Autophagy-inhibiting biomimetic nanodrugs enhance photothermal therapy and boost antitumor immunity.

The instinctive protective stress responses of tumor cells hamper low-temperature photothermal therapy (LTPTT), resulting in tumor recurrence and metastasis. The rapid blood clearance and low-efficiency tumor enrichment of nanomedicines also decrease the efficacy of LTPTT. In this study, we fabricated coassembled photothermal agents (indocyanine green, ICG) and autophagy inhibitors (chloroquine, CQ) and red blood cell and cancer cell hybrid membrane (RCm)-camouflaged ICGCQ@RCm nanoparticles (ICGCQ@RCm NPs) to enhance tumor LTPTT. The ICGCQ@RCm NPs exhibited prolonged blood drug circulation and markedly enhanced drug accumulation in tumor tissues. The ICGCQ@RCm NPs reduced the thermal tolerance of tumor cells to sensitize ICG-mediated LTPTT by inhibiting protective autophagy. The ICGCQ@RCm NPs exerted strong immunogenic cell death (ICD) after efficient LTPTT to activate antitumor immunity. In addition, ICGCQ@RCms optimized the therapeutic efficacy by imaging-guided LTPTT, taking advantage of the near-infrared (NIR) fluorescence of ICG. Consequently, the ICGCQ@RCm NPs effectively inhibited tumors under mild LTPTT, significantly suppressed tumor metastasis and prolonged the survival time of tumor-bearing mice. Furthermore, the ICGCQ@RCm NPs showed high biosafety in vitro and in vivo. The ICGCQ@RCm NPs demonstrated tumor-targeting and imaging-guided autophagy inhibition-sensitized LTPTT using two Food and Drug Administration (FDA)-approved drugs, which have great potential for clinical application.

Versatile Nanodrugs Containing Glutathione and Heme Oxygenase 1 Inhibitors Enable Suppression of Antioxidant Defense System in a Two-Pronged Manner for Enhanced Photodynamic Therapy.

The antioxidant defense system in malignant cells, which involves antioxidant enzymes and antioxidant molecules, is an innate barrier to photodynamic therapy (PDT). Because of the complexity of the endogenous antioxidant mechanisms of these cells, simply inhibiting individual antioxidant pathways has a limited effect on improving the lethality of ROS. To enhance the efficacy of PDT for tumor treatment, a versatile nanoparticle (NP)-based drug is developed, which the authors call PZB NP, containing the glutathione inhibitor l-buthionine sulfoximine (BSO) and the heme oxygenase 1 (HO-1) inhibitor protoporphyrin zinc(II) (ZnPP) to suppress the innate antioxidant defense system of cancer cells in a two-pronged manner. BSO reduces intracellular glutathione levels to minimize ROS elimination and protein protection during PDT, and ZnPP inhibits the ROS-stimulated upregulation of the antioxidant HO-1, thus preventing ROS removal by cells after PDT. Thus, BSO and ZnPP synergistically suppress the antioxidant defense systems of cancer cells both during and after protoporphyrin-IX-mediated PDT in a two-pronged manner, resulting in tumor cell death through excess oxidative pressure. The results demonstrate that the construction of nanodrugs having dual antioxidation defense suppression properties is a promising route for the development of highly efficient ROS-based therapies.

Diagnostic utility of circulating plasma microRNA-101a in severity of coronary heart disease.

BACKGROUND: For evaluating the severity of coronary heart disease (CHD), coronary arteriography may not be available everywhere due to technical limitations. MicroRNA-101a (miR-101a) associated with inflammation and cholesterol homeostasis. However, whether it related to presence and stratification of CHD is still unknown. AIM: We aim to evaluate the value of miR-101a in stratifying CHD patients. METHODS: We enrolled 200 CHD patients and 100 controls, and 200 CHD patients were divided into two groups of low and high SYNTAX score (SYNTAX score ≤ 22 versus SYNTAX score ≥ 33). Intergroup comparisons of miR-101a level were compared among the controls and two groups of low and high SYNTAX score. Correlation between miR-101a and blood lipid profiles was analyzed. The logistic regression analysis were conducted to evaluate the risk factors of CHD. RESULTS: Relative level of miR-101a in the controls, SYNTAX score ≤ 22 and SYNTAX score ≥ 33 group were 4.61 (1.24-8.91), 3.28 (0.58-6.75) and 2.29 (1.04-3.62), respectively (p < 0.001). All lipid profiles significantly associated with miR-101a expression (all p < 0.001). The odds ratio (OR) of miR-101a in univariate analysis was 0.41 (95% CI, 0.33-0.52). After adjusting for the traditional risk factors, such as blood profiles and history of smoking, the odds ratio of miR-101a was 0.63 (95% CI, 0.47-0.43), which closely associated with CHD (p = 0.002). CONCLUSIONS: Circulating miR-101a may be considered as a novel biomarker for evaluating the presence and severity of CHD.

