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1.  Combined Cancer Photothermal-Chemotherapy Based on Doxorubicin/Gold Nanorod-Loaded Polymersomes 
Theranostics  2015;5(4):345-356.
Gold nanorods (GNRs) are well known in photothermal therapy based on near-infrared (NIR) laser absorption of the longitudinal plasmon band. Herein, we developed an effective stimulus system -- GNRs and doxorubicin co-loaded polymersomes (P-GNRs-DOX) -- to facilitate co-therapy of photothermal and chemotherapy. DOX can be triggered to release once the polymersomes are corrupted under local hyperthermic condition of GNRs induced by NIR laser irradiation. Also, the cytotoxicity of GNRs caused by the residual cetyltrimethylacmmonium bromide (CTAB) was reduced by shielding the polymersomes. The GNRs-loaded polymersomes (P-GNRs) can be efficiently taken up by the tumor cells. The distribution of the nanomaterial was imaged by IR-820 and quantitatively analyzed by ICP-AES. We studied the ablation of tumor cells in vitro and in vivo, and found that co-therapy offers significantly improved therapeutic efficacy (tumors were eliminated without regrowth.) compared with chemotherapy or photothermal therapy alone. By TUNEL immunofluorescent staining of tumors after NIR laser irradiation, we found that the co-therapy showed more apoptotic tumor cells than the other groups. Furthermore, the toxicity study by pathologic examination of the heart tissues demonstrated a lower systematic toxicity of P-GNRs-DOX than free DOX. Thus, the chemo-photothermal treatment based on polymersomes loaded with DOX and GNRs is a useful strategy for maximizing the therapeutic efficacy and minimizing the dosage-related side effects in the treatment of solid tumors.
doi:10.7150/thno.10731
PMCID: PMC4329499
polymersomes; gold nanorod; NIR; photothermal therapy; chemotherapy.
2.  Cognitive impairments in patients with spinocerebellar ataxia types 1, 2 and 3 are positively correlated to the clinical severity of ataxia symptoms 
Aims: This study is to assess cognitive function in patients with spinocerebellar ataxia types 1, 2 and 3 (SCA1, SCA2 and SCA3). Methods: We performed neuropsychological examinations on 8 SCA1 patients, 2 SCA2 patients, and 8 SCA3 patients, as well as 32 healthy subjects matching these patients in age, gender, nationality, and years of education. The neuropsychological examinations were focused on testing executive functions, visuo-spatial perception and verbal memory, attention, immediate and delayed recall, logical thinking function and orientation function. Results: SCA1 patients had significantly impaired executive function, visuo-spatial perception, and attention compared to healthy subjects. Cognitive disorders such as immediate and delayed recall, executive function and verbal memory were observed in SCA2 and SCA3 patients, while attention and visuo-spatial function were not affected. The severity of motor impairment was determined using the international cooperative ataxia rating scale, the scores of which ranged from 11 to 78. The number of patients with mild ataxia, moderate ataxia and severe ataxia was 3, 11, and 3, respectively, with the most severe ataxia occurring on a patient with SCA1. The scores of activities of daily living scale ranged from 20 to 66. Conclusions: Our results showed that mild executive dysfunction occurred in patients with SCA1, SCA2 and SCA3, and verbal fluency and word memory dysfunctions were detected in patients with SCA2 and SCA3. In addition, we found that the decreased logical thinking function and orientation function were observed in patients with SCA1, SCA2 and SCA3. The cognitive status was correlated with the clinical severity of ataxia symptoms rather than age, age of onset, years of education and the duration of disease.
PMCID: PMC4307551  PMID: 25664104
Spinocerebellar ataxia; cognitive impairment; executive function; attention
3.  Diffusion Tensor Imaging of Spinocerebellar Ataxia Type 12 
Background
Spinocerebellar ataxias (SCAs) are autosomal-dominant neurodegenerative diseases that are clinically and genetically heterogeneous. SCAs are characterized by a range of neurological symptoms. SCA12 is an autosomal-dominant (AD) ataxia caused by a CAG repeat expansion mutation in a presumed promoter region of the gene PPP2R2B in a non-coding region on chromosome 5q32. This study sought to determine changes in different positions in a single Uyghur SCA12 pedigree by measuring the apparent diffusion coefficient (ADC) and fractional anisotropy (FA).
