Xanthotoxol suppresses non-small cell lung cancer progression and might improve patients' prognosis.

BACKGROUND: Developing novel and effective drugs with less toxicity is urgent for non-small cell lung cancer (NSCLC) therapy. Xanthotoxol (Xan) is the major natural component of the medical plant Angelica dahurica with potential anti-cancer activities. PURPOSE: In this study, we aimed to demonstrate the effect and underlying mechanism of Xan in NSCLC and evaluate the effectiveness of Xan in NSCLC patients. METHODS: CCK8, colony formation, EdU, flow cytometry, and transwell assays were carried out to investigate the anti-NSCLC activity of Xan in vitro. In addition, the xenograft mouse model was established to evaluate the anti-NSCLC effect of Xan in vivo. Moreover, bioinformatics analysis was performed to establish a prediction model based on RNA sequencing data. Furthermore, Western blot was used to detect the expression of proteins regulated by Xan. RESULTS: Xan inhibited the cell viability, colony formation capacity, DNA replication, cell cycle transition, migration and invasion, as well as inducing apoptosis of NSCLC cells. In addition, Xan suppressed NSCLC xenograft growth in vivo without obvious toxicity. Interestingly, bioinformatics analyses based on the RNA sequencing data indicated that Xan exerted inhibitory effects on NSCLC cells by down-regulating signals contributing to NSCLC progression and demonstrated that Xan was effective in ameliorating the prognosis of NSCLC patients with a new proposed prediction model. Moreover, Xan was shown to regulate cell cycle arrest, apoptosis, and epithelial-mesenchymal transition (EMT)-associated genes through downregulating PI3K-AKT signaling, thus suppressing NSCLC proliferation and metastasis. CONCLUSIONS: Taken together, our work proved that Xan induced cell cycle arrest, facilitated apoptosis, and inhibited EMT processes through downregulating the PI3K-AKT pathway to suppress NSCLC progress. Moreover, we also proposed a new model for evaluating Xan as a novel and effective drug in NSCLC treatments.

Copy number profiling of circulating free DNA predicts transarterial chemoembolization response in advanced hepatocellular carcinoma.

Transarterial chemoembolization (TACE) is the most commonly used treatment for advanced hepatocellular carcinoma (HCC), but still lacks accurate real-time biomarkers for monitoring its therapeutic efficacy. Here, we explored whether copy number profiling of circulating free DNA (cfDNA) could be utilized to predict responses and prognosis in HCC patients with TACE treatment. In total, 266 plasma cfDNA samples were collected from 64 HCC patients, 57 liver cirrhosis (LC) patients and 32 healthy volunteers. We performed low-depth whole-genome sequencing (LD-WGS) on cfDNA samples to conduct copy number variant (CNV) analysis and tumour fraction (TFx) quantification. Then, the correlation between TFx/CNVs and therapeutic efficacy, treatment outcomes and lipiodol deposition were explored. The change in TFx during TACE treatment was associated with patients' tumour burden, and could accurately and earlier predict treatment response and prognosis, providing an alternative strategy other than mRECIST. Meanwhile, the chromosomal 16q/NQO1 amplification indicated worse therapeutic response; in patients who underwent multiple TACE sessions, TFx change during their first TACE treatment reflected the long-term survival; additionally, the copy number amplification of chromosome 1q, 3p, 6p, 8q, 10p, 12q, 18p or 18q affected lipiodol deposition. Overall, we have provided a new liquid biopsy approach for future TACE management of HCC patients.

[Effect of Xuebijing injection on endothelial microparticles and renal cortical microcirculation in septic rats].

