A Multifunctional, Highly Biocompatible, and Double-Triggering Caramelized Nanotheranostic System Loaded with Fe3O4 and DOX for Combined Chemo-Photothermal Therapy and Real-Time Magnetic Resonance Imaging Monitoring of Triple Negative Breast Cancer.

Purpose: Owing to lack of specific molecular targets, the current clinical therapeutic strategy for triple negative breast cancer (TNBC) is still limited. In recent years, some nanosystems for malignancy treatment have received considerable attention. In this study, we prepared caramelized nanospheres (CNSs) loaded with doxorubicin (DOX) and Fe3O4 to achieve the synergistic effect of combined therapy and real-time magnetic resonance imaging (MRI) monitoring, so as to improve the diagnosis and therapeutic effect of TNBC. Methods: CNSs with biocompatibility and unique optical properties were prepared by hydrothermal method, DOX and Fe3O4 were loaded on it to obtain Fe3O4/DOX@CNSs nanosystem. Characteristics including morphology, hydrodynamic size, zeta potentials and magnetic properties of Fe3O4/DOX@CNSs were evaluated. The DOX release was evaluated by different pH/near-infrared (NIR) light energy. Biosafety, pharmacokinetics, MRI and therapeutic treatment of Fe3O4@CNSs, DOX and Fe3O4/DOX@CNSs were examined in vitro or in vivo. Results: Fe3O4/DOX@CNSs has an average particle size of 160 nm and a zeta potential of 27.5mV, it demonstrated that Fe3O4/DOX@CNSs is a stable and homogeneous dispersed system. The hemolysis experiment of Fe3O4/DOX@CNSs proved that it can be used in vivo. Fe3O4/DOX@CNSs displayed high photothermal conversion efficiency, extensive pH/heat-induced DOX release. 70.3% DOX release is observed under the 808 nm laser in the pH = 5 PBS solution, obviously higher than pH = 5 (50.9%) and pH = 7.4 (less than 10%). Pharmacokinetic experiments indicated the t1/2ß, and AUC0-t of Fe3O4/DOX@CNSs were 1.96 and 1.31 -fold higher than those of DOX solution, respectively. Additionally, Fe3O4/DOX@CNSs with NIR had the greatest tumor suppression in vitro and in vivo. Moreover, this nanosystem demonstrated distinct contrast enhancement on T2 MRI to achieve real-time imaging monitoring during treatment. Conclusion: Fe3O4/DOX@CNSs is a highly biocompatible, double-triggering and improved DOX bioavailability nanosystem that combines chemo-PTT and real-time MRI monitoring to achieve integration of diagnosis and treatment of TNBC.

Self-assembly of paramagnetic amphiphilic copolymers for synergistic therapy.

Engineering nanoparticles (NPs) with multifunctionality has become a promising strategy for cancer theranostics. Herein, theranostic polymer NPs are fabricated via the assembly of amphiphilic paramagnetic block copolymers (PCL-b-PIEtMn), in which IR-780 and doxorubicin (DOX) were co-encapsulated, for magnetic resonance (MR) and near infrared fluorescence (NIRF) imaging as well as for photo thermal therapy (PTT)-enhanced chemotherapy. The synthesized amphiphilic paramagnetic block copolymers demonstrated high relaxivity (r1 = 7.05 mM-1 s-1). The encapsulated DOX could be released with the trigger of near infrared (NIR) light. In vivo imaging confirmed that the paramagnetic NPs could be accumulated effectively at the tumor sites. Upon the NIR laser irradiation, tumor growth was inhibited by PTT-enhanced chemotherapy. The advantages of the reported system lie in the one-step convergence of multiple functions (i.e., imaging and therapy agents) into a one delivery vehicle and the dual mode imaging-guided synergistic PTT and chemotherapy. This study represents a new drug delivery vehicle of paramagnetic NPs for visualized theranostics.

Pluronic F127-functionalized molybdenum oxide nanosheets with pH-dependent degradability for chemo-photothermal cancer therapy.

