Intracellular Mutual Amplification of Oxidative Stress and Inhibition Multidrug Resistance for Enhanced Sonodynamic/Chemodynamic/Chemo Therapy.

Emerging noninvasive treatments, such as sonodynamic therapy (SDT) and chemodynamic therapy (CDT), have developed as promising alternatives or supplements to traditional chemotherapy. However, their therapeutic effects are limited by the hypoxic environment of tumors. Here, a biodegradable nanocomposite-mesoporous zeolitic-imidazolate-framework@MnO2 /doxorubicin hydrochloride (mZMD) is developed, which achieves enhanced SDT/CDT/chemotherapy through promoting oxidative stress and overcoming the multidrug resistance. The mZMD decomposes under both ultrasound (US) irradiation and specific reactions in the tumor microenvironment (TME). The mZM composite structure reduces the recombination rate of e- and h+ to improve SDT. MnO2 not only oxidizes glutathione in tumor cells to enhance oxidative stress, but also converts the endogenic H2 O2 into O2 to improve the hypoxic TME, which enhances the effects of chemotherapy/SDT. Meanwhile, the generated Mn2+ catalyzes the endogenic H2 O2 into ·OH for CDT, and acts as magnetic resonance imaging agent to guide therapy. In addition, dissociated Zn2+ further breaks the redox balance of TME, and co-inhibits the expression of P-glycoprotein (P-gp) with generated ROS to overcome drug resistance. Thus, the as-prepared intelligent biodegradable mZMD provides an innovative strategy to enhance SDT/CDT/chemotherapy.

Evaluation of whole axillary status with lymphatic contrast-enhanced ultrasound in patients with breast cancer.

OBJECTIVES: This study aims to evaluate the whole axillary status of patients with breast cancer by lymphatic contrast-enhanced ultrasound (LCEUS). METHODS: LCEUS was applied for 169 patients with suspected breast cancer. Abnormal patterns in lymphatic channels, sentinel lymph nodes (SLNs), and non-enhanced but abnormal lymph nodes were investigated. The signs of distorted, attenuated, netted, or interrupted lymphatic channels, defective-filling or no-filling SLNs, and the appearance of non-enhanced but abnormal lymph nodes were designated as features of axillary metastasis. A positive outcome was given when any of the abnormal patterns was found in the LCEUS. The diagnostic efficiencies were calculated to differentiate the axillary lymphatic status using LCEUS for the whole axilla, compared with conventional ultrasound (US) and LCEUS for SLNs. RESULTS: The LCEUS procedure was successfully performed for 157 breast cancer patients with axillary dissection. Compared to normal axillae, abnormal patterns had a significantly higher frequency in metastatic axillae (p = 0.000). Using conventional US to evaluate the whole axillae, the diagnostic sensitivity, specificity, and accuracy were 69.1%, 71.9%, and 70.7%, respectively. When LCEUS was used for SLN evaluation to predict the whole axilla, the diagnostic sensitivity, specificity, and accuracy were 66.2%, 89.9%, and 79.6%, respectively. When LCEUS was used as the whole axillary evaluation method, the diagnostic sensitivity, specificity, and accuracy were 76.5%, 86.5%, and 82.2%, respectively. CONCLUSION: LCEUS can be an accurate method to observe the whole axillae in breast cancer patients. Lymphatic channels, SLNs, and non-enhanced but abnormal lymph nodes constitute the LCEUS for whole axillary evaluation. KEY POINTS: • LCEUS can be an accurate method to observe the whole axillae in breast cancer patients. • Three aspects in the LCEUS for whole axillary evaluation are the lymphatic channels, sentinel lymph nodes (SLNs), and non-enhanced but abnormal lymph nodes. • Signs of distorted, attenuated, netted, or interrupted lymphatic channels, defective-filling or no-filling SLNs, and the appearance of non-enhanced but abnormal lymph nodes were considered as features of axillary metastasis.

Design of DNA Aptamer-Functionalized Magnetic Short Nanofibers for Efficient Capture and Release of Circulating Tumor Cells.