OBJECTIVE: To clarify the characteristics of renal cortical microcirculation and its relationship with the expression of plasma endothelial microparticle (EMP) in septic rats, and to evaluate the effect of Xuebijing injection as an adjuvant therapy of antibiotics on septic AKI. METHODS: The 8-10 weeks old specific pathogen free (SPF) male Sprague-Dawley (SD) rats were divided into sham operation group (Sham group), positive drug control group and Xuebijing group by the random number table method, with 10 rats in each group. The cecal ligation and puncture (CLP) with large ligation (ligated 75% of the cecum) was used to prepare a rat high-grade sepsis model; in the Sham group, the cecum was stretched without ligation or puncture. Due to the high mortality of CLP with large ligation, Xuebijing injection (4 mL/kg, 12 hours per time) and imipenem/cilastatin injection (90 mg/kg, 6 hours per time) were administered to the rats in the Xuebijing group via the tail vein immediately after the model was produced. Normal saline and imipenem/cilastatin were administered to the rats by the same methods in the positive drug control group. The rats in the Sham group were treated with the same volume of normal saline as any of the other two groups at the same frequency. At 48 hours after model reproduction, the mean arterial pressure (MAP) and blood lactic acid (Lac) of the rats were measured. The renal cortical microcirculation was monitored by using side stream dark-field imaging. Renal hypoxia signals were assessed by pimonidazole chloride immunohistochemistry. Plasma EMP levels were determined by using flow cytometry, and then the correlation between EMP and microcirculation parameters of renal cortex was analyzed. At the same time, the serum creatinine (SCr) was measured, and the renal injury score (Paller score) was used to evaluate the severity of renal tissue pathological damage. RESULTS: Compared with the Sham group, perfused vessel density (PVD), microvascular flow index (MFI) and MAP in the positive drug control group and the Xuebijing group decreased significantly, the positive expression of hypoxia probe (pimonidazole) increased, Lac, EMP, Paller score and SCr increased significantly. However, compared with the positive drug control group, the renal cortical microcirculation in the Xuebijing group was improved significantly, PVD and MFI were increased significantly [PVD (mm/mm2): 16.20±1.20 vs. 9.77±1.12, MFI: 2.46±0.05 vs. 1.85±0.15, both P < 0.05], Lac was reduced significantly (mmol/L: 4.81±1.23 vs. 6.08±1.09, P < 0.05), MAP increased slightly [mmHg (1 mmHg = 0.133 kPa): 84.00±2.00 vs. 80.00±2.00, P > 0.05], suggested that Xuebijing injection improved renal microcirculation perfusion in septic rats, and this effect did not depend on the change of MAP. The positive expression of pemonidazole in renal cortex of the Xuebijing group was significantly lower than that of the positive drug control group [(35.89±1.13)% vs. (44.93±1.37) %, P < 0.05], suggested that Xuebijing injection alleviated renal hypoxia. The plasma EMP levels of rats in the Xuebijing group were significantly lower than those in the positive drug control group (×106/L: 3.49±0.17 vs. 5.78±0.22, P < 0.05), and the EMP levels were significantly negatively correlated with PVD and MFI (r values were -0.94 and -0.95, respectively, both P < 0.05), indicated that the increase of plasma EMP was highly correlated with renal microcirculation disorder, and Xuebijing injection inhibited the increase of plasma EMP levels. The Paller score in the Xuebijing group was significantly lower than that in the positive drug control group (46.90±3.84 vs. 62.70±3.05, P < 0.05), and the level of SCr was also significantly lower than that in the positive drug control group (µmol/L: 121.1±12.4 vs. 192.7±23.9, P < 0.05), which suggested that Xuebijing injection relieved kidney injury and improved renal function in septic rats. CONCLUSIONS: As an adjuvant therapy of antibiotics, Xuebijing injection could inhibit the expression of plasma EMP in rats with sepsis, improve renal cortex microcirculation, and reduce kidney injury.

Epidemiology of Sepsis-Associated Acute Kidney Injury in Beijing, China: A Descriptive Analysis.