Material/Methods
A single Uyghur pedigree was collected and was confirmed to possess SCA12 by genetic diagnosis, among which 13 cases were patients and 54 cases were “healthy” individuals. Five patients were presymptomatic and 15 individuals selected as a control group were examination in the same time. DTI was performed on a 1.5T scanner, with b=1000 s/mm2 and 15 directions. ADC and FA were measured by regions of interest positioned in the corticospinal tract at the level of the pons (pons), superior peduncle (SCP), middle cerebellar peduncle (MCP), cerebellar cortex (CeC), cerebral cortex (CC), and cerebellar vermis (CV) white matter.
Results
Compared with the controls, the ADC was significantly elevated in the CeC, SCP, CC, and CV regions in SCA12 patients. The FA significantly decreased in the CC region in SCA12 patients and the CC and CV regions in SCA12 presymptomatic patients. The course of the disease, SARA score, and ADC values in CV showed highly positive correlations.
Conclusions
SCA12 pedigree patients exhibited microstructural damage in the brain white matter. The damage in white matter fiber may first occur in the CC and CV regions in SCA12 presymptomatic patients. The ADC values in the CV region could reflect disease severity in SCA12 patients.
doi:10.12659/MSM.891104
PMCID: PMC4199396  PMID: 25274186
Anisotropy; Diffusion Tensor Imaging; Spinocerebellar Ataxias
4.  Correlation of PCSK9 Gene Polymorphism with Cerebral Ischemic Stroke in Xinjiang Han and Uygur Populations 
Background
Cerebral ischemic stroke (CIS) is a major cause of morbidity and mortality. Its main pathological basis is atherosclerosis (AS); in turn, the main risk factor in AS is dyslipidemia. Human proprotein convertase subtilisin/kexin9 (PCSK9) plays a key role in regulating plasma low-density lipoprotein (LDL) cholesterol levels. We sought to assess the association between PCSK9 and CIS in Chinese Han and Uygur populations.
Material/Methods
We selected 408 CIS patients and 348 control subjects and used a single-base terminal extension (SNaPshot) method to detect the genotypes of the 20 single-nucleotide polymorphisms (SNPs) in PCSK9.
Results
Distribution of SNP8 (rs529787) genotypes showed a significant difference between CIS and control participants (P=0.049). However, when analyzing Han and Uygur populations separately, we found that only Han subjects showed distribution of SNP1 (rs1711503), SNP2 (rs2479408), and SNP8 (rs529787) alleles that was significantly different between CIS and control participants (P=0.028, P=0.013, P=0.006, respectively), and distribution of SNP2 (rs2479408) in the dominant model (CC vs. CG + GG) was significantly different between CIS and control participants (P=0.013), even after adjustment for covariates (OR: 75.262, 95% confidence interval [CI]: 7.232–783.278, P<0.001). Distribution of the 2 haplotypes (A-C and G-C) (rs1711503 and rs2479408) was significantly different between CIS and control participants (both, P=0.011).
Conclusions
Both rs1711503 and rs2479408 of PCSK9 genes were associated with CIS in the Han population of China. A-C haplotype may be a genetic marker of CIS risk in this population.
doi:10.12659/MSM.892091
PMCID: PMC4189717  PMID: 25266949
Atherosclerosis; Ethnic Groups; Ischemic Attack; Transient; Proprotein Convertases
5.  Innovative pharmaceutical development based on unique properties of nanoscale delivery formulation 
Nanoscale  2013;5(18):8307-8325.
The advent of nanotechnology has reignited interest in the field of pharmaceutical science for the development of nanomedicine. Nanomedicinal formulations are nanometer-sized carrier materials designed for increasing the drug tissue bioavailability, thereby improving the treatment of systemically applied chemotherapeutic drugs. Nanomedicine is a new approach to deliver the pharmaceuticals through different routes of administration with safer and more effective therapies compared to conventional methods. To date, various kinds of nanomaterials have been developed over the years to make delivery systems more effective for the treatment of various diseases. Even though nanomaterials have significant advantages due to their unique nanoscale properties, there are still significant challenges in the improvement and development of nanoformulations with composites and other materials. Here in this review, we highlight the nanomedicinal formulations aiming to improve the balance between the efficacy and the toxicity of therapeutic interventions through different routes of administration and how to design nanomedicine for safer and more effective ways to improve the treatment quality. We also emphasize the environmental and health prospects of nanomaterials for human health care.