The isolation of viable circulating tumor cells (CTCs) from blood is of paramount significance for early stage detection and individualized therapy of cancer. Currently, CTCs isolated by conventional magnetic separation methods are tightly coated with magnetic materials even after attempted coating removal treatments, which is not conducive for subsequent analysis of CTCs. Herein, we developed DNA aptamer-functionalized magnetic short nanofibers (aptamer-MSNFs) for efficient capture and release of CTCs. In our work, polyethylenimine (PEI)-stabilized Fe3O4 nanoparticles with a mean diameter of 22.6 nm were first synthesized and encapsulated within PEI/poly(vinyl alcohol) nanofibers via a blended electrospinning process. After a homogenization treatment to acquire the MSNFs, surface conjugation of the DNA aptamer was performed through thiol-maleimide coupling. The formed aptamer-MSNFs, with a mean diameter of 350 nm and an average length of 9.6 µm, display a saturated magnetization of 12.3 emu g-1, are capable of specifically capturing cancer cells with an efficiency of 87%, and enable the nondestructive release of cancer cells with a release efficiency of 91% after nuclease treatment. In particular, the prepared aptamer-MSNFs displayed a significantly higher release efficiency than commercial magnetic beads. The designed aptamer-MSNFs may hold great promise for CTC capture and release as well as for other cell sorting applications.

A Microfluidic Chip Integrated with Hyaluronic Acid-Functionalized Electrospun Chitosan Nanofibers for Specific Capture and Nondestructive Release of CD44-Overexpressing Circulating Tumor Cells.

Detection of circulating tumor cells (CTCs) in peripheral blood is of paramount significance for early-stage cancer diagnosis, estimation of cancer development, and individualized cancer therapy. Herein, we report the development of hyaluronic acid (HA)-functionalized electrospun chitosan nanofiber (CNF)-integrated microfludic platform for highly specific capture and nondestructive release of CTCs. First, electrospun CNFs were formed and modified with zwitterion of carboxyl betaine acrylamide (CBAA) via Michael addition reaction and then targeting ligand HA through a disulfide bond. We show that the formed nanofibers still maintain the smooth fibrous morphology after sequential surface modifications, have a good hemocompatibility, and exhibit an excellent antifouling property due to the CBAA modification. After being embedded within a microfluidic chip, the fibrous mat can capture cancer cells (A549, a human lung cancer cell line) with an efficiency of 91% at a flow rate of 1.0 mL/h. Additionally, intact release of cancer cells is able to be achieved after treatment with glutathione for 40 min to have a release efficiency of 90%. Clinical applications show that 9 of 10 nonsmall-cell lung cancer patients and 5 of 5 breast cancer patients are diagnosed to have CTCs (1 to 18 CTCs per mL of blood). Our results suggest that the developed microfluidic system integrated with functionalized CNF mats may be employed for effective CTCs capture for clinical diagnosis of cancer.

Periostin promotes the chemotherapy resistance to gemcitabine in pancreatic cancer.

Pancreatic ductal adenocarcinoma (PDAC) ranks fourth among cancer-related deaths. The nucleoside analog gemcitabine has been the cornerstone of adjuvant chemotherapy in PDAC for decades. However, gemcitabine resistance develops within weeks of chemotherapy initiation, which might be intrinsic to cancer cells and influenced by tumor microenvironment. Recently, pancreatic stellate cells (PSCs) have greatly increased our attention on tumor microenvironment-mediated drug resistance. Periostin is exclusively overexpressed in PSCs and the stroma of PDAC creating a tumor-supportive microenvironment in the pancreas. However, whether periostin contributed to chemoresistance in PDAC remains unknown. Therefore, we focused on the role of periostin in PDAC by observing the effects of silencing this gene on gemcitabine resistance in vitro and in vivo aiming to explore the possible molecular mechanism. In this study, the pancreatic cancer cell (PCC) proliferation and apoptosis were assayed to investigate the sensitivity to gemcitabine after silencing periostin. We provide the evidence that periostin not only drives the carcinogenic process itself but also significantly associated with gemcitabine-induced apoptosis. These findings collectively indicated that periostin increases the chemoresistance to gemcitabine. Thus, targeting periostin might offer a new opportunity to overcome the gemcitabine resistance of PDAC.