BACKGROUND: Sepsis is the most common contributing factor towards development of acute kidney injury (AKI), which is strongly associated to poor prognostic outcomes. There are numerous epidemiological studies about sepsis-associated acute kidney injury (S-AKI), however current literature is limited with the majority of studies being conducted only in the intensive care unit (ICU) setting. The aim of this study was to assess the epidemiology of S-AKI in all hospitalized in-patients. METHODS: This was a retrospective population-based study using a large regional population database in Beijing city from January, 2005 to December, 2017. It included patients with S-AKI. Patients with pre-existing end-stage kidney disease (ESKD), previous history of kidney transplantation, or being pregnant were excluded. Patients' demographic characteristics, incidence, risk factors and outcomes of S-AKI were analyzed. The contrast between different time periods, different levels of hospitals, and types of the hospitals (traditional Chinese medicine hospitals (TCMHs) and western medicine hospitals (WMHs)) was also compared using Mann-Whitney U-test. RESULTS: A total of 19,579 patients were included. The overall incidence of S-AKI in all in-patients was 48.1%. The significant risk factors by multivariate analysis for AKI included: age, male, being treated in a level-II hospital, pre-existing hypertension, chronic kidney disease (CKD), cirrhosis, atrial fibrillation (AF), ischemic heart disease (IHD), being admitted from emergency room, ICU admission, shock, pneumonia, intra-abdominal infection, bloodstream infection, respiratory insufficiency, acute liver injury, disseminated intravascular coagulation (DIC) and metabolic encephalopathy. The overall mortality rate in this cohort was 55%. The multivariate analysis showed that the significant risk factors for mortality included: age, being treated in a level-II hospital and TCMHs, being admitted from emergency room, pre-existing comorbidities (CKD, malignancy, cirrhosis and AF), shock, pneumonia, intra-abdominal infection, bloodstream infection, central nervous system (CNS) infection and respiratory insufficiency. CONCLUSION: AKI is a common complication in patients with sepsis, and its incidence increases over time, especially when ICU admission is required. Exploring interventional strategies to address modifiable risk factors will be important to reduce incidence and mortality of S-AKI.

Demethyleneberberine induces cell cycle arrest and cellular senescence of NSCLC cells via c-Myc/HIF-1α pathway.

BACKGROUND: Demethyleneberberine (DMB) is a natural active component of medicinal plant Cortex phellodendri chinensis with favorable bioactivity. However, the role of DMB in suppressing non-small cell lung cancer (NSCLC) remains unknown. PURPOSE: In this study, we aimed to examine the effect and underlying mechanism of DMB in suppressing NSCLC. METHODS: CCK8 assay and colony formation assay were utilized to assess the efficiency of DMB on the viability and colony formation capacity of NSCLC cells. Flow cytometry and ß-Galactosidase Staining Kit were utilized to determine the efficiency of DMB on the cell cycle and cellular senescence of NSCLC cells. RT-qPCR and Western blot were used to detect the effect of DMB on cell cycle and cellular senescence related gene and protein expression of NSCLC cells. In vivo tumor model was established to evaluate the anti NSCLC effect of DMB. In addition, RNA-seq analysis was performed to detect the differential gene expression after DMB treatments. RESULTS: In this study, we revealed that DMB exhibits efficient inhibitory effect on NSCLC cell proliferation and tumor xenografts growth in vivo. We also demonstrated that DMB could inhibit cell migration by suppressing epithelial-mesenchymal transition (EMT) and trigger cell cycle arrest by down-regulating the expression of cell cycle related genes in NSCLC cells. In addition, DMB treatment efficiently induces cellular senescence of NSCLC cells. From the RNA-seq analysis, we found that DMB accelerates senescence through suppressing HIF-1α expression, which was further elucidated by overexpressing HIF-1α in NSCLC to reduce the inhibitory effect of DMB. Furthermore, we also revealed that DMB decreases the expression of c-Myc, an up-stream protein of HIF-1α. CONCLUSIONS: Taken together, we first report that DMB inhibits NSCLC progress through inducing cell cycle arrest and triggering cellular senescence by downregulating c-Myc/HIF-1α pathway.

Xuebijing injection in septic rats mitigates kidney injury, reduces cortical microcirculatory disorders, and suppresses activation of local inflammation.

