearly suggest that the synthetic Gd-Au DENPs are amenable for dual-modality MR/CT imaging of breast cancer cells.
PMCID: PMC3722039  PMID: 23888113
PAMAM dendrimers; gold nanoparticles; gadolinium; PEGylation; CT imaging; MR imaging; breast cancer cells
5.  Dendrimer-entrapped gold nanoparticles as potential CT contrast agents for blood pool imaging 
Nanoscale Research Letters  2012;7(1):190.
The purpose of this study was to evaluate dendrimer-entrapped gold nanoparticles [Au DENPs] as a molecular imaging [MI] probe for computed tomography [CT]. Au DENPs were prepared by complexing AuCl4- ions with amine-terminated generation 5 poly(amidoamine) [G5.NH2] dendrimers. Resulting particles were sized using transmission electron microscopy. Serial dilutions (0.001 to 0.1 M) of either Au DENPs or iohexol were scanned by CT in vitro. Based on these results, Au DENPs were injected into mice, either subcutaneously (10 μL, 0.007 to 0.02 M) or intravenously (300 μL, 0.2 M), after which the mice were imaged by micro-CT or a standard mammography unit. Au DENPs prepared using G5.NH2 dendrimers as templates are quite uniform and have a size range of 2 to 4 nm. At Au concentrations above 0.01 M, the CT value of Au DENPs was higher than that of iohexol. A 10-μL subcutaneous dose of Au DENPs with [Au] ≥ 0.009 M could be detected by micro-CT. The vascular system could be imaged 5 and 20 min after injection of Au DENPs into the tail vein, and the urinary system could be imaged after 60 min. At comparable time points, the vascular system could not be imaged using iohexol, and the urinary system was imaged only indistinctly. Findings from this study suggested that Au DENPs prepared using G5.NH2 dendrimers as templates have good X-ray attenuation and a substantial circulation time. As their abundant surface amine groups have the ability to bind to a range of biological molecules, Au DENPs have the potential to be a useful MI probe for CT.
PMCID: PMC3323415  PMID: 22429280
6.  Enhancing the specificity and efficiency of polymerase chain reaction using polyethyleneimine-based derivatives and hybrid nanocomposites 
There is a general necessity to improve the specificity and efficiency of the polymerase chain reaction (PCR), and exploring the PCR-enhancing mechanism still remains a great challenge. In this paper we report the use of branched polyethyleneimine (PEI)-based derivatives and hybrid nanocomposites as a novel class of enhancers to improve the specificity and efficiency of a nonspecific PCR system. We show that the surface-charge polarity of PEI and PEI derivatives plays a major role in their effectiveness to enhance the PCR. Positively charged amine-terminated pristine PEI, partially (50%) acetylated PEI (PEI-Ac50), and completely acetylated PEI (PEI-Ac) are able to improve PCR efficiency and specificity with an optimum concentration order of PEI < PEI-Ac50 < PEI-Ac, whereas negatively charged carboxyl-terminated PEI (PEI-SAH; SAH denotes succinamic acid groups) and neutralized PEI modified with both polyethylene glycol (PEG) and acetyl (Ac) groups (PEI-PEG-Ac) are unable to improve PCR specificity and efficiency even at concentrations three orders of magnitude higher than that of PEI. Our data clearly suggests that the PCR-enhancing effect is primarily based on the interaction between the PCR components and the PEI derivatives, where electrostatic interaction plays a major role in concentrating the PCR components locally on the backbones of the branched PEI. In addition, multiwalled carbon nanotubes modified with PEI and PEI-stabilized gold nanoparticles are also able to improve the PCR specificity and efficiency with an optimum PEI concentration less than that of the PEI alone, indicating that the inorganic component of the nanocomposites may help improve the interaction between PEI and the PCR components. The developed PEI-based derivatives or nanocomposites may be used as efficient additives to enhance other PCR systems for different biomedical applications.
PMCID: PMC3289439  PMID: 22393296
polyethyleneimine; gold nanoparticles; multiwalled carbon nanotubes; nanocomposites; polymerase chain reaction; specificity; efficiency
7.  Aminopropyltriethoxysilane-mediated surface functionalization of hydroxyapatite nanoparticles: synthesis, characterization, and in vitro toxicity assay 
We report on aminopropyltriethoxysilane (APTS)-mediated surface modification of nanohydroxyapatite with different surface functional groups for potential biomedical applications. In this study, nanohydroxyapatite covalently linked with APTS (n-HA-APTS) was reacted with acetic anhydride or succinic anhydride to produce neutralized (n-HA-APTS. Ac) or negatively charged (n-HA-APTS.SAH) nanohydroxyapatite, respectively. Nanohydroxyapatite formed with amine, acetyl, and carboxyl groups was extensively characterized using Fourier transform infrared spectroscopy, transmission electron microscopy, 1H nuclear magnetic resonance spectroscopy, X-ray diffraction, inductively coupled plasma-atomic emission spectroscopy, and zeta potential measurements.