UTMD inhibits pancreatic cancer growth and metastasis by inducing macrophage polarization and vessel normalization.

Pancreatic cancer (PaCa) is a hypovascular type of tumor and is not very responsive to conventional chemotherapy due to the problem of low drug accumulation. Recent advancements in ultrasound targeted microbubble destruction (UTMD) have improved drug delivery into target tissues. UTMD operates via microbubble interaction with vascular endothelial cells; however, the molecular mechanism and interrelationship in the PaCa microenvironment remain enigmatic. Tumor-associated macrophages (TAMs) have different phenotypes and regulate tumorigenesis. Using a PaCa orthotopic model, we established that UTMD improved chemotherapy by redirecting TAM polarization from M2 macrophages to tumor-inhibiting M1 macrophages, remodeling vessel normalization, and inducing anti-tumor immune responses. Tumor vascular maturity and function were also improved, and an insignificant change in vascular density resulting in enhanced blood perfusion and inhibited tumor growth and metastasis were observed. Therefore, this research unveils the crucial role of TAM polarization on UTMD-induced tumor vessel normalization and inhibition of tumor progression. These findings offer a novel insight into UTMD-mediated drug delivery for anti-tumor and anti-angiogenic treatment.

Protection of electroactive biofilms against hypersaline shock by quorum sensing.

Quorum sensing (QS) is an ideal strategy for boosting the operating performance of electroactive biofilms (EABs), but its potential effects on the protection of electroactive biofilms against environmental shocks (e.g., hypersaline shock) have been rarely revealed. In this study, a QS signaling molecule, the N-(3-oxo-dodecanoyl)-L-homoserine lactone, was employed to promote the anti-shock property of the EABs against extreme saline shock. The maximum current density of the QS-regulated biofilm recovered to 0.17 mA/cm2 after 10% salinity exposure, which was much higher than those of its counterparts. The laser scanning confocal microscope confirmed a thicker and more compact biofilm with the presence of the QS signaling molecule. The extracellular polymeric substances (EPS) might play a crucial role in the anti-shocking behaviors, as the polysaccharides in EPS of QS-biofilm had doubled compared to the groups with acylase (the QS quencher). The microbial community analysis indicated that the QS molecule enriched the relative abundance of key species including Pseudomonas sp. and Geobacter sp., which were both beneficial to the stability and electroactivity of the biofilms. The functional genes related to the bacterial community were also up-regulated with the presence of the QS molecule. These results highlight the importance of QS effects in protecting electroactive biofilm under extreme environmental shock, which provides effective and feasible strategies for the future development of microbial electrochemical technologies.

The facilitating role of phycospheric heterotrophic bacteria in cyanobacterial phosphonate availability and Microcystis bloom maintenance.