ETHNOPHARMACOLOGICAL RELEVANCE: Xuebijing injections originate from the traditional Chinese medicine (TCM) prescription XuefuZhuyu Decoction. It is composed of five Chinese herbal extracts; Carthami flos, Paeoniae radix rubra, Chuanxiong rhizoma, Salviae miltiorrhizae, and Angelicae Sinensis radix. The China Food and Drug Administration approved Xuebijing injections as a TCM preparation for the adjuvant treatment of sepsis. AIM OF THE STUDY: This study aims to determine the effects of Xuebijing injections as an adjuvant to antibiotics for the treatment of renal microcirculatory dysfunction and renal inflammation in rats with sepsis. MATERIALS AND METHODS: The rats received a sham operation (Sham), sham operation followed by Xuebijign injection (Sxbj), cecal ligation and puncture (CLP), or CLP followed by Xuebijing injection (Cxbj). Renal microvascular perfusion in the cortex and oxygenation were assessed at different times after sepsis induction. Renal levels of interleukin (IL)-1ß, IL-6, tumor necrosis factor (TNF)-α, and high mobility group box (HMGB)-1 were measured. Urinary TIMP-2 × IGFBP-7 and neutrophil gelatinase-associated lipocalin (NGAL) were measured as kidney biomarkers, and serum creatinine (SCr) was used to assess kidney injury. Tissue samples were stained for histologic evaluation. RESULTS: The induction of sepsis increased local inflammation and decreased renal microvascular perfusion and oxygenation. Compared with the CLP group, the Cxbj group displayed improvements in microvascular perfusion and oxygenation (p < 0.05). The CLP group had significant increases in renal inflammatory biomarkers (IL-1ß, IL-6, TNF-α, and HMGB-1; p < 0.05) and Xuebijing injection reduced the levels of these markers. The levels of urinary TIMP-2 × IGFBP-7, NAGL, and SCr were lower in the Cxbj group than in the CLP group (p < 0.05), and the CLP group had a higher Paller score than the Cxbj group (p < 0.05). However, the CLP and Cxbj groups had no significant difference in mortality. CONCLUSIONS: This study into the early stages of sepsis in a rat model indicated that as an adjuvant therapy to antibiotics, Xuebijing injection improved renal perfusion and oxygenation, suppressed renal inflammation, and ameliorated kidney dysfunction. However, Xuebijing injection had no impact on mortality.

Targeted sequencing reveals the mutational landscape responsible for sorafenib therapy in advanced hepatocellular carcinoma.

Rationale: The existence of primary and acquired drug resistance is the main obstacle for the effect of multi-kinase inhibitor sorafenib and regorafenib in advanced hepatocellular carcinoma (HCC). However, plenty of patients did not significantly benefit from sorafenib treatment and little is known about the mechanism of drug resistance. Methods: Laser capture microdissection was used to acquire matched normal liver and tumor tissues on formalin-fixed paraffin-embedded specimens collected before sorafenib therapy from the first surgery of 119 HCC patients. Ultra-deep sequencing (~1000×) targeting whole exons of 440 genes in microdissected specimens and siRNA screen in 7 cell lines were performed to find mutations associated with differential responses to sorafenib. Patient-derived xenograft models were employed to determine the role of TP53 in response to sorafenib. Lentiviruses harboring wild-type and c.G52C-mutant OCT4 were applied to explore the function of OCT4 in resistance to sorafenib. ChIP-PCR assay for analysis of OCT4 transcriptional activity was performed to explore the affinity with the KITLG promoter. Statistical analyses were used to associate levels of p53 and OCT4 with tumor features and patient outcomes. Results: Total 1,050 somatic mutations and 26 significant driver genes were identified. SiRNA screening in 7 HCC cell lines was further performed to identify mutations associated with differential responses to sorafenib. A recurrent nonsynonymous mutation c.G52C in OCT4 (OCT4mut) was strongly associated with good response to sorafenib, whereas the stop-gain mutation in TP53 showed the opposite outcome both in vitro and in vivo. OCT4wt-induced stem cell factor (encoded by KITLG gene, SCF) expression and cross-activation of c-KIT/FLT3-BRAF signals were identified indispensably for sorafenib resistance, which could be reversed by the combination of c-KIT tyrosine kinase inhibitors or neutralizing antibody against SCF. Mechanistically, an OCT4 binding site in upstream of KITLG promoter was identified with a higher affinity to wildtype of OCT4 rather than G52C-mutant form, which is indispensable for OCT4-induced expression of KITLG and sorafenib resistance. Conclusion: Our study reported a novel somatic mutation in OCT4 (c.G52C) responsible for the sorafenib effect, and also shed new light on the treatment of HCC through the combination of specific tyrosine kinase inhibitors according to individual genetic patterns.

Adjuvant 131I-metuximab for hepatocellular carcinoma after liver resection: a randomised, controlled, multicentre, open-label, phase 2 trial.