doi:10.1039/c3nr01525d
PMCID: PMC3934102  PMID: 23860639
6.  Multifunctional hybrid silica nanoparticles for controlled doxorubicin loading and release with thermal and pH dually response 
Controlled drug loading and release into tumor cells to increase the intracellular drug concentration is a major challenge for cancer therapy due to resistance and inefficient cellular uptake. Here a temperature and pH dually responsive PNiPAM/AA@SiO2 core-shell particles with internal controlled release were designed and fabricated for efficient cancer treatment, which could recognize the intrinsic pH differences between cancers and normal tissues. Upon lowering the temperature, doxorubicin was loaded into the PNiPAM/AA@SiO2 nanoparticles, whereas by increasing the acidity, previously loaded doxorubicin was quickly released. Comparing with common mesoporous silica particles (MSNs), this core-shell particle has more uniform size and better dispersity. In addition, dried PNiPAM/AA@SiO2 nanoparticles could be easily redispersed in distilled water. The in vitro cell culture experiments showed that not only PNiPAM/AA@SiO2 particles were more biocompatible and lower cytotoxic than MSN, but also DOX@PNiPAM/AA@SiO2 had higher drug releasing efficiency in the lysosomes and stronger inhibitory effect on tumor cell growth than DOX@MSN. All these features indicated that PNiPAM/AA@SiO2 particles have great potential in therapy applications.
doi:10.1039/C2TB00223J
PMCID: PMC3609667  PMID: 23543911
7.  Correlation between the single nucleotide polymorphisms of the human phosphodiesterase 4D gene and the risk of cerebral infarction in the Uygur and Han ethnic groups of Xinjiang, China 
In this study, the correlation between the single nucleotide polymorphisms (SNPs) at rs2910829 and rs918592 in the phosphodiesterase 4D (PDE4D) gene and cerebral infarction in the Uygur and Han ethnic groups of Xinjiang, China were examined. The study population consisted of 373 Uygur and Han patients with cerebral infarction and 377 Uygur and Han control participants with no nervous system diseases. Polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) and gene sequencing methods were used to assess the SNPs at the rs2910829 and rs918592 loci in the PDE4D gene. The differences in genotype and allele frequency distribution were compared between the two groups. The C allele frequency of the rs2910829 locus in the PDE4D gene of the cerebral infarction group (81.0%) was significantly higher than that of the control group (76.4%) (P<0.05). Furthermore, the A allele frequency of the rs918592 locus in the PDE4D gene in the Uygur cerebral infarction group was significantly higher than that of the Uygur control group (P<0.05). There were no significant differences in the genotype and allele frequency distributions between the Uygur and Han groups (P>0.05). The A allele of the rs918592 locus may be associated with the occurrence of cerebral infarction in the Uygur population. In addition, it was indicated that the C allele of the rs2910829 locus in the PDE4D gene confers susceptibility to cerebral infarction; however, no significant difference was identified between Uygur and Han patients with cerebral infarction.
doi:10.3892/etm.2013.1370
PMCID: PMC3861451  PMID: 24348782
phosphodiesterase 4D; single nucleotide polymorphism; cerebral infarction; Uygur
8.  Genome-Wide Association Studies for Growth and Meat Production Traits in Sheep 
PLoS ONE  2013;8(6):e66569.
Background
Growth and meat production traits are significant economic traits in sheep. The aim of the study is to identify candidate genes affecting growth and meat production traits at genome level with high throughput single nucleotide polymorphisms (SNP) genotyping technologies.