Traditional cancer therapies carry a risk of serious side effects and toxicity. Developing an alternative treatment modality that is highly effective, has low toxicity and is noninvasive is urgently required. Here, we exploited molybdenum oxide (MoOx) nanosheets as a drug carrier and degradable photothermal agent to provide a chemo-photothermal combination cancer therapy. The MoOx nanosheets were synthesized by a one-pot hydrothermal method and then modified with pluronic F127 to improve physiological stability and biocompatibility. The F127-modified nanosheets (MoOX@F127) showed ultrahigh drug loading efficiency (DLE) of doxorubicin (DOX) (DLE%; 65%, W(load DOX)/[W(load DOX) + WMoOx@F127]), strong near-infrared (NIR) absorption and desirable pH-dependent degradability. After intravenous injection, MoOx@F127 nanosheets were degraded at physiological pH and were rapidly excreted from normal organs, while they were effectively accumulated and retained long-term in the more acidic tumor tissue. This simultaneously ensured effective tumor ablation after NIR irradiation and avoided long-term retention and toxicity in vivo. Compared to chemotherapy or photothermal therapy alone, in vitro and in vivo tumor ablation studies have shown a notably improved synergistic effect of the combination therapy. Our study presents a multifunctional nanosystem with a desirable degradability for chemo-photothermal combination cancer therapy that has great potential in biomedical applications.

Sorafenib and gadolinium co-loaded liposomes for drug delivery and MRI-guided HCC treatment.

To improve the poor water solubility of sorafenib and to monitor its distribution and the early feedback effects on its in vivo treatment efficacy in a precise manner, sorafenib (SF) and gadolinium (Gd) co-loaded liposomes (SF/Gd-liposomes) were prepared. The simultaneous imaging and therapy efficacies of the SF/Gd-liposomes were tested. The solubility of SF in SF/Gd-liposomes was significantly increased from 0.21 µg/mL to 250 µg/mL. The imaging capability of SF/Gd-liposomes were tested by in-vitro and the in-vivo imaging ability tests and the results confirmed that SF/Gd-liposomes could be served as an effective contrast agent. The design of SF/Gd-liposomes allowed the MRI-guided in vivo visualization of the delivery and biodistribution of liposome. In the in vivo antitumor studies, SF/Gd-liposomes had better antitumor effects in H22 tumor-bearing mice than SF solution (oral or i.v. administration) (P<0.05). These findings indicated that the SF/Gd-liposomes could be used as the promising nano-carriers for the MRI-guided in vivo visualization of the delivery and HCC treatment.

Cigarette smoke extract induces the proliferation of normal human urothelial cells through the NF-κB pathway.

Bladder cancer is a common genitourinary malignant disease worldwide. Convincing evidence shows that cigarette smoke (CS) is a crucial risk factor for bladder cancer, yet the role of the NF-κB signaling pathway in the development of CS-associated bladder cancer has not been fully elucidated. In the present study, we found that exposure to cigarette smoke extract (CSE) induced proliferation and triggered the transition of normal human urothelial cells from G1 to S phase. Moreover, CSE exposure enhanced the expression of cyclin D1 and proliferating cell nuclear antigen (PCNA) and decreased the expression of p21 in SV-HUC-1 cells. Furthermore, the levels of nuclear NF-κB p65/p50 were significantly elevated by CSE. Pre-treatment with the NF-κB inhibitor (PDTC) reversed CSE-triggered cell proliferation. Taken together, our study revealed that CSE induced proliferation of normal human urothelial cells through the NF-κB pathway, and these data enhance our understanding of the CSE-related carcinogenesis of bladder cancer.

Theranostic Polymeric Micelles for the Diagnosis and Treatment of Hepatocellular Carcinoma.

