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Liu X.,Zhejiang University | Liu X.,Chinese Institute of Clinical Medicine | Huang Q.,Zhejiang University | Huang Q.,Chinese Institute of Clinical Medicine | And 10 more authors.
Journal of Materials Chemistry B | Year: 2017

Modification of drug delivery systems (DDSs) with stimuli-responsive elements could significantly increase the tumor-specific delivery of anticancer drugs. Herein we synthesized a novel multiple stimuli-responsive SN38 prodrug, named PEG-S-S-SN38, by conjugating PEG (MW: 2000) and SN38 with disulfide bonds and carbonic ester linkages as linkers for efficient delivery of SN38. The amphiphilic PEG-S-S-SN38, with a high SN38 loading content, could self-assemble into nanoparticles (NPs) with a stable diameter of ∼73 nm. PEG-S-S-SN38 NPs release SN38 very slowly at physiological pH, while they quickly release SN38 in the presence of GSH, esterase and H2O2, all of which are abundant in the cytoplasm of cancer cells. PEG-S-S-SN38 NPs could be quickly internalized into tumor cells, achieve vesicular escape and nuclear localization, and exhibit remarkable in vitro anticancer activity similar to SN38. Encouragingly, PEG-S-S-SN38 NPs exhibit the same effects on cell cycle regulations as SN38 in vitro. Most importantly, the inhibition rate of tumor growth induced by PEG-S-S-SN38 NPs in a xenograft tumor model reached 72.49% ± 6.26%, which was nearly double that of the corresponding clinical drug CPT-11 (38.64% ± 13.04%) at a dosage equivalent to 10 mg kg−1 SN38. Our data suggest that the multi-stimuli responsiveness of PEG-S-S-SN38 NPs remarkably enhances their therapeutic activity against heterogeneous or mixed cell population in tumors, making this new DDS a promising alternative to CPT-11 for cancer treatment. © The Royal Society of Chemistry.


Yan G.-J.,Nanjing University | Mei X.,Nanjing University | Yang J.,Nanjing University | Zhu J.,ACEA Inc | And 3 more authors.
Chinese Chemical Letters | Year: 2013

The study was designed to explore the potential applications of the real-time cell electronic analysis technology in the quality evaluation of natural medicines. The natural medicinal Flos Carthami was discussed as a methodological example and the specific time/dose-dependent cell response profiles (TCRPs) were produced by the real-time cell electronic analysis technology. The similarity and bioactivity were obtained by analyzing all TCRPs. Meanwhile, an HPLC method according to the Chinese Pharmacopeia (edition 2010) was used to evaluate the quality of Flos Carthami. The correlation was obtained by comparing the results produced by the two different approaches. By analyzing the data, five different samples of Flos Carthami can produce remarkably similar TCRPs. The quality of Flos Carthami was evaluated by both the HPLC and the TCRPs analysis-based approaches and similar results were obtained. The results suggest that the same natural medicine from different locations could produce similar TCRPs. By analyzing the TCRPs, the bioactivity and quality evaluation of natural medicines can be obtained. This technology is a physiologically relevant approach for the quality evaluation of natural medicines. The ultimate aim of our study is to establish a new standard for quality evaluation. © 2013 Ramin Ghorbani-Vaghei. Published by Elsevier B.V. on behalf of Chinese Chemical Society. All rights reserved.


Deng Y.,Fudan University | Ran W.,Fudan University | Man S.,Fudan University | Li X.,Fudan University | And 4 more authors.
Antimicrobial Agents and Chemotherapy | Year: 2015

Acanthamoeba sp. parasites are the causative agents of Acanthamoeba keratitis, fatal granulomatous amoebic encephalitis, and cutaneous infections. However, there are currently no effective drugs for these organisms. Here, we evaluated the activity of the antimalarial agent artemether against Acanthamoeba castellanii trophozoites and identified potential targets of this agent through a proteomic approach. Artemether exhibited in vitro amoebicidal activity in a time- and dose-dependent manner and induced ultrastructural modification and cell apoptosis. The iTRAQ quantitative proteomic analysis identified 707 proteins that were differentially expressed after artemether treatment. We focused on phosphoglycerate dehydrogenase and phosphoserine aminotransferase in the serine biosynthesis pathway because of their importance to the growth and proliferation of protozoan and cancer cells. The expression of these proteins in Acanthamoeba was validated using quantitative real-time PCR and Western blotting after artemether treatment. The changes in the expression levels of phosphoserine aminotransferase were consistent with those of phosphoglycerate dehydrogenase. Therefore, the downregulation of phosphoserine aminotransferase may be due to the downregulation of phosphoglycerate dehydrogenase. Furthermore, exogenous serine might antagonize the activity of artemether against Acanthamoeba trophozoites. These results indicate that the serine biosynthesis pathway is important to amoeba survival and that targeting these enzymes would improve the treatment of Acanthamoeba infections. Artemether may be used as a phosphoglycerate dehydrogenase inhibitor to control or block Acanthamoeba infections. Copyright © 2015, American Society for Microbiology. All Rights Reserved.


PubMed | Fudan University, Tokai University and ACEA Bio Hangzhou Co.
Type: Journal Article | Journal: Antimicrobial agents and chemotherapy | Year: 2015

Acanthamoeba sp. parasites are the causative agents of Acanthamoeba keratitis, fatal granulomatous amoebic encephalitis, and cutaneous infections. However, there are currently no effective drugs for these organisms. Here, we evaluated the activity of the antimalarial agent artemether against Acanthamoeba castellanii trophozoites and identified potential targets of this agent through a proteomic approach. Artemether exhibited in vitro amoebicidal activity in a time- and dose-dependent manner and induced ultrastructural modification and cell apoptosis. The iTRAQ quantitative proteomic