Methodology and Results
Using Illumina OvineSNP50 BeadChip, we performed a GWA study in 329 purebred sheep for 11 growth and meat production traits (birth weight, weaning weight, 6-month weight, eye muscle area, fat thickness, pre-weaning gain, post-weaning gain, daily weight gain, height at withers, chest girth, and shin circumference). After quality control, 319 sheep and 48,198 SNPs were analyzed by TASSEL program in a mixed linear model (MLM). 36 significant SNPs were identified for 7 traits, and 10 of them reached genome-wise significance level for post-weaning gain. Gene annotation was implemented with the latest sheep genome Ovis_aries_v3.1 (released October 2012). More than one-third SNPs (14 out of 36) were located within ovine genes, others were located close to ovine genes (878bp-398,165bp apart). The strongest new finding is 5 genes were thought to be the most crucial candidate genes associated with post-weaning gain: s58995.1 was located within the ovine genes MEF2B and RFXANK, OAR3_84073899.1, OAR3_115712045.1 and OAR9_91721507.1 were located within CAMKMT, TRHDE, and RIPK2 respectively. GRM1, POL, MBD5, UBR2, RPL7 and SMC2 were thought to be the important candidate genes affecting post-weaning gain too. Additionally, 25 genes at chromosome-wise significance level were also forecasted to be the promising genes that influencing sheep growth and meat production traits.
Conclusions
The results will contribute to the similar studies and facilitate the potential utilization of genes involved in growth and meat production traits in sheep in future.
doi:10.1371/journal.pone.0066569
PMCID: PMC3692449  PMID: 23825544
9.  Zinc Fingers and Homeoboxes 2 Inhibits Hepatocellular Carcinoma Cell Proliferation and Represses Expression of Cyclins A and E 
Gastroenterology  2012;142(7):1559-1570.e2.
BACKGROUND & AIMS
Zinc-fingers and homeoboxes 2 (ZHX2) represses transcription of several genes associated with liver cancer. However, little is known about the role of ZHX2 in development of hepatocellular carcinoma (HCC). We investigated the mechanisms by which ZHX2 might affect proliferation of HCC cells.
METHODS
We overexpressed and knocked down ZHX2 in HCC cells and analyzed the effects on proliferation, colony formation, and the cell cycle. We also analyzed the effects of ZHX2 overexpression in growth of HepG2.2.15 tumor xenografts in nude mice. Chromatin immunoprecipitation and luciferase reporter assays were used to measure binding of ZHX2 target promoters. Levels of ZHX2 in HCC samples were evaluated by immunohistochemistry.
RESULTS
ZHX2 overexpression significantly reduced proliferation of HCC cells and growth of tumor xenografts in mice; it led to G1 arrest and reduced levels of cyclins A and E in HCC cell lines. ZHX2 bound to promoter regions of CCNA2 (which encodes Cyclin A) and CCNE1 (which encodes cyclin E) and inhibited their transcription. Knockdown of cyclin A or cyclin E reduced the increased proliferation mediated by ZHX2 knockdown. Nuclear localization of ZHX2 was required for it to inhibit proliferation of HCC cells in culture and in mice. Nuclear localization of ZHX2 was reduced in human HCC samples, even in small tumors (diameter<5 cm), compared to adjacent non-tumor tissues. Moreover, reduced nuclear levels of ZHX2 correlated with reduced survival times of patients, high levels of tumor microvascularization, and hepatocyte proliferation.
CONCLUSIONS
ZHX2 inhibits HCC cell proliferation, by preventing expression of cyclins A and E, and reduces growth of xenograft tumors in mice. Loss of nuclear ZHX2 might be an early step in the development of HCC.
doi:10.1053/j.gastro.2012.02.049
PMCID: PMC3367107  PMID: 22406477
mouse model; carcinogenesis; shRNA; CCK-8
10.  Analysis of copy number variations in the sheep genome using 50K SNP BeadChip array 
BMC Genomics  2013;14:229.
Background
In recent years, genome-wide association studies have successfully uncovered single-nucleotide polymorphisms (SNPs) associated with complex traits such as diseases and quantitative phenotypes. These variations account for a small proportion of heritability. With the development of high throughput techniques, abundant submicroscopic structural variations have been found in organisms, of which the main variations are copy number variations (CNVs). Therefore, CNVs are increasingly recognized as an important and abundant source of genetic variation and phenotypic diversity.