BACKGROUND: Phosphonates are the main components in the global phosphorus redox cycle. Little is known about phosphonate metabolism in freshwater ecosystems, although rapid consumption of phosphonates has been observed frequently. Cyanobacteria are often the dominant primary producers in freshwaters; yet, only a few strains of cyanobacteria encode phosphonate-degrading (C-P lyase) gene clusters. The phycosphere is defined as the microenvironment in which extensive phytoplankton and heterotrophic bacteria interactions occur. It has been demonstrated that phytoplankton may recruit phycospheric bacteria based on their own needs. Therefore, the establishment of a phycospheric community rich in phosphonate-degrading-bacteria likely facilitates cyanobacterial proliferation, especially in waters with scarce phosphorus. We characterized the distribution of heterotrophic phosphonate-degrading bacteria in field Microcystis bloom samples and in laboratory cyanobacteria "phycospheres" by qPCR and metagenomic analyses. The role of phosphonate-degrading phycospheric bacteria in cyanobacterial proliferation was determined through coculturing of heterotrophic bacteria with an axenic Microcystis aeruginosa strain and by metatranscriptomic analysis using field Microcystis aggregate samples. RESULTS: Abundant bacteria that carry C-P lyase clusters were identified in plankton samples from freshwater Lakes Dianchi and Taihu during Microcystis bloom periods. Metagenomic analysis of 162 non-axenic laboratory strains of cyanobacteria (consortia cultures containing heterotrophic bacteria) showed that 20% (128/647) of high-quality bins from eighty of these consortia encode intact C-P lyase clusters, with an abundance ranging up to nearly 13%. Phycospheric bacterial phosphonate catabolism genes were expressed continually across bloom seasons, as demonstrated through metatranscriptomic analysis using sixteen field Microcystis aggregate samples. Coculturing experiments revealed that although Microcystis cultures did not catabolize methylphosphonate when axenic, they demonstrated sustained growth when cocultured with phosphonate-utilizing phycospheric bacteria in medium containing methylphosphonate as the sole source of phosphorus. CONCLUSIONS: The recruitment of heterotrophic phosphonate-degrading phycospheric bacteria by cyanobacteria is a hedge against phosphorus scarcity by facilitating phosphonate availability. Cyanobacterial consortia are likely primary contributors to aquatic phosphonate mineralization, thereby facilitating sustained cyanobacterial growth, and even bloom maintenance, in phosphate-deficient waters. Video Abstract.

The widespread capability of methylphosphonate utilization in filamentous cyanobacteria and its ecological significance.

Aquatic ecosystems comprise almost half of total global methane emissions. Recent evidence indicates that a few strains of cyanobacteria, the predominant primary producers in bodies of water, can produce methane under oxic conditions with methylphosphonate serving as substrate. In this work, we have screened the published 2 568 cyanobacterial genomes for genetic elements encoding phosphonate-metabolizing enzymes. We show that phosphonate degradation (phn) gene clusters are widely distributed in filamentous cyanobacteria, including several bloom-forming genera. Algal growth experiments revealed that methylphosphonate is an alternative phosphorous source for four of five tested strains carrying phn clusters, and can sustain cellular metabolic homeostasis of strains under phosphorus stress. Liberation of methane by cyanobacteria in the presence of methylphosphonate occurred mostly during the light period of a 12 h/12 h diurnal cycle and was suppressed in the presence of orthophosphate, features that are consistent with observations in natural aquatic systems under oxic conditions. The results presented here demonstrate a genetic basis for ubiquitous methane emission via cyanobacterial methylphosphonate mineralization, while contributing to the phosphorus redox cycle.

Ultrasound-enhanced fluorescence imaging and chemotherapy of multidrug-resistant tumors using multifunctional dendrimer/carbon dot nanohybrids.

Development of innovative nanomedicine enabling enhanced theranostics of multidrug-resistant (MDR) tumors remains to be challenging. Herein, we report the development of a newly designed multifunctional yellow-fluorescent carbon dot (y-CD)/dendrimer nanohybrids as a platform for ultrasound (US)-enhanced fluorescence imaging and chemotherapy of MDR tumors. Generation 5 (G5) poly(amidoamine) dendrimers covalently modified with efflux inhibitor of d-α-tocopheryl polyethylene glycol 1000 succinate (G5-TPGS) were complexed with one-step hydrothermally synthesized y-CDs via electrostatic interaction. The formed G5-TPGS@y-CDs complexes were then physically loaded with anticancer drug doxorubicin (DOX) to generate (G5-TPGS@y-CDs)-DOX complexes. The developed nanohybrids display a high drug loading efficiency (40.7%), strong y-CD-induced fluorescence emission, and tumor microenvironment pH-preferred DOX release profile. Attributing to the DOX/TPGS dual drug design, the (G5-TPGS@y-CDs)-DOX complexes can overcome the multidrug resistance (MDR) of cancer cells and effectively inhibit the growth of cancer cells and tumors. Furthermore, the introduction of US-targeted microbubble destruction technology was proven to render the complexes with enhanced intracellular uptake and anticancer efficacy in vitro and improved chemotherapeutic efficacy and fluorescence imaging of tumors in vivo due to the produced sonoporation effect. The developed multifunctional dendrimer/CD nanohybrids may represent an advanced design of nanomedicine for US-enhanced theranostics of different types of MDR tumors.