Theranostics, which combine molecular imaging (diagnostics) and drug delivery (therapeutics) in a single platform, have recently shown great potential in cancer therapy. In this article, a polymeric micelle was designed and prepared for simultaneous magnetic resonance imaging (MRI) and treatment of hepatocellular carcinoma (HCC). Theranostic micelles were assembled using Poly(lactic acid)-poly(ethylene glycol)-poly(L-lysine)-diethylenetriamine pentaacetic acid (PLA-PEG-PLL-DTPA) and PLA-PEG-PLL-Biotin. The HCC therapeutic paclitaxel (PTX) was encapsulated in the cores and Gd ions for imaging were chelated to the DTPA moieties. Biotinylated alpha-fetoprotein (AFP) antibodies were linked to the micelle surface by a biotin-avidin reaction to form targeted Gd/PTX-loaded micelles (TGPM). TGPM were of spherical or ellipsoidal shape with uniform particle size distribution (147.50 ± 4.71 nm), positive zeta potential (24.45 ± 1.04 mV), and high encapsulation efficiency (88.76 ± 1.64%) and drug loading (1.59 ± 0.06%). The cytotoxicity of TGPM in HepG2 cells was superior to that of Taxol or Gd/PTX-loaded micelles (GPM). In MRI tests in vitro, the T1 relaxivity of TGPM was 21.589 mM(-1) s(-1), 4.4 times higher than Magnevist (r1 = 4.8 mM(-1) s(-1)). In H22 tumor-bearing mice, TGPM significantly increased tumor imaging intensity (more than 3 times) and prolonged imaging time (from 1 to 6 h) compared to Magnevist. In vivo, TGPM exhibited higher anti-tumor efficiency than Taxol and GPM. These results indicate that TGPM has great potential in HCC theranostics.

Tunable SERS-tags-hidden gold nanorattles for theranosis of cancer cells with single laser beam.

With the use of gold nanostructures, photothermal therapy (PTT) of cancer has great advantages compared to conventional methods, such as noninvasive targeted destruction and easily operation. Generally speaking, respective diagnosis and therapy of tumor require at least two instruments, leading to incongruence of tumor borders between diagnosis and therapy. To tackle this problem, tunable SERS-tags-hidden gold nanorattles (STHGNRs) have been designed and developed here for theranosis of cancer with single laser beam. The surface plasma resonance peak of STHGNRs can be tuned from visible region to near-infrared region by controlling the cavity size and shell thickness. The outer shells not only improve the stability of the SERS reporters but also enhance the brightness by more than two order magnitude compared to gold nanoparticles. In vitro study, immuno STHGNRs can serve as theranosis agents simultaneously for sensitive and efficient theranosis of cancer cells.

A randomized, double-blind, placebo-controlled trial of a Chinese herbal Sophora flower formula in patients with symptomatic haemorrhoids: a preliminary study.

Dried flowers and buds of Sophora japonica (Huaihua) are used in China, Japan and Korea for treating haematemesis and bleeding haemorrhoids. This study compared the clinical safety and efficacy of a Sophora flower formula with a placebo for the conservative treatment of symptomatic haemorrhoids. The study was a prospective, double-blind, randomized placebo-controlled trial. The clinical effective rate, symptom score and the incidence of important clinical events were used as observation indices to evaluate the effect of the Sophora flower formula. The results showed that after 7 days of treatment, improvement was observed in 87.0% of the patients' major symptoms in the Sophora flower formula group compared with 81.8% of those in the placebo group. After 14 days, 78.2% patients in the Sophora flower formula group were asymptomatic, whereas 40.9% of those in the placebo group exhibited residual symptoms. However, the difference between both groups was not statistically significant. As the bowel habits of the patients improved and as the patients took sitz baths, their symptoms improved drastically, regardless of the use of the Sophora flower formula. These findings indicate that the traditional Chinese Sophora flower formula is clinically safe; however, its effects on haemorrhoids need to be studied in a larger sample size and with different dosages. The present study results may be a potential clinical reference for physicians prescribing medications for patients with symptomatic haemorrhoids.

Gadolinium-loaded chitosan nanoparticles as magnetic resonance imaging contrast agents for the diagnosis of tumor.