Results
Analyses of CNVs in the genomes of three sheep breeds were performed using the Ovine SNP50 BeadChip array. A total of 238 CNV regions (CNVRs) were identified, including 219 losses, 13 gains, and six with both events (losses and gains), which cover 60.35 Mb of the sheep genomic sequence and correspond to 2.27% of the autosomal genome sequence. The length of the CNVRs on autosomes range from 13.66 kb to 1.30 Mb with a mean size of 253.57 kb, and 75 CNVRs events had a frequency > 3%. Among these CNVRs, 47 CNVRs identified by the PennCNV overlapped with the CNVpartition. Functional analysis indicated that most genes in the CNVRs were significantly enriched for involvement in the environmental response. Furthermore, 10 CNVRs were selected for validation and 6 CNVRs were further experimentally confirmed by qPCR. In addition, there were 57 CNVRs overlapped in our new dataset and other published ruminant CNV studies.
Conclusions
In this study, we firstly constructed a sheep CNV map based on the Ovine SNP50 array. Our results demonstrated the differences of two detection tools and integration of multiple algorithms can enhance the detection of sheep genomic structure variations. Furthermore, our findings would be of help for understanding the sheep genome and provide preliminary foundation for carrying out the CNVs association studies with economically important phenotypes of sheep in the future.
doi:10.1186/1471-2164-14-229
PMCID: PMC3626776  PMID: 23565757
11.  Mitaplatin Increases Sensitivity of Tumor Cells to Cisplatin by Inducing Mitochondrial Dysfunction 
Molecular Pharmaceutics  2012;9(3):634-644.
Tumor resistance to chemotherapy is the major obstacle to employ cisplatin, one of the broadly used chemotherapeutic drugs, for effective treatment of various tumors in the clinic. Most acknowledged mechanisms of cancer resistance to cisplatin focus on increased nuclear DNA repair or detoxicity of cisplatin. We previously demonstrated that there was a unique metabolic profile in cisplatinresistant (CP-r) human epidermoid adenocarcinoma KB-CP 20 and hepatoma BEL 7404-CP 20 cancer cells. In this study, we further defined hyperpolarized mitochondrial membrane potentials (Δψm) in CP-r KB-CP 20 and BEL 7404-CP 20 cells compared to the cisplatin-sensitive (CP-s) KB-3-1 and BEL 7404 cells. Based on the mitochondrial dysfunction, mitaplatin was designed with two mitochondrial-targeting moieties [dichloroacetate (DCA) units] to the axial positions of a six-coordinate Pt(IV) center to sensitize cisplatin resistance. It was found that mitaplatin induced more apoptosis in CP-r KB-CP 20 and BEL 7404-CP 20 cells than that of cisplatin, DCA and cisplatin/DCA compared on an equal molar basis. There was more platinum accumulation in mitaplatin-treated CP-r cells due to enhanced transmembrane permeability of lipophilicity, and mitaplatin also showed special targeting to mitochondria. Moreover, in the case of treatment with mitaplatin, the dramatic collapse of Δψm was shown in a dose-dependent manner, which was confirmed by FACS and confocal microscopic measurements. Reduced glucose utilization of CP-r cells was detected with specifically inhibited phosphorylation of pyruvate dehydrogenase (PDH) at Ser-232, Ser-293, and Ser-300 of the E1α subunit when treated with mitaplatin, which was indicated to modulate the abnormal glycolysis of resistant cells. The present study suggested novel mitochondrial mechanism of mitaplatin circumventing cisplatin resistance toward CP-r cells as a carrier across membrane to produce CP-like cytotoxicity and DCA-like mitochondria-dependent apoptosis. Therefore, mitochondria targeting compounds would be more vulnerable and selective to overcome cisplatin resistance due to the unique metabolic properties of CP-r cancer cells.
doi:10.1021/mp200571k
PMCID: PMC3310394  PMID: 22289032
mitaplatin; cisplatin; cancer resistance; mitochondrial dysfunction
12.  Imaging, Autoradiography, and Biodistribution of 188Re-Labeled PEGylated Nanoliposome in Orthotopic Glioma Bearing Rat Model 
Abstract
The 188Re-labeled pegylated nanoliposome (abbreviated as 188Re-Liposome) was prepared and evaluated for its potential as a theragnostic agent for glioma. 188Re-BMEDA complex was loaded into the pegylated liposome core with pH 5.5 ammonium sulfate gradient to produce 188Re-Liposome. Orthotopic Fischer344/F98 glioma tumor-bearing rats were prepared and intravenously injected with 188Re-Liposome. Biodistribution, pharmacokinetic study, autoradiography (ARG), histopathology, and nano-SPECT/CT imaging were conducted for the animal model. The result showed that 188Re-Liposome accumulated in the brain tumor of the animal model from 0.28%±0.09% injected dose (ID)/g (n=3) at 1 hour to a maximum of 1.95%±0.35% ID/g (n=3) at 24 hours postinjection. The tumor-to-normal brain uptake ratio (T/N ratio) increased from 3.5 at 1 hour to 32.5 at 24 hours. Both ARG and histopathological images clearly showed corresponding tumor regions with high T/N ratios. Nano-SPECT/CT detected a very clear tumor image from 4 hours till 48 hours. This study reveals the potential of 188Re-Liposome as a theragnostic agent for brain glioma.