In vitro 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide colorimetric assay revealed that the slight toxicity of the amine-functionalized n-HA-APTS could be eliminated by post-functionalization of APTS amines to form acetyl and carboxyl groups. Blood compatibility assessment demonstrated that the negligible hemolytic activity of the pristine nanohydroxyapatite particles did not appreciably change after APTS-mediated surface functionalization.
APTS-mediated functionalization of nanohydroxyapatite with different surface groups may be useful for further functionalization of nanohydroxyapatite with biologically active materials, thereby providing possibilities for a broad range of biomedical applications.
PMCID: PMC3260038  PMID: 22267929
aminopropyltriethoxysilane; hydroxyapatite nanoparticles; surface functionalization; acetylation; carboxylation; toxicity
8.  Multifunctional dendrimer/combretastatin A4 inclusion complexes enable in vitro targeted cancer therapy 
We report here a unique approach to using multifunctional dendrimer/combretastatin A4 (CA4) inclusion complexes for targeted cancer therapeutics.
Amine-terminated generation 5 polyamidoamine dendrimers were first partially acetylated to neutralize a significant portion of the terminal amines, and then the remaining dendrimer terminal amines were sequentially modified with fluorescein isothiocyanate as an imaging agent and folic acid as a targeting ligand. The multifunctional dendrimers formed (G5.NHAc-FI-FA) were utilized to encapsulate the anticancer drug, CA4, for targeted delivery into cancer cells overexpressing folic acid receptors.
The inclusion complexes of G5.NHAc-FI-FA/CA4 formed were stable and are able to significantly improve the water solubility of CA4 from 11.8 to 240 μg/mL. In vitro release studies showed that the multifunctional dendrimers complexed with CA4 could be released in a sustained manner. Both 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide colorimetric assay and morphological cell observation showed that the inhibitory effect of the G5.NHAc-FI-FA/CA4 complexes was similar to that of free CA4 at the same selected drug concentration. More importantly, the complexes were able to target selectively and display specific therapeutic efficacy to cancer cells overexpressing high-affinity folic acid receptors.
Multifunctional dendrimers may serve as a valuable carrier to form stable inclusion complexes with various hydrophobic anticancer drugs with improved water solubility, for targeting chemotherapy to different types of cancer.
PMCID: PMC3205130  PMID: 22072871
PAMAM dendrimers; combretastatin A4; inclusion complexes; targeted cancer therapy
9.  Long-Term Exposure to Airborne Particles and Arterial Stiffness: The Multi-Ethnic Study of Atherosclerosis (MESA) 
Environmental Health Perspectives  2011;119(6):844-851.
Increased arterial stiffness could represent an intermediate subclinical outcome in the mechanistic pathway underlying associations between average long-term pollution exposure and cardiovascular events.
We hypothesized that 20 years of exposure to particulate matter (PM) ≤ 2.5 and 10 μm in aerodynamic diameter (PM2.5 and PM10, respectively) would be positively associated with arterial stiffness in 3,996 participants from the Multi-Ethnic Study of Atherosclerosis (MESA) who were seen at six U.S. study sites.
We assigned pollution exposure during two decades preceding a clinical exam (2000–2002) using observed PM10 from monitors nearest participants’ residences and PM10 and PM2.5 imputed from a space-time model. We examined three log-transformed arterial stiffness outcome measures: Young’s modulus (YM) from carotid artery ultrasound and large (C1) and small (C2) artery vessel compliance from the radial artery pulse wave. All associations are expressed per 10 μg/m3 increment in PM and were adjusted for weather, age, sex, race, glucose, triglycerides, diabetes, waist:hip ratio, seated mean arterial pressure, smoking status, pack-years, cigarettes per day, environmental tobacco smoke, and physical activity. C1 and C2 models were further adjusted for heart rate, weight, and height.
Long-term average particle exposure was not associated with greater arterial stiffness measured by YM, C1, or C2, and the few associations observed were not robust across metrics and adjustment schemes.
Long-term particle mass exposure did not appear to be associated with greater arterial stiffness in this study sample.
PMCID: PMC3114821  PMID: 21245016
air pollution; arterial stiffness; environmental air pollutants; epidemiology
10.  Neighborhood Resources for Physical Activity and Healthy Foods and Incidence of Type 2 Diabetes Mellitus 
Archives of internal medicine  2009;169(18):1698-1704.
Despite increasing interest in the extent to which features of residential environments contribute to incidence of type 2 diabetes mellitus, no multisite prospective studies have investigated this question. We hypothesized that neighborhood resources supporting physical activity and healthy diets are associated with a lower incidence of type 2 diabetes.
Person-level data came from 3 sites of the Multi-Ethnic Study of Atherosclerosis, a population-based, prospective study of adults aged 45 to 84 years at baseline. Neighborhood data were derived from a population-based residential survey. Type 2 diabetes was defined as a fasting glucose level of 126 mg/dL or higher (≥7 mmol/L) or taking insulin or oral hypoglycemic agents. We estimated the hazard ratio of type 2 diabetes incidence associated with neighborhood (US Census tract) resources.