Long non coding RNA-UCA1 contributes to cardiomyocyte apoptosis by suppression of p27 expression.

BACKGROUND/AIMS: Urothelial carcinoma-associated 1 (UCA1) is a recently identified long non coding RNA (lncRNA). However, few studies have explored its role in cardiomyocytes after focal cardiac ischemia reperfusion injury (CIR). METHODS: Rat CIR models were established using ligation of the Lower Anterior Descending artery (LAD). Cell apoptosis and reactive oxygen species (ROS) production in cardiac tissues were explored using immunohistochemistry and DHE staining. lncRNA expression patterns were detected using microarray and validated by qPCR. Cell viability and apoptosis were examined using MTT assay and flow cytometry. RESULTS: CIR significantly induced cell apoptosis and ROS production in the rat model. The results of microarray demonstrated the reduced expression of UCA1, which was validated by qPCR. Follow-up experiments showed that UCA1 was involved in H2O2-induced cell apoptosis. We further showed that UCA1 negatively correlated with the expression of p27. Moreover, overexpression of p27 could induce primary cardiomyocyte apoptosis. CONCLUSIONS: Reduction of UCA1 levels plays a pro-apoptotic role in primary cardiomyocytes partially through stimulation of p27 protein expression. These results are in agreement with the observed levels of UCA1, p27 and apoptosis after cardiac I/R injury, suggesting that UCA1 might have an important role during I/R injury.

Effect of local chain deformability on the temperature-induced morphological transitions of polystyrene-b-poly(N-isopropylacrylamide) micelles in aqueous solution.

The effect of temperature on the micellar morphology of two polystyrene-b-poly(N-isopropylacrylamide) (PS-b-PNIPAM) diblock copolymers in an aqueous solution was investigated by dynamic light scattering (DLS) and transmission electron microscopy (TEM). At 25 °C, a mixture of vesicles and spheres are observed for the micelles of PS65-b-PNIPAM108, while PS65-b-PNIPAM360 exhibits mixed cylindrical and spherical micellar morphology. Upon increasing the temperature, the micellar morphology becomes spherical for PS65-b-PNIPAM108 at 60 °C and for PS65-b-PNIPAM360 at 40 °C. Such vesicle-to-sphere and cylinder-to-sphere transitions of micellar morphology are reversible when the micellar solutions are cooled back to 25 °C. However, these temperature-induced morphological transitions of the PS-b-PNIPAM micelles are contrary to the theoretical prediction. Qualitative analysis of the free energy shows that vesicular or cylindrical micelles tend to form at higher temperatures if only the overall volume change of the PNIPAM block is considered. The contradiction between the experimental results and theoretical prediction is interpreted in terms of the local deformability of the PNIPAM chains. At elevated temperatures, the collapsed PNIPAM globules are less deformable and must occupy larger areas at the micellar interface, although the overall volume is smaller at higher temperatures. This will lead to a larger repulsion between the PNIPAM globules and a remarkable increase in the free energy of the corona; thus, the formation of vesicles or cylinders at higher temperatures is prohibited.

Speckle-tracking imaging to monitor myocardial function after coronary artery bypass graft surgery.

OBJECTIVES: The purpose of this study was to investigate the changes in myocardial function in patients after coronary artery bypass graft (CABG) surgery using longitudinal and circumferential strain on speckle-tracking imaging. METHODS: A total of 145 patients who successfully underwent CABG surgery with a left ventricular ejection fraction (LVEF) of 50% or greater were enrolled in this study. Patients were classified into 4 groups based on age: group 1 (33-59 years), group 2 (60-64 years), group 3 (65-69 years), and group 4 (70-79 years). Routine echocardiography and longitudinal and circumferential strain measurements on speckle-tracking imaging were performed 1 week before and 1, 3, and 6 months after the CABG. RESULTS: In all groups, longitudinal strain increased significantly at 3 and 6 months after CABG therapy compared to baseline (P < .05). A significant increase in circumferential strain was found 1 month after the CABG in groups 1, 2, and 3, and a continuous increase in the parameter was observed in all groups 3 months after therapy (P < .05). However, the LVEF, left ventricular end-diastolic dimension, and stroke volume measured by routine echocardiography were not significantly changed after successful CABG treatment in all groups during 6 months of follow-up. CONCLUSIONS: Based on the results of our study in all age groups, speckle-tracking imaging parameters are more effective than the LVEF, left ventricular end-diastolic dimension, and stroke volume for monitoring improvement in myocardial function after CABG surgery.