The Long-Term Fate of the Sonoporated Pancreatic Cancer Cells is Uncorrelated With the Degree of Model Molecular Loading.

Studies have determined that ultrasound-activated microbubbles can increase the membrane permeability of tumor cells by triggering membrane perforation (sonoporation) to improve drug loading. However, because of the distinct cavitation events adjacent to each cell, the degree of drug loading appeared to be heterogeneous. The relationship between the long-term fate trend and the degree of drug loading remains unclear. To investigate the time-lapse viability of diversity loading cells, fluorescein isothiocyanate-dextran (FITC-dextrans) was used as a molecular model mixed with 2% v/v SonoVue microbubbles (Bracco, Milan, Italy) and exposed to various peak negative pressures (0.25 MPa, 0.6 MPa, 1.2 MPa), 1 MHz frequency and 300 µs pulse duration. To select a suitable parameter, the cavitation activity was measured, and the cell analysis was performed by flow cytometry under these acoustic pressures. The sonoporated cells were then categorized into 3 sub-groups by flow cytometry according to the various fluorescence intensity distributions to analyze their long-term fate. We observed that the stable cavitation occurred at 0.25 MPa and microbubbles underwent ultra-harmonic emission, and obvious broadband signals were observed at 0.6 MPa and 1.2 MPa, suggesting the occurs of inertial cavitation. The cell analysis further showed the maximum delivery efficiency and cell viability at 0.6 MPa, and it was selected for the following experiment. The categorization displayed that the fluorescence intensity of FITC-dextrans in sub-groups 2 and 3 were approximate 5.62-fold and 19.53-fold higher than that in sub-group 1, respectively. After separation of these sub-groups, the apoptosis and necrosis ratios in all 3 sub-groups of sonoporated cells gradually increased with increasing culture time and displayed no significant difference in either the apoptosis (p > 0.05) or necrosis (p > 0.05) ratio after 6 h and 24 h of culture, respectively. Further analysis using Western blot verified that the long-term fate of sonoporated cells involves the mitochondrial signaling proteins. These results provide better insight into the role of cavitation-enhanced permeability and a critical guide for acoustic cavitation designs.

Multifunctional PVCL nanogels with redox-responsiveness enable enhanced MR imaging and ultrasound-promoted tumor chemotherapy.

Development of versatile nanoplatforms that simultaneously integrate therapeutic and diagnostic features for stimuli-responsive delivery to tumors remains a great challenge. In this work, we report a novel intelligent redox-responsive hybrid nanosystem composed of MnO2 nanoparticles (NPs) and doxorubicin (DOX) co-loaded within poly(N-vinylcaprolactam) nanogels (PVCL NGs) for magnetic resonance (MR) imaging-guided and ultrasound-targeted microbubble destruction (UTMD)-promoted tumor chemotherapy. Methods: PVCL NGs were first synthesized via a precipitation polymerization method, decorated with amines using ethylenediamine, and loaded with MnO2 NPs through oxidation with permanganate and DOX via physical encapsulation and Mn-N coordination bonding. The as-prepared DOX/MnO2@PVCL NGs were well characterized. UTMD-promoted cellular uptake and therapeutic efficacy of the hybrid NGs were assessed in vitro, and a xenografted tumor model was used to test the NGs for MR imaging and UTMD-promoted tumor therapy in vivo.Results: The as-prepared DOX/MnO2@PVCL NGs with a size of 106.8 nm display excellent colloidal stability, favorable biocompatibility, and redox-responsiveness to the reductive intracellular environment and tumor tissues having a relatively high glutathione (GSH) concentration that can trigger the synchronous release of Mn2+ for enhanced T1-weighted MR imaging and DOX for enhanced cancer chemotherapy. Moreover, the DOX/MnO2@PVCL NGs upon the UTMD-promotion exhibit a significantly enhanced tumor growth inhibition effect toward subcutaneous B16 melanoma owing to the UTMD-improved cellular internalization and tumor penetration. Conclusion: Our work thereby proposes a promising theranostic nanoplatform for stimuli-responsive T1-weighted MR imaging-guided tumor chemotherapy.