The aim of our study was to prepare gadolinium loaded chitosan nanoparticles (Gd-CSNPs) for magnetic resonance imaging (MRI). The chitosan nanoparticles (CSNPs) were prepared by ionic gelation method with sodium tripolyphosphate. The Gd ions were conjugated to the surface of CSNPs through diethylenetriamine pentaacetic acid (DTPA) using N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (EDC) and N-hydroxysuccinimide (NHS) to obtain Gd-CSNPs. The physicochemical properties of CSNPs and Gd-CSNPs were measured by transmission electron microscope, dynamic light scattering and inductively coupled plasma optical emission spectroscopy, respectively. The cell toxicity evaluation was performed in mouse B16 cells by MTT assay. The T1-weighed magnetic resonance images were measured by a 3.0 T Sigma scanner. The morphologies of the CSNPs and Gd-CSNPs were spherical or ellipsoidal in shape. The mean sizes of the CSNPs and Gd-CSNPs were 110.9 +/- 6.8 nm and 153.0 +/- 7.5 nm, respectively. The zeta potentials of the CSNPs and Gd-CSNPs were 22.30 +/- 0.77 mV and 13.91 +/- 4.26 mV, respectively. The relaxation rates of Gd-CSNPs and Magnevist were 7.509 mM(-1) x s(-1) and 3.052 mM(-1) x s(-1), respectively. The Gd-CSNPs exhibited high T1 relaxivity and no obvious cytotoxicity was observed under the experimental concentrations in mouse B16 melanoma cells. These results indicated that the Gd-CSNPs had great potential as MRI contrast agents for the early diagnosis of tumor.

Transcutaneous electrical nerve stimulation on ST36 and SP6 acupoints prevents hyperglycaemic response during anaesthesia: a randomised controlled trial.

BACKGROUND AND OBJECTIVE: Hyperglycaemia is a common result of stress signals caused by pain and surgical procedure. Volatile anaesthetics also directly manipulate glucose homeostasis by affecting pancreatic insulin release and induce hyperglycaemia without surgical stress. We determined the preoperative application of transcutaneous electrical nerve stimulation (TENS) to the Chinese acupoints ST36 (Zusanli) and SP6 (Sanyinjiao) as a complementary therapy for controlling plasma glucose and improving insulin resistance during anaesthesia. METHODS: We designed a single-blind, randomised controlled clinical study of female patients, scheduled for elective hysterectomy. The 52 patients consented to enrolment and were assigned to receive either TENS (n = 26) on bilateral ST36 and SP6 acupoints with continuous mode at a frequency of 15 Hz and the intensity of 10 mA synchronously for 30 min or non-stimulation (placebo group, n = 26) preoperatively. Haemodynamics, blood glucose and plasma insulin were measured during general anaesthesia. RESULTS: At baseline, there was no significant difference between the TENS group and the placebo group in plasma glucose and insulin levels as well as homeostasis model assessment (HOMA) index. In the placebo group, plasma glucose, insulin and HOMA index increased during induction of general anaesthesia, surgical incision, and throughout the operation. Plasma glucose and insulin levels as well as HOMA index were significantly lower in the TENS group as compared to the placebo group at different time points after discontinuation of TENS application. These results indicate the positive effect of prevention of hyperglycaemia and the increased sensitivity of plasma insulin in the TENS group. CONCLUSION: We found TENS at bilateral ST36 and SP6 acupoints to be an alternative means of managing the plasma glucose level and improving insulin resistance perioperatively.

[Application value of 3T 1H-magnetic resonance spectroscopy in diagnosing tumors of bone and soft tissue].