Relationship between epicardial adipose tissue volume measured using coronary computed tomography angiography and atherosclerotic plaque characteristics in patients with severe coronary artery stenosis.

AIM: To investigate the relationship between epicardial adipose tissue (EAT) volume and coronary plaque composition. METHODS: EAT volume (measured using coronary computed tomography angiography) and coronary plaque characteristics were assessed on a per-segment basis (modified 15-segment American College of Cardiology/American Heart Association classification) in patients with severe coronary artery stenosis. Coronary plaques were classified into four types: 1, calcified plaques; 2, mixed plaques (calcification dominant); 3, mixed plaques (non-calcification dominant); and 4, non-calcified plaques. The gold standard for luminal stenosis was conventional coronary angiography. RESULTS: In 365 patients (mean age 58.7 ± 8.0 years), EAT volume was 169.85 ± 29.94 ml. There were no significant between-group differences in patient characteristics. Statistically significant differences in EAT volume between non-calcified and calcified plaque groups were observed. EAT volume showed a positive correlation with total cholesterol and low-density-lipoprotein cholesterol, and a very weak correlation with age, triglyceride, body mass index and high-density-lipoprotein cholesterol. CONCLUSION: EAT volume was higher in the presence of non-calcified and mixed plaques in patients with ≥50% severe coronary artery stenosis.

Synthesis and biological evaluation of a novel 99mTc cyclopentadienyl tricarbonyl complex ([(Cp-R)99mTc(CO)3]) for sigma-2 receptor tumor imaging.

We report the design, synthesis and biological evaluation of a novel (99m)Tc 4-(4-cyclohexylpiperazine-1-yl)-butan-1-one-1-cyclopentadienyltricarbonyl technetium ([(99m)Tc]5) as a potential SPECT tracer for imaging of σ(2) receptors in tumors. [(99m)Tc]5 was prepared in 25±5% isolated radiochemical yield with radiochemical purity of >99% via double-ligand transfer (DLT) reaction from the ferrocene precursor 2b (4-(4-cyclohexylpiperazine-1-yl)-1-ferrocenylbutan-1-one). The corresponding Re-complex 4 and the ferrocenyl complex 2b showed relatively high affinity towards σ(2) receptors in in vitro competition binding assay (K(i) values of 4 and 2b were 64.4±18.5 nM and 43.6±21.3 nM, respectively) and moderate to high selectivity versus σ(1) receptors (K(i)σ(1)/K(i)σ(2) ratios were 12.5 and 95.5, respectively). The logD value of [(99m)Tc]5 was determined to be 2.52±0.33. Biodistribution studies in mice revealed comparably high initial brain uptake of [(99m)Tc]5 and slow washout. Administration of haloperidol 5 min prior to injection of [(99m)Tc]5 significantly reduced the radiotracer uptake in brain, heart, lung, and spleen by 40-50% at 2h p.i.. Moreover, [(99m)Tc]5 showed high uptake in C6 glioma cell lines (8.6%) after incubation for 1h. Blocking with haloperidol to compete with [(99m)Tc]5 significantly reduced the cell uptake. Preliminary blocking study in C6-brain-tumor bearing rats showed that [(99m)Tc]5 binds to σ receptors in the brain-tumor specifically. These results are encouraging for further exploration of (99m)Tc-labeled probes for σ(2) receptor tumor imaging in vivo.

Frustrated molecular packing in highly ordered smectic phase of side-chain liquid crystalline polymer with rigid polyacetylene backbone.

Using poly(5-{[(4'-heptoxy-4-biphenylyl)carbonyl]oxy}-1-pentyne) as an example, we demonstrate the incorporative accommodation of the rigid polyacetylene backbones and the mesogenic pendants, which leads to a highly ordered smectic (Sm) phase with a frustrated structure. The polymer exhibits a recognizable sheetlike molecular shape due to its rigid backbone and relatively short spacer (three methylene units), and the building block of the liquid crystalline (LC) phase is the whole molecule. In the LC phase, five layers of the molecules stack as a smectic A (SmA) block, and adjacent SmA blocks glide halfway of the molecular width from one to another. In scanning tunneling microscopy (STM) experiments, the STM tip scrape is found to generate a regular nanopattern with periodic electron conductivity, of which the spacing is determined by the side-chain length.