Nano-confined squaraine dye assemblies: new photoacoustic and near-infrared fluorescence dual-modular imaging probes in vivo.

For the purpose of near-infrared (NIR) fluorescence and photoacoustic (PA) tomography dual-modular imaging, self-assembly of squaraine (SQ) dyes is constructed in the hydrophobic phospholipid bilayers of liposomes (SQ⊂L) with variable mixing ratios of SQ and phospholipids from 1:500 to 1:10 (w/w). When doping minimal amounts of SQ, molecularly dispersed SQ in bilayers shows remarkable fluorescence. Interesting, the PA signal is enhanced with increase of SQ in the nanoconfined bilayer region, which is attributed to the formation of SQ-based H-aggregates and enhanced thermal conversion efficiency (η). SQ⊂L shows satisfactory chemical and thermal stabilities and photobleaching resistance. SQ⊂L is well-distributed in the cytoplasm of MCF-7 cells and its fluorescence signal remains for 7 days without dramatic quenching owing to the good stability of SQ⊂L. Furthermore, SQ⊂L is subjected to in vivo NIR fluorescence imaging to evaluate the whole-body biodistribution in organ level. Particularly, PA imaging with deeper tissue penetration capability is utilized to investigate the heterogeneous distribution SQ⊂L inside solid tumor. The majority of SQ⊂L are enriched in the area where the blood vessels are generated, implying that the liposomal nanocarriers exhibit lower tumor tissue penetration capability after the vascular leakage. This result is validated by histological examination of tumor tissue in parallel.

Diabetes and risk of glaucoma: systematic review and a Meta-analysis of prospective cohort studies.

AIM: To quantify the association between diabetes and glaucoma using Meta-analysis. METHODS: PubMed and Embase were searched using medical subject headings and key words related to diabetes and glaucoma. The inclusion criteria were: 1) the study design was a prospective cohort study; 2) the exposure of interest was diabetes; 3) the outcome of interest was primary open angle glaucoma (POAG); 4) risk ratios (RR) and the corresponding 95% confidence interval (CI). Data were pooled using fixed effects models to take into account heterogeneity between studies. Seven prospective studies were selected. Diabetes increased the incidence of glaucoma by 36% (OR=1.36, 95% CI=1.25-1.50). There was no evidence of statistical heterogeneity (I2=0, P=0.53) or publication bias (the funnel plot did not identify obvious asymmetry). RESULTS: Seven prospective cohort studies were incorporated in this Meta-analysis. The pooled RR of the association between POAG and diabetes based on the risk estimates of the seven cohort studies was 1.36 (95%CI=1.24-1.50), with no significant heterogeneity across studies (I2=0; P=0.526). The sensitivity analysis yielded a range of RRs from 1.34 (95%CI=1.22-1.48) to1.40 (95%CI=1.18-1.67). CONCLUSION: Diabetes is associated with a significantly increased risk of glaucoma.

Comparison of isolated-check visual evoked potential and standard automated perimetry in early glaucoma and high-risk ocular hypertension.

AIM: To compare the diagnostic performance of isolated-check visual evoked potential (icVEP) and standard automated perimetry (SAP), for evaluating the application values of icVEP in the detection of early glaucoma. METHODS: Totally 144 subjects (288 eyes) were enrolled in this study. icVEP testing was performed with the Neucodia visual electrophysiological diagnostic system. A 15% positive-contrast (bright) condition pattern was used in this device to differentiate between glaucoma patients and healthy control subjects. Signal-to-noise ratios (SNR) were derived based on a multivariate statistic. The eyes were judged as abnormal if the test yielded an SNR≤1. SAP testing was performed with the Humphrey Field Analyzer II. The visual fields were deemed as abnormality if the glaucoma hemifield test results outside normal limits; or the pattern standard deviation with P<0.05; or the cluster of three or more non-edge points on the pattern deviation plot in a single hemifield with P<0.05, one of which must have a P<0.01. Disc photographs were graded as either glaucomatous optic neuropathy or normal by two experts who were masked to all other patient information. Moorfields regression analysis (MRA) used as a separate diagnostic classification was performed by Heidelberg retina tomograph (HRT). RESULTS: When the disc photograph grader was used as diagnostic standard, the sensitivity for SAP and icVEP was 32.3% and 38.5% respectively and specificity was 82.3% and 77.8% respectively. When the MRA Classifier was used as the diagnostic standard, the sensitivity for SAP and icVEP was 48.6% and 51.4% respectively and specificity was 84.1% and 78.0% respectively. When the combined structural assessment was used as the diagnostic standard, the sensitivity for SAP and icVEP was 59.2% and 53.1% respectively and specificity was 84.2% and 84.6% respectivlely. There was no statistical significance between the sensitivity or specificity of SAP and icVEP, regardless of which diagnostic standard was based on. CONCLUSION: The diagnostic performance of icVEP is not better than that of SAP in the detection of early glaucoma.

In Situ Construction and Characterization of Chlorin-Based Supramolecular Aggregates in Tumor Cells.