Among 2285 participants, 233 new type 2 diabetes cases occurred during a median of 5 follow-up years. Better neighborhood resources, determined by a combined score for physical activity and healthy foods, were associated with a 38% lower incidence of type 2 diabetes (hazard ratio corresponding to a difference between the 90th and 10th percentiles for resource distribution, 0.62; 95% confidence interval, 0.43–0.88 adjusted for age, sex, family history of diabetes, race/ethnicity, income, assets, educational level, alcohol use, and smoking status). The association remained statistically significant after further adjustment for individual dietary factors, physical activity level, and body mass index.
Better neighborhood resources were associated with lower incidence of type 2 diabetes, which suggests that improving environmental features may be a viable population-level strategy for addressing this disease.
PMCID: PMC2828356  PMID: 19822827
11.  Influence of dendrimer surface charge on the bioactivity of 2-methoxyestradiol complexed with dendrimers 
Soft matter  2010;6(11):2539-2545.
We report the complexation of a potential anticancer agent 2-methoxyestradiol (2-ME) with generation 5 (G5) poly(amidoamine) dendrimers having different surface functional groups for therapeutic applications. The complexation experiment shows that approximately 6–8 drug molecules can be complexed with one dendrimer molecule regardless the type of the dendrimer terminal groups. The bioactivity of 2-ME complexed with dendrimers was found to be significantly dependent on the surface charge of G5 dendrimers. In vitro cell biological assays show that amine, hydroxyl, and acetamide-terminated G5 dendrimers with positive, slightly positive, and close to neutral surface charges, respectively are able to deliver 2-ME to inhibit cancer cell growth. In contrast, 2-ME complexed with carboxyl-terminated G5 dendrimers with negative surface charges does not show its inherent bioactivity. Further molecular dynamics simulation studies show that the compact structure of carboxylated G5 dendrimers complexed with 2-ME does not allow the release of the drug molecules even at a pH of 5.0, which is the typical pH value in lysosome. Our findings indicate that the surface modification of dendrimers with different charges is crucial for the development of formulations of various anticancer drugs for therapeutic applications.
PMCID: PMC2941193  PMID: 20852741
12.  Comparison of the Internalization of Targeted Dendrimers and Dendrimer-Entrapped Gold Nanoparticles into Cancer Cells 
Biopolymers  2009;91(11):936-942.
Dendrimer-based nanotechnology significantly advances the area of targeted cancer imaging and therapy. Herein, we compared the difference of surface acetylated fluorescein isocyanate (FI) and folic acid (FA) modified generation 5 (G5) poly(amidoamine) dendrimers (G5.NHAc-FI-FA), and dendrimer-entrapped gold nanoparticles with similar modifications ([(Au0)51.2-G5.NHAc-FI-FA]) in terms of their specific internalization to FA receptor (FAR)-overexpressing cancer cells. Confocal microscopic studies show that both G5.NHAc-FI-FA and [(Au0)51.2-G5.NHAc-FI-FA] exhibit similar internalization kinetics regardless of the existence of Au nanoparticles (NPs). Molecular dynamics simulation of the two different nanostructures reveals that the surface area and the FA moiety distribution from the center of the geometry are slightly different. This slight difference may not be recognized by the FARs on the cell membrane, consequently leading to similar internalization kinetics. This study underlines the fact that metal or inorganic NPs entrapped within dendrimers interact with cells in a similar way to that of dendrimers lacking host NPs.
PMCID: PMC2901835  PMID: 19603491
dendrimers; gold nanoparticles; internalization; cancer cells
13.  Cross-Sectional and Longitudinal Associations of Neighborhood Cohesion and Stressors with Depressive Symptoms in the Multiethnic Study of Atherosclerosis (MESA) 
Annals of epidemiology  2009;19(1):49-57.
This study examined associations of neighborhood social cohesion, violence and aesthetic quality with depressive symptoms amongst 2619 healthy adults aged 45-84 years enrolled in the Multiethnic Study of Atherosclerosis.
Neighborhood characteristics were estimated by surveying a separate sample of area residents. Measures of aesthetic environment, social cohesion, and violence were combined into a summary score with increasing scores indicating more favorable environments. Depressive symptoms were measured using the Center for Epidemiologic Studies Depression (CES-D) scale. Marginal maximum likelihood estimation was used to assess associations of neighborhood characteristics with CES-D score at baseline and with the odds of developing incident depression (CES-D score ≥16 or use of antidepressants) over a 4-5 year follow-up among persons with CESD<16 at baseline. Models were adjusted for age, income, education, and race/ethnicity.
Lower levels of social cohesion and aesthetic quality and higher levels of violence were associated with higher mean CES-D scores in men and women (p-value for trend <0.01, adjusted mean difference in CES-D per 1 SD increase in summary score -1.01 (95% CI: -1.85, -0.17) and -1.08 (-1.88, -0.28) in men and women respectively). Associations of neighborhood characteristics with incident depression were in the expected direction for women but confidence intervals were wide (OR of incident depression 0.89 (0.63, 1.26)). No association was seen for men (OR=0.96 (0.74, 1.25)). Conclusions: Neighborhood social cohesion, aesthetic quality and violence are associated with the presence of depressive symptoms in residents.
PMCID: PMC2763272  PMID: 19064189
mental health; depression; residence characteristics; epidemiology; social environment

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