BACKGROUND: Effective adjuvant treatment after hepatectomy for hepatocellular carcinoma (HCC) is an important area of research. Radioactive iodine (131I)-labelled metuximab is a radiolabelled monoclonal antibody against the CD147 (also known as basigin or HAb18G) antigen that is expressed in HCC. We aimed to examine the role of 131I-metuximab as an adjuvant therapy after HCC resection. METHODS: This randomised, controlled, multicentre, open-label, phase 2 trial was done at five medical centres in China. Patients aged 18-75 years who underwent curative-intent resection of histologically confirmed HCC expressing CD147 were randomly assigned (1:1) by a computer-generated random sequence, stratified by centre, to receive either adjuvant transarterial injection of one dose of 27·75 MBq/kg 131I-metuximab 4-6 weeks after the hepatectomy (treatment group) or no adjuvant treatment (control group). Patients and physicians were not masked to the study groups. The primary outcome was 5-year recurrence-free survival (RFS) in the intention-to-treat population. This trial is registered with ClinicalTrials.gov, NCT00819650. FINDINGS: Between April 1, 2009, and Nov 30, 2012, 485 patients were screened for eligibility. 329 (68%) of these patients were excluded and 156 (32%) were randomly assigned to receive either 131I-metuximab (n=78) or no adjuvant treatment (n=78). The median follow-up was 55·9 months (IQR 18·6-79·4). In the intention-to-treat population, the 5-year RFS was 43·4% (95% CI 33·6-55·9) in the 131I-metuximab group and 21·7% (14·2-33·1) in the control group (hazard ratio 0·49 [95% CI 0·34-0·72]; Z=2·96, p=0·0031). 131I-metuximab-associated adverse events occurred within the first 4 weeks in 34 (45%) of 76 patients, seven (21%) of whom had grade 3 or 4 adverse events. These adverse events were all resolved with appropriate treatment within 2 weeks of being identified. INTERPRETATION: Adjuvant 131I-metuximab treatment significantly improved the 5-year RFS of patients after hepatectomy for HCC tumours expressing CD147. This treatment was well tolerated by patients. FUNDING: State Key Project on Infectious Diseases of China.

Donor-acceptor conjugated polymer-based nanoparticles for highly effective photoacoustic imaging and photothermal therapy in the NIR-II window.

We prepared novel conjugated polymer based NIR-II nanoparticles, which display extremely high photothermal conversion efficiency (65%). Both in vitro and in vivo investigations revealed that the as-prepared nanoparticles exhibit excellent theranostic properties including an extremely high cancer cell killing ability, admirable tumor elimination efficiency (100%) and a remarkable photoacoustic imaging contrast enhancing ability.

Artificial Engineered Natural Killer Cells Combined with Antiheat Endurance as a Powerful Strategy for Enhancing Photothermal-Immunotherapy Efficiency of Solid Tumors.

Although photothermal therapy (PTT) is preclinically applied in solid tumor treatment, incomplete tumor removal of PTT and heat endurance of tumor cells induces significant tumor relapse after treatment, therefore lowering the therapeutic efficiency of PTT. Herein, a programmable therapeutic strategy that integrates photothermal therapeutic agents (PTAs), DNAzymes, and artificial engineered natural killer (A-NK) cells for immunotherapy of hepatocellular carcinoma (HCC) is designed. The novel PTAs, termed as Mn-CONASHs, with 2D structure are synthesized by the coordination of tetrahydroxyanthraquinone and Mn2+ ions. By further adsorbing polyetherimide/DNAzymes on the surface, the DNAzymes@Mn-CONASHs exhibit excellent light-to-heat conversion ability, tumor microenvironment enhanced T1 -MRI guiding ability, and antiheat endurance ability. Furthermore, the artificial engineered NK cells with HCC specific targeting TLS11a-aptamer decoration are constructed for specifically eliminating any possible residual tumor cells after PTT, to systematically enhance the therapeutic efficacy of PTT and avoid tumor relapse. Taken together, the potential of A-NK cells combined with antiheat endurance as a powerful strategy for immuno-enhancing photothermal therapy efficiency of solid tumors is highlighted, and the current strategy might provide promising prospects for cancer therapy.

Semiconducting polymer-based nanoparticles for photothermal therapy at the second near-infrared window.