doi:10.1089/cbr.2011.1052
PMCID: PMC3231795  PMID: 22145660
autoradiography; glioma; liposomes; Nano-SPECT/CT; 188Re; theragnostic agent
13.  Atomic Force Microscopy Study of Conformational Change of Immobilized Calmodulin 
Maintaining the biological functionality of immobilized proteins is the key to the success of numerous protein-based biomedical devices. To that end, we studied conformational change of calmodulin (CaM) immobilized on chemical patterns. 1-cysteine mutated calmodulin was immobilized on a mercapto-terminated surface through the cysteine-Hg-mercapto coupling. Utilizing Atomic Force Microscope (AFM), the average height of the immobilized calmodulin was determined to be 1.87 ± 0.19 nm. After incubation in EGTA solution, the average height of protein changed to 2.26 ± 0.21 nm, indicating conformational change of CaM to Apo-CaM. The immobilized CaM also demonstrated conformational change upon the reaction with known calmodulin antagonist chlorpromazine (CPZ). After incubation in CPZ solution, the average height of CPZ-bound CaM increased to 2.32 ± 0.20 nm, demonstrating the immobilized CaM still has the similar response as in bulk solution. These results show that immobilization of calmodulin on a solid support does not interfere with the ability of the protein to bind calcium and calmodulin antagonists. Our results demonstrate the feasibility of employing AFM to probe and understand protein conformational changes.
doi:10.1021/la2016885
PMCID: PMC3164926  PMID: 21766850
calmodulin; protein conformation change; AFM
14.  A novel EGFR-targeted gene delivery system based on complexes self-assembled by EGF, DNA, and activated PAMAM dendrimers 
Epidermal growth factor receptor (EGFR)-targeted gene delivery is a promising approach in gene therapy against EGFR-positive cancer. In addition, macromolecules, such as polyamidoamine (PAMAM) dendrimers, are potential nonviral gene carriers in this therapy because of their biocompatibility and modifiable features. To achieve the goal of selectively enhancing the transfection efficiency in EGFR-positive cancer cells, the researchers developed chemical approaches of EGF-dendrimer conjugate, which were effective but complicated. Studies on liposomes reveal that self-assembly is another effective but simpler approach in EGF modification. Moreover, properly activated PAMAM dendrimers exhibit higher transfection efficiency, but little research has been done on its ligand-modification. In this study, we developed and characterized a novel gene-delivery system based on activated EGF-dendriplexes, which is formed via self-assembly by EGF and complexes prepared by activated PAMAM dendrimer and plasmid DNA. Such complexes exhibit desired features compared to nonmodified or non-activated dendriplexes in vitro, including selective enhancement of transfection efficiency in EGFR-positive cells, decreased cytotoxicity, and low agonist effect. In vivo experimentation shows their EGFR-positive tumor targeted biodistribution and increased transfection efficiency at EGFR-positive tumors. Our results demonstrated that activated EGF-dendriplexes are safe and effective carriers for delivering gene drugs to EGFR-positive cells, which makes these complexes a promising targeted nonviral gene-delivery system for auxiliary cancer therapy.
doi:10.2147/IJN.S30671
PMCID: PMC3428245  PMID: 22942644
activated dendriplexes; transfection efficiency; EGFR targeting; self-assembled EGF modification
15.  A novel lipid-based nanomicelle of docetaxel: evaluation of antitumor activity and biodistribution 
Purpose
A lipid-based, nanomicelle-loaded docetaxel (M-DOC) was designed and characterized. Optical imaging was employed to evaluate the pharmacokinetics and antitumor efficacy of docetaxel in vivo.