We demonstrate in situ construction and characterization of supramolecular aggregates from chlorin p6 (Cp6) molecules in tumor cells. Fully deprotonated Cp6 molecules in neutral condition were partially protonated inside the acidic lysosomes of cells and significantly increased the hydrophobicity of them that resulted in simultaneous formation of J-type aggregates. Importantly, the formation of J-aggregates was fully characterized in artificial tissues by UV-vis, circular dichroism (CD) and transmission electron microscope (TEM) techniques. Compared to the monomers, the J-aggregates exhibited 55-fold enhanced thermal conversion efficiency (η) at the optimal excitation wavelength (690 nm). The remarkably increased heat effect contributed to the stronger photoacoustic (PA) signals, leading to at least 2 orders of magnitude increase of the tumor-to-normal tissue ratio (T/N), which was defined as the PA signal ratio between tumor site and surrounding normal tissue. We envision that this proof-of-concept study will open a new way to develop tumor environment-induced self-assembly for variable biomedical applications.

In Situ Formation of Nanofibers from Purpurin18-Peptide Conjugates and the Assembly Induced Retention Effect in Tumor Sites.

An assembly-induced retention effect for enhanced tumor photoacoustic (PA) imaging and therapeutics is described. A responsive small-molecule precursor is prepared that simultaneously self-assembles into nanofibers in tumor sites that exhibit an assembly-induced retention effect, which results in an improved PA imaging signal and enhanced therapeutic efficacy. This successful proof-of-concept study paves the way to develop novel supramolecular biomaterials for cancer diagnostics and therapeutics.

Co-self-assembled nanoaggregates of BODIPY amphiphiles for dual colour imaging of live cells.

Co-self-assembled vesicular nanoparticles of two structurally comparable amphiphilic boron-dipyrromethene (BODIPY) dyes with dequenchable dual colour fluorescence were prepared for ratiometric imaging of live cells.

Synthesis and molecular recognition studies on small-molecule inhibitors for thioredoxin reductase.

Thioredoxin reductase (TrxR), which is overexpressed in many aggressive cancers, plays a crucial role in redox balance and antioxidant function, including defense of oxidative stress, control of cell proliferation, and regulation of cell apoptosis. Deactivation of TrxR can destroy the homeostasis of the cancer cells, inducing elevation of reactive oxygen species (ROS) levels and the oxidation of enzymatic substrates. Here, we synthesized and identified a new gold(I) small molecule (D9) that possesses two strong electron-donating moieties, i.e., 4-methylphenyl alkynyl and thionyldiphenyl phosphine, exhibiting an enhanced p-π conjunction effect. The resulting compound shows the increased soft Lewis acids and the stability of gold(I). And we demonstrated that D9 could efficiently and specifically inhibit the activity of TrxR in vitro and in vivo, and it could effectively avoid the ligand exchange with albumin that was one of the most abundant proteins in blood. We believe that these comprehensive studies on the relationship between the structure and performance will provide inspiring information on the precise synthesis and design of new compounds for targeting TrxR.

Anti-bacterial and in vivo tumor treatment by reactive oxygen species generated by magnetic nanoparticles.

Photodynamic therapy is widely used in clinics and for anti-bacterial applications. The major challenge is the limited depth of tissue penetration of light and poor targetability. In this study, magnetite nanoparticles were used as a highly sensitive T2-weighted MR imaging contrast agents to target the tumor and mimic horseradish peroxidase (HRP), which could catalyze the decomposition of hydrogen peroxide to generate reactive oxygen species (ROS) to inhibit the tumor in vivo. In these experiments, MNPs were demonstrated to possess the enzyme-mimicking activity in different pH values, and the activity was dependent on the size of the MNPs: the smaller the size, the higher the activity. We demonstrated that MNPs showed highly efficient anti-bacterial (E. coli) activity in presence of H2O2. The E. coli inhibition ratio reached nearly 100% at optimal concentration. The anti-tumor activity was evaluated through HeLa cell viability under treatment with MNPs and H2O2. Consequently, the cell viability was significantly decreased and more than 80% of HeLa cells were dead after treatment with MNPs and H2O2 under different pH values. MR imaging was used to demonstrate the tumor targetability of 13 nm MNPs in vitro and in vivo. Consequently, the relaxivity of the 13 nm MNPs was determined to be r2 = 104 s-1 mM-1. The MR signal was much more negative and the intensity was significantly diminished with the increase of the concentration of 13 nm MNPs in vitro. The tumor signal was clearly visualized and a 3-fold decrease of the MR signal intensity of the tumor site of the mice was observed after 24 h-post treatment with the 13 nm MNPs. Finally, the tumor inhibition in vivo was investigated using 6 nm MNPs in BALB/c nude female mice bearing subcutaneously implanted HeLa cells on the right flank. The results show statistically significant efficacy in delaying tumor growth from day 6, and an approximately 99% tumor inhibition ratio was shown by the combination of MNPs and H2O2 after treatment for 17 days. By leveraging the passive targeting and MR imaging properties, we expect that the enzyme-mimicking MNPs could be used for cancer theranostics and may open up a new avenue for the treatment of epidermal infections.