We designed novel diketopyrrolopyrrole polymer based nanoparticles (DPP-IID-FA), which exhibited strong light absorption and excellent photothermal conversion in the NIR optical window, and displayed high biocompatibility and photostability. Furthermore, our nanoparticles could be efficiently uptaken by cancer cells and exhibited outstanding anticancer ability both in vitro and in vivo under NIR-II laser irradiation.

Self-Quenched Metal-Organic Particles as Dual-Mode Therapeutic Agents for Photoacoustic Imaging-Guided Second Near-Infrared Window Photochemotherapy.

The nanosized metal-organic particles (NMOPs) recently have attracted tremendous attentions in biomedical applications. However, few studies have developed metal-organic nanoparticles (NMOPs) as near-infrared (NIR) II phototherapeutic agents and as Fenton-like agents for cancer theranostics. Herein, directly using organic dye and Cu(II)-ion complexes to construct NMOPs, as dual-mode therapeutic agent for PA imaging-guided photochemotherapy in NIR II window, is reported. The NMOPs are simply an assembly of Cu(II) ion and tetrahydroxyanthraquinone (THQ) complexes [Cu(II)-THQ] n through the coordination effect, van der Waals force, and π-π interactions. After modification of polyethylene glycol (PEG-(NH2)2), the obtained Cu-THQNPs endow excellent biocompatibility and stability in physiological conditions. Because of the strong absorption at NIR II window and photoinduced electrontransfer (PET) mechanism, the Cu-THQNPs not only acted as an excellent photothermal agent with extremely high light-to-heat conversion ability (51.34%) at 1064 nm for phototherapy but also explored as the PA contrast agent for precisely tracking and guiding the therapy in vivo. Most strikingly, our Cu-THQNPs can be degraded by tumor-specific acidic-cleaving of the coordination bonds and follow by the slow release of Cu(II) into tumors, which can act as Fenton-like agents to generate •OH from H2O2 for enhancing the antitumor efficacy in vivo. With almost 100% prevention of the tumor growth for ca. 14 days and no obvious toxicity based on blood biochemical/histological analysis, this work highlights the Cu-THQNPs as an efficient NIR II therapeutic agent for precise cancer theranostics.

A fluorescent turn on nanoprobe for simultaneous visualization of dual-targets involved in cell apoptosis and drug screening in living cells.

Herein, a novel dual-responsive two-color fluorescent nanoprobe has been designed for the fluorescence activation imaging of cell apoptosis in living cells. The nanoprobe consists of a gold nanoparticle core functionalized with a dense layer of DNA aptamers and peptides, which shows high affinity and specific response to cytochrome c (Cyt c) and caspase-3, respectively. The formation of the aptamer-Cyt c complex and the cleavage of the specific peptide by caspase-3 can liberate the dye labelled aptamers and peptides from the surface of gold nanoparticles, and then recover their fluorescence. The turn-on and specific recognition properties of our nanoprobe allow for the sensitive and selective detection of Cyt c concentration and caspase-3 activity both in solutions and in living cells. The here proposed nanoprobe with the abilities of real-time monitoring the cell apoptosis and evaluating the apoptosis-related drug efficacy might serve as a potential interesting tool for studying the molecular mechanisms of apoptosis regulation or screening the apoptosis-based drugs.

Smart Cu(II)-aptamer complexes based gold nanoplatform for tumor micro-environment triggered programmable intracellular prodrug release, photodynamic treatment and aggregation induced photothermal therapy of hepatocellular carcinoma.

This study describes smart Cu(II)-aptamer complexes based gold nanoplatform for tumor micro-environment triggered programmable prodrug release, in demand photodynamic therapy and aggregation induced photothermal ablation of hepatocellular carcinoma. The nanoplatform is consist of monodispersed gold nanoparticle (GNP) that is binding to HCC cell specific targeting aptamers (TLS11a) through Au-S bond; the aptamer is labeled with Ce6 at the 5'end and coordinated with Cu(II) through (GA)10 repeating bases to load AQ4N at the 3' end. In normal physiological conditions, the fluorescence and ROS generation ability of Ce6 are quenched by GNPs via RET; but in cancerous cells, the fluorescence and the ROS generation of Ce6 could be recovered by cleavage of Au-S bond through high level of intracellular GSH for real-time imaging and in demand PDT. Meanwhile, the prodrug AQ4N release could be triggered by acid-cleavage of coordination bonds, then accompanied by a release of Cu(II) that would induce the electrostatic aggregation of GNPs for photo-thermal ablation; furthermore, the significantly enhanced chemotherapy efficiency could be achieved by PDT produced hypoxia to convert AQ4N into AQ4. In summary, here described nanoplatform with tumor cell specific responsive properties and programmable PDT/PTT/chemotherapy functions, might be an interesting synergistic strategy for HCC treatment.