Specific capture and release of circulating tumor cells using a multifunctional nanofiber-integrated microfluidic chip.

AIM: To develop a multifunctional nanofibrous mat-embedded microfluidic chip system for specific capture and intact release of circulating tumor cells. MATERIALS & METHODS: Electrospun polyethylenimine/polyvinyl alcohol nanofibers were functionalized with zwitterions to reduce the nonspecific adhesion of blood cells, followed by modification with arginine-glycine-aspartic acid peptide via an acid-sensitive benzoic imine bond. RESULTS: The nanofiber-embedded microchip can be applied for capturing various types of cancer cells and circulating tumor cells with high efficiency and considerable purity. The captured cancer cells can be released from the nanofibrous substrates within 30 min. CONCLUSION: The developed multifunctional nanofiber-embedded microfluidic chip may have a great potential for clinical applications.

Single enzyme loaded nanoparticles for combinational ultrasound-guided focused ultrasound ablation and hypoxia-relieved chemotherapy.

Constructing nanosystems that synergistically combine therapeutic and diagnostic features is of great interest to the nanomedicine community but also remains a tremendous challenge. Methods: In this work, we report novel catalytic nanoparticles composed of the enzyme catalase, encapsulated in a polymer shell and surface decorated with pH-sensitive poly(ethylene glycol) (PEGylated nCAT). These nanoparticles were used as a promoter for ultrasound (US)-guided focused ultrasound (FUS) ablation and hypoxia alleviation for application in Doxorubicin-based chemotherapy. Results: The PEGylated nCAT produced highly effectively O2 from endogenous H2O2 to ameliorate the hypoxic and therefore poor-acoustic tumor environment. The generated O2 was utilized as 1) a contrast agent for US imaging; 2) strengthening agent for FUS ablation and 3) normoxia inducer to enhance chemotherapeutic efficacy. The PEGylated nCAT exhibited favorable enzyme activity after long-term storage, and after exposure to proteolytic conditions and elevated temperatures. The pH-responsive PEGylation contributed on the one hand to an extended in vivo circulation time over 48 h and on the other hand enabled PEG cleavage in the vicinity of cancer cells to facilitate cellular uptake. Conclusion: The developed PEGylated nCAT can therefore effectively combine US-guided FUS and chemotherapy and can be regarded as a highly promising theranostic platform.

Real-Time Elastography in the diagnosis of prostate cancer: a systematic review.

AIM: To evaluate the diagnostic accuracy of real-time elastography as a method for detecting prostate cancer. MATERIAL AND METHODS: Relevant studies applying real-time elastography as the diagnostic modality and biopsy as the reference standard, published by March 1, 2018 were retrieved from PubMed, EMBASE, Web of Science and Cochrane Library databases. Two independent reviewers inspected all these articles to confirm the matching of the inclusion criteria. One reviewer with methodological expertise extracted the data from the included studies. Sensitivity, specificity and diagnostic odds ratio (DOR) were used to obtain overall estimates. Randomized effect method, meta-regression and subgroup analysis were performed. RESULTS: Twenty-four studies out of 1156 identified articles met the inclusion criteria. Three groups were set: analysisby patient (Group 1), by core (Group 2), and by image (Group 3) and subgroups set in Group 1. The pooled estimate ofreal-time elastography sensitivity/ specificity/ DOR calculated with the identical P-value 0.00. Within subgroups "Asia" and"PSA>=10 ng/ml", the pooled sensitivity, specificity and DOR were 0.83, 0.65 (p=0.01, I2=73.40%; p=0.02, I2=69.5%), 0.80, 0.82 (p=0.66, I2=0.00%; p=0.58, I2=0.00%) and 20.2, 8.67 (p=0.09, I2=54.2%; p=0.20, I2=35.5%), respectively. In these three groups, the areas under the SROC curve were 0.7417, 0.9246, and 0.6213 independently. CONCLUSIONS: Real-time elastography is a promising, reliable modality for the non-invasive diagnosis of patients with prostate cancer. The diagnostic accuracy of real-time elastography correlates tightly to the presence of higher PSA level and may help avoid unnecessary biopsy. It seems to be a useful tool in systemic biopsy.