OBJECTIVE: To study benign and malignant bone and soft tissue tumors with 1H-magnetic resonance spectroscopy (1H-MRS) at 3 Tesla MR scanner and assess the value of 1H-MRS in diagnosing bone and soft tissue tumors and distinguishing benign from malignant tumors. METHODS; Totally 49 patients with clinically and pathologically confirmed bone and soft tissue tumors were enrolled in this study. 1H-MRS was performed before treatment with point-resolved spectroscopy sequence. The imaging characteristics of 1H-MRS for bone and soft tissue tumors were observed and the possible differences between benign and malignant tumors was compared. Since spectra were directly found under single-voxel proton MRS brain examination, the peak height of choline containing compounds (Cho) opposite to the creatine (Cr) and the Cho peak were observed, and then the malignancies of the tumors were judged. Cho/Cr value was calculated and used to distinguishing benign tumors from malignancies. RESULTS: 1H-MRS spectra of bone and soft tissue tumors were different from those of the normal muscles, and such difference also existed between benign and malignant tumors. The Cho peak disappeared or was extremely low among benign tumors. The Cho/Cr values of malignant tumors and benign tumors were 3.13 +/- 0.9 and 1.34 +/- 1.02, respectively (P = 0.02). Using 1.79 as the threshold value, the Cho/Cr value had sensitivity, specificity, and accuracy of 94%, 80%, and 90%, respectively, in diagnosing malignancies. CONCLUSIONS: The increased Cho level, as measured by 1H-MRS, is related with the bone and soft tissue malignant tumor. Cho/Cr value is useful in distinguishing benign tumors from malignancies. 1H-MRS can be an important supplement to the conventional magnetic resonance imaging.

[Changes of 3-tesla 31P-MR spectroscopy of bone and soft tissue tumors].

OBJECTIVE: To study the characteristic changes of 31P-MR spectroscopy of bone and soft tissue tumors. METHODS: 41 patients were examined by phosphorus surface coil of 3 tesla MR machine, including 18 benign tumor foci and 28 malignant foci, and adjacent normal muscles. The areas under the peaks of various metabolites in the spectra were measured, including phosphomonoester (PME), inorganic phosphours (Pi), phosphodiester (PDE), phosphocreatine (Pcr), adenosine triphosphate (ATP) gamma, alpha, beta. The ratios of the metabolites to beta-ATP, NTP and Pcr were calculated. Intracellular pH was calculated according to the chemical shift change of Pi relative to Pcr. RESULTS: The ratios of Pcr/PME and PME/NTP in benign and malignant tumor groups were significantly different from those of the normal group (P<0.05). Between benign and malignant tumor groups, the ratios of PME/beta-ATP and PME/NTP were significantly different (P<0.05). CONCLUSION: Pcr/PME and PME/NTP are potential diagnostic indexes of bone and soft tissue tumors. PME/beta-ATP and PME/NTP are potential indexes of differential diagnosis of bone and soft tissue tumors.

[Reliability and validity of the Occupational Stress Scale for Chinese offshore oil platform workers].

OBJECTIVE: To evaluate the validity and reliability of the Occupational Stress Scale (OSS) for Chinese offshore oil platform workers. METHODS: A 51-item self-administered questionnaire developed in the light of Cooper's questionnaire and company's special situation was used to investigate 561 subjects. RESULTS: 51 occupational stress items relating to offshore oil production were subjected to factor analysis, and nine latent factors were identified, which explained 62.5% of the total variance. According to the contents described by the items included in each factor, they were respectively defined as: "the interface between job and family/social life (factor 1)", "career and achievement (factor 2)", "safety (factor 3)", "management problem and relationship with others at work (factor 4)", "physical factors of workplace (factor 5)", "platform living environment (factor 6)", "role in management (factor 7)", "ergonomics (factor 8)" and "organization structure (factor 9)". Significant difference in the score of five factors was observed among 12 different job categories by analysis of variance. After adjusting for potential confounding factors (age, educational level), hierarchical multiple regression analysis indicated that the score of the OSS was significantly and positively correlated with the poor mental health of the workers (P < 0.01). The consistent test between OSS and each factor showed that Cronbach's alpha were 0.72 - 0.91. CONCLUSION: The OSS is a valid and reliable tool for measuring occupational stress, and can be used to explore occupational stress and its influence on health and safety problems in offshore oil workers.