Lipid micelles packaged with semiconducting polymer dots as simultaneous MRI/photoacoustic imaging and photodynamic/photothermal dual-modal therapeutic agents for liver cancer.

Incorporating multiple imaging modalities and simultaneous therapeutic functions together into one single nano-formulation is of great importance for developing high-performance clinical-translatable theranostic agents. Herein, we fabricated multifunctional lipid-micelles incorporated with semiconducting polymer dots and a photosensitizer (referred as Pdots/Ce6@lipid-Gd-DOTA micelles) for combined magnetic resonance imaging (MRI)/photoacoustic imaging (PAI) and photodynamic (PDT)/photothermal (PTT) dual-modal therapy that induced by a single laser to achieve enhanced cancer therapeutic efficiency. The Pdots/Ce6@lipid-Gd-DOTA micelles with excellent water dispersibility were comprised of a core with poly[2,6-(4,4-bis-(2-ethylhexyl)-4H-cyclopenta[2,1-b;3,4-b']-dithiophene)-alt-4,7-(2,1,3-benzo-thiadiazole)] dots (Pdots) and Ce6 molecules inside, and a lipid-PEG outlayer conjugated with gadolinium-1,4,7,10-tetraacetic acid. The prepared Pdots/Ce6@lipid-Gd-DOTA micelles exhibited extremely low cytotoxicity, and had excellent MR- and PA-imaging contrast-enhancement ability, which could synchronously offer anatomical information and morphological information of tumors. Moreover, both Pdots and Ce6 photosensitizer, encapsulated inside the lipid-Gd-DOTA micelles, exhibited high NIR absorption at 670 nm and were applied to combine photothermal and photodynamic therapy simultaneously to achieve enhanced synergistic cancer therapeutic efficiency both in vitro and in vivo. In summary, our studies demonstrated that Pdots/Ce6@lipid-Gd-DOTA micelles with multi-diagnosis modalities and simultaneous dual-modal photo-therapy functions might be a potential interesting theranostic platform for tumor treatment.

Chlorin e6 Conjugated Poly(dopamine) Nanospheres as PDT/PTT Dual-Modal Therapeutic Agents for Enhanced Cancer Therapy.

Photodynamic therapy (PDT), using a combination of chemical photosensitizers (PS) and light, has been successfully applied as a noninvasive therapeutic procedure to treat tumors by inducing apoptosis or necrosis of cancer cells. However, most current clinically used PS have suffered from the instability in physiological conditions which lead to low photodynamic therapy efficacy. Herein, a highly biocompatible poly(dopamine) (PDA) nanoparticle conjugated with Chlorin e6 (referenced as the PDA-Ce6 nanosphere) was designed as a nanotherapeutic agent to achieve simultaneous photodynamic/photothermal therapy (PDT/PTT). Compared to the free Ce6, the PDA-Ce6 nanosphere exhibited significantly higher PDT efficacy against tumor cells, because of the enhanced cellular uptake and subsequently greater reactive oxygen species (ROS) production upon laser irradiation at 670 nm. Meanwhile, the PDA-Ce6 nanosphere could be also used as a photoabsorbing agent for PTT, because of the excellent photothermal conversion ability of PDA nanoparticle under laser irradiation at 808 nm. Moreover, our prepared nanosphere had extremely low dark toxicity, while excellent phototoxicity under the combination laser irradiation of 670 and 808 nm, both in vitro and in vivo, compared to any single laser irradiation alone. Therefore, our prepared PDA-Ce6 nanosphere could be applied as a very promising dual-modal phototherapeutic agent for enhanced cancer therapy in future clinical applications.

Nanocluster of superparamagnetic iron oxide nanoparticles coated with poly (dopamine) for magnetic field-targeting, highly sensitive MRI and photothermal cancer therapy.