Biodegradable, pH-Sensitive Hollow Mesoporous Organosilica Nanoparticle (HMON) with Controlled Release of Pirfenidone and Ultrasound-Target-Microbubble-Destruction (UTMD) for Pancreatic Cancer Treatment.

The dense extracellular matrix (ECM) and hypovascular networks were often found in solid pancreatic tumors form an impenetrable barrier, leading to limited uptake of chemotherapeutics and thus undesirable treatment outcomes. Methods: A biodegradable nanoplatform based on hollow mesoporous organosilica nanoparticle (HMON) was designed as an effective delivery system for pirfenidone (PFD) to overcome the challenges in pancreatic tumor treatment. By varying pH producing a mildly acidic environment to emulate tumor cells, results in cleavage of the acetal bond between HMON nanoparticle and gating molecular, gemcitabine (Gem), enabling its controlled release. Results: The in vitro and in vivo immunocytochemistry evaluations demonstrated an excellent ECM regulation efficacy of the nanoplatform and therefore the improved penetration of drug into the cells. The technique employed was especially enhanced when mediated with ultrasound target microbubble destruction (UTMD). Evaluations culminated with pancreatic cancer bearing mice and demonstrated therapeutic efficacy, good biodegradability, and negligible systemic toxicity. Conclusion: the designed Gem gated biodegradable nanosystem is expected to provide an alternative way of improving antitumor efficacy by down-regulation of ECM levels and offers a passive-targeted therapy for pancreatic cancer treatment.

Heavy metal migration and risk transference associated with cyanobacterial blooms in eutrophic freshwater.

The distribution of metals in cyanobloom-forming lakes, and potential risks of these metals during irrigation with water derived from the bloom were evaluated in this study. Seven metals were monitored throughout a cyanobacterial bloom season in Lake Taihu. Cyanobloom bio-dilution of the targeted metals could be explained by the negative relationships between total phytoplankton metal contents (Cu, Fe, Zn, Pb and Cr) and Chl a concentrations (p<0.05). Meanwhile, the ratios of extracellular bound to total cellular bound metals (Cu, Zn, Pb, Cr and Cd) were positively correlated with the ratios of cyanophyta to total phytoplankton (p<0.01), indicating the enhanced extracellular bound of these metals during cyanobloom period. Secondly, Cd, Pb and Cr were detected in several local vegetables. In comparison to reference vegetables, vegetables (e.g., radish, soybean, and cowpea), which were irrigated with cyanobloom broth collected from Lake Taihu, presented high health risk index (HRI) and were not safe for human consumption. Collectively, the frequent dominant colonial Microcystis blooms which performed high metal affinity might mediate the distribution of heavy metals in lake and potentially transferred these pollutants into terrestrial system.

UTMD-Promoted Co-Delivery of Gemcitabine and miR-21 Inhibitor by Dendrimer-Entrapped Gold Nanoparticles for Pancreatic Cancer Therapy.