Materials and methods
The M-DOC was prepared using the emulsion-diffusion method. Transmission electron microscopy and dynamic light scattering were used to assess the morphology and particle size of the M-DOC. Critical micelle concentrations, their stability under physiological conditions, and their encapsulation efficiency – as measured by high-performance liquid chromatography – were assessed. Pharmacological features were evaluated in two different animal models by comparing M-DOC treatments with docetaxel injections (I-DOC). Bioluminescence imaging was used to assess antitumor activity and docetaxel distribution in vivo, using nude mice injected with luciferase-expressing MDA-MB-231 human breast tumor cells. In addition, animals injected with B16 melanoma cells were used to measure survival time and docetaxel distribution.
Results
The M-DOC was prepared as round, uniform spheres with an effective diameter of 20.8 nm. The critical micelle concentration of the original emulsion was 0.06%. Satisfactory encapsulation efficiency (87.6% ± 3.0%) and 12-hour stability were achieved. Xenograft results demonstrated that the M-DOC was more effective in inhibiting tumor growth, without significantly changing body weight. Survival was prolonged by 12.6% in the M-DOC group. Tumor growth inhibitory rates in the M-DOC and I-DOC groups were 91.2% and 57.8% in volume and 71.8% and 44.9% in weight, respectively. Optical bioluminescence imaging of tumor growths yielded similar results. Area under the curve(0–6 hour) levels of docetaxel in blood and tumors were significantly higher in the M-DOC group (15.9 ± 3.2 μg/mL−1, 601.1 ± 194.5 μg/g−1) than in the I-DOC group (7.2 ± 1.7 μg/mL−1, 357.8 ± 86.2 μg/g−1). The fluorescent dye 1,1-dioctadecyl-3,3,3,3′-tetramethylindotricarbocyanine iodide mimicked M-DOC in optical imaging, and accumulated more in tumors in comparison with I-DOC.
Conclusion
These results suggest that the lipid-based nanomicelle system was effective in inhibiting tumor growth, with little toxicity. Moreover, we have developed a noninvasive optical imaging method for antitumor drug evaluation, which merits further analysis for potential clinical applications.
doi:10.2147/IJN.S29827
PMCID: PMC3405881  PMID: 22848167
docetaxel; lipid-based micelles; antitumor activity; in vivo optical imaging
16.  Size-Dependent Localization and Penetration of Ultrasmall Gold Nanoparticles in Cancer Cells, Multicellular Spheroids, and Tumors in Vivo 
ACS Nano  2012;6(5):4483-4493.
This work demonstrated that ultrasmall gold nanoparticles (AuNPs) smaller than 10 nm display unique advantages over nanoparticles larger than 10 nm in terms of localization to, and penetration of, breast cancer cells, multicellular tumor spheroids, and tumors in mice. Au@tiopronin nanoparticles that have tunable sizes from 2 to 15 nm with identical surface coatings of tiopronin and charge were successfully prepared. For monolayer cells, the smaller the Au@tiopronin NPs, the more AuNPs found in each cell. In addition, the accumulation of Au NPs in the ex vivo tumor model was size-dependent: smaller AuNPs were able to penetrate deeply into tumor spheroids, whereas 15 nm nanoparticles were not. Owing to their ultrasmall nanostructure, 2 and 6 nm nanoparticles showed high levels of accumulation in tumor tissue in mice after a single intravenous injection. Surprisingly, both 2 and 6 nm Au@tiopronin nanoparticles were distributed throughout the cytoplasm and nucleus of cancer cells in vitro and in vivo, whereas 15 nm Au@tiopronin nanoparticles were found only in the cytoplasm, where they formed aggregates. The ex vivo multicellular spheroid proved to be a good model to simulate in vivo tumor tissue and evaluate nanoparticle penetration behavior. This work gives important insights into the design and functionalization of nanoparticles to achieve high levels of accumulation in tumors.