In this paper, a core­shell nanocomposite of clusters of superparamagnetic iron oxide nanoparticles coated with poly(dopamine) (SPION clusters@PDA) is fabricated as a magnetic field-directed theranostic agent that combines the capabilities of highly sensitive magnetic resonance imaging (MRI) and photothermal cancer therapy. The highly concentrated SPION cluster core is suitable for sensitive MRI due to its superparamagnetic properties, and the poly(dopamine) coating layer can induce cancer cell death under near-infrared (NIR) laser irradiation because of the photothermal conversion ability of PDA. MRI scanning reveals that the nanocomposite has relatively high r2 and r2(*) relaxivities, and the r2(*) values are nearly threefold higher than the r2 values because of the clustering of the SPIONs in the nanocomposite core. Due to the rapid response to magnetic field gradients, enhanced cellular uptake of our nanocomposite mediated by an external magnetic field can be achieved, thus producing significantly enhanced local photothermal killing efficiency against cancer cells under NIR irritation.

Multifunctional PEG modified DOX loaded mesoporous silica nanoparticle@CuS nanohybrids as photo-thermal agent and thermal-triggered drug release vehicle for hepatocellular carcinoma treatment.

The combination of a multi-therapeutic mode with a controlled fashion is a key improvement in nanomedicine. Here, we synthesized polyethylene glycol (PEG)-modified doxorubicin (DOX)-loaded mesoporous silica nanoparticle (MSN) @CuS nanohybrids as efficient drug delivery carriers, combined with photothermal therapy and chemotherapy to enhance the therapeutic efficacy on hepatocellular carcinoma (HCC). The physical properties of the nanohybrids were characterized by transmission electron microscopy (TEM), N2 adsorption and desorption experiments and by the Vis-NIR absorption spectra. The results showed that the doxorubicin could be stored in the inner pores of mesoporous silica nanoparticles; the CuS nanoparticles, which are coated on the surface of a mesoporous silica nanoparticle, could serve as efficient photothermal therapy (PTT) agents; the loaded drug release could be easily triggered by NIR irradiation. The combination of the PTT treatment with controlled chemotherapy could further enhance the cancer ablation ability compared to any of the single approaches alone. Hence, the reported PEG-modified DOX-loaded mesoporous silica nanoparticle@CuS nanohybrids might be very promising therapeutic agents for HCC treatment.

Correlation between different Chinese medicine syndromes and changes in microcirculation in septic shock patients.

OBJECTIVE: To investigate the correlation between different Chinese medicine (CM) syndromes and variations in microcirculation in septic shock patients. METHODS: seventy Septic shock patients were divided into four groups: heat damaging qi-yin group (HDQY, 23 cases); yin exhaustion and yang collapse group (YEYC, 26 cases); excessive heat in Fu organ group (EHFO, 10 cases); and heat damaging nutrient-blood group (HDNB, 11 cases). Sublingual microcirculation parameters were observed by sidestream dark-field (SDF) imaging and scored by Acute Physiology and Chronic Health Evaluation II (APACHE II) and the Sequential Organ Failure Assessment (SOFA), and parameters of microcirculation perfusion variations and prognoses were analyzed. RESULTS: Compared with those with qi-yin heat damage, perfused vessel density (PVD) in other groups decreased dramatically (P<0.05), and APACHE II scores increased significantly (P<0.05). In addition, the recovery time was prolonged substantially (P<0.05), and the mixed venous oxygen saturation (SVO2) decreased (P<0.05). Blood lactic acid increased significantly (P<0.05), and the mixed SVO decreased (P<0.05), in the YEYC group. Compared with the thermal injury camp blood group, sublingual microcirculation parameter variations showed no obvious difference in the YEYC and EHFO groups (P>0.05). There were significant positive correlations between CM syndromes and APACHE II scoring in different groups (r=0.512, P<0.05). There were negative correlations between PVD and APACHE II scoring (r=-0.378, P=0.043), the proportion of perfused vessels (PPV) and APACHE II scoring (r=-0.472, P=0.008), as well as between the microvascular flow index (MFI) and APACHE II scoring (r=-0.424, P=0.023) in different patients. CONCLUSION: Sublingual microcirculation may serve as a clinical diagnostic parameter of the patient condition, as well as being a prognostic indicator.