Conventional chemotherapy of pancreatic cancer (PaCa) suffers the problems of low drug permeability and inherent or acquired drug resistance. Development of new strategies for enhanced therapy still remains a great challenge. Herein, we report a new ultrasound-targeted microbubble destruction (UTMD)-promoted delivery system based on dendrimer-entrapped gold nanoparticles (Au DENPs) for co-delivery of gemcitabine (Gem) and miR-21 inhibitor (miR-21i). Methods: In this study, Gem-Au DENPs/miR-21i was designed and synthesized. The designed polyplexes were characterized via transmission electron microscopy (TEM), Gel retardation assay and dynamic light scattering (DLS). Then, the optimum exposure parameters were examined by an ultrasound exposure platform. The cellular uptake, cytotoxicity and anticancer effects in vitro were analyzed by confocal laser microscopy, spectra microplate reader, flow cytometry and a chemiluminescence imaging system. Lastly, the anticancer effects in vivo were evaluated by contrast-enhanced ultrasound (CEUS), hematoxylin and eosin (H&E) staining, TUNEL staining and comparison of tumor volume. Results: The results showed that the Gem-Au DENPs/miR-21i can be uptake by cancer cells and the cellular uptake was further facilitated by UTMD with an ultrasound power of 0.4 W/cm2 to enhance the cell permeability. Further, the co-delivery of Gem and miR-21i with or without UTMD treatment displayed 82-fold and 13-fold lower IC50 values than the free Gem, respectively. The UTMD-promoted co-delivery of Gem and miR-21i was further validated by in vivo treatment and showed a significant tumor volume reduction and an increase in blood perfusion of xenografted pancreatic tumors. Conclusion: The co-delivery of Gem and miR-21i using Au DENPs can be significantly promoted by UTMD technology, hence providing a promising strategy for effective pancreatic cancer treatments.

Design and synthesis of functionalized coordination polymers as recyclable heterogeneous photocatalysts.

The functionalized ligand 9,10-anthraquinone-1,4-dicarboxylate acid (H2AQDC) was designed and synthesized in order to develop metal-organic coordination polymers as heterogeneous catalysts with a photosensitizing feature. Two major considerations of the ligand design are anthraquinone moieties for photosensitizing to harvest light and carboxylate groups for polymeric coordination toward less solubility. A series of transition metal complexes based on this ligand were synthesized subsequently, namely {Co(AQDC)(H2O)3·2H2O}n (Co-AQDC), {Ni(AQDC)(H2O)3·2H2O}n (Ni-AQDC), {[Cu(AQDC)(H2O)3][Cu(AQDC)(H2O)2(DMF)]·(H2O)4}n (Cu-AQDC), {Zn1.5(AQDC)(OH)(H2O)2·H2O}n (Zn-AQDC), {Ag2(AQDC)(CH3OH)}n (Ag-AQDC). Both the ligand and its transition metal complexes are able to catalyze the visible-light driven oxidation reactions of alkynes into 1,2-diketones in air under mild conditions, in which compound Ni-AQDC demonstrates the best activity. This catalyst can be easily isolated from the reaction mixture by filtration with a trace amount of loss in solution and is ready for recycled use after simple washing and drying without any need for regeneration. Remarkably, the catalyst shows no loss of activity after five catalytic cycles and X-ray powder diffraction proves no change in the structure after five runs. This designed metal-organic coordination polymer represents an environmentally friendly, economical and recyclable photocatalyst, constituting a good candidate for photocatalytic organic syntheses in terms of green chemistry.

TGF-ß1 and TIMP1 double directional rAAV targeted by UTMD in atherosclerotic vulnerable plaque.

In the present study, we determined whether ultrasound-targeted microbubble destruction (UTMD) combined with dual targeting of transforming growth factor (TGF)-ß1 and tissue inhibitors of metalloproteinase (TIMP) 1 recombinant adeno-associated virus (rAAV) can stabilize atherosclerotic vulnerable plaques. First, we used rabbit model to detect the TGF-ß1/TIMP1 virus therapy result. H&E staining was used to evaluate the tissues. The protein levels of TGF-ß1 and TIMP1 were detected in rabbit models. The THP-1 cells were induced into macrophages, and transfected with TGF-ß1 and TIMP1 rAAV under optimized UTMD. The expression of TGF-ß1 and TIMP1 was measured by RT-PCR and western blotting. We found that the apoptotic rates were induced when compared to the control group. The rAAV virus group showed a significant decrease in the p-ERT and p-AKT expression. These data support the hypothesis that TGF-ß1 and TIMP1 are crucial in the regulation of atherosclerotic plaques.