doi:10.1021/nn301282m
PMCID: PMC3370420  PMID: 22540892
ultrasmall gold nanoparticles; multicellular tumor spheroid; penetration behavior; drug delivery; cancer therapy
17.  Octadecyltrichlorosilane (OTS)-coated ionic liquid drops: Micro-reactors for homogenous catalytic reactions at designated interfaces 
Summary
An ionic liquid (IL), 1-butyl-3-methylimidazolium chloride ([Bmim]Cl) can assemble on prefabricated carboxylic acid–terminated chemical patterns on octadecyltrichlorosilane (OTS) film. The chemical pattern controls the position, shape and size of the IL on the surface. After the IL assembly – by incubating IL drops assembled on sample surface in an OTS silane vapor – an OTS layer was coated on the IL drop surface which encapsulated the IL drop. The OTS-coated capsule can exist stably under aqueous solution. The OTS coating protected the IL drops from being instantaneously dissolved by other solutions. We found that a homogenous catalyst (FeCl3) dissolved in [Bmim]Cl can be assembled together on the chemical patterns and subsequently encapsulated together with [Bmim]Cl by OTS coating. The pinhole defects within the vapor-coated silane layer provide space for the catalyst inside the capsule and reactants outside the capsule to meet and react. When the OTS-coated capsule containing a FeCl3/IL mixture was soaked under H2O2 solution, the Fe3+ ions catalyzed the decomposition reaction of hydrogen peroxide at the vapor-coated OTS-water interface. Since the shape and position of the interface is defined by the underneath chemical pattern, our findings show that the OTS-coated IL drops assembled on chemical patterns can be used as novel micro-reactors. This allows homogenous catalytic reactions to occur at the designated interfaces.
doi:10.3762/bjnano.3.4
PMCID: PMC3304328  PMID: 22428094
AFM; catalyst encapsulation; chemical pattern; ionic liquid; OTS
18.  Microglia and Microglia-Like Cell Differentiated from DC Inhibit CD4 T Cell Proliferation 
PLoS ONE  2009;4(11):e7869.
The central nervous system (CNS) is generally regarded as a site of immune privilege, whether the antigen presenting cells (APCs) are involved in the immune homeostasis of the CNS is largely unknown. Microglia and DCs are major APCs in physiological and pathological conditions, respectively. In this work, primary microglia and microglia-like cells obtained by co-culturing mature dendritic cells with CNS endothelial cells in vitro were functional evaluated. We found that microglia not only cannot prime CD4 T cells but also inhibit mature DCs (maDCs) initiated CD4 T cells proliferation. More importantly, endothelia from the CNS can differentiate maDCs into microglia-like cells (MLCs), which possess similar phenotype and immune inhibitory function as microglia. Soluble factors including NO lie behind the suppression of CD4 T cell proliferation induced by both microglia and MLCs. All the data indicate that under physiological conditions, microglia play important roles in maintaining immune homeostasis of the CNS, whereas in a pathological situation, the infiltrated DCs can be educated by the local microenvironment and differentiate into MLCs with inhibitory function.
doi:10.1371/journal.pone.0007869
PMCID: PMC2773419  PMID: 19924241
19.  Blockade of Tim-3 Pathway Ameliorates Interferon-γ Production from Hepatic CD8+ T Cells in a Mouse Model of Hepatitis B Virus Infection 
T cell immunoglobulin- and mucin-domain-containing molecule-3 (Tim-3) has been reported to participate in the pathogenesis of inflammatory diseases. However, whether Tim-3 is involved in hepatitis B virus (HBV) infection remains unknown. Here, we studied the expression and function of Tim-3 in a hydrodynamics-based mouse model of HBV infection. A significant increase of Tim-3 expression on hepatic T lymphocytes, especially on CD8+ T cells, was demonstrated in HBV model mice from day 7 to day 18. After Tim-3 knockdown by specific shRNAs, significantly increased IFN-γ production from hepatic CD8+ T cells in HBV model mice was observed. Very interestingly, we found Tim-3 expression on CD8+ T cells was higher in HBV model mice with higher serum anti-HBs production. Moreover, Tim-3 knockdown influenced anti-HBs production in vivo. Collectively, our data suggested that Tim-3 might act as a potent regulator of antiviral T-cell responses in HBV infection.
doi:10.1038/cmi.2009.5
PMCID: PMC4002548  PMID: 19254478
Tim-3; HBV; CD8+ T cell; hydrodynamic injection; shRNA

Results 1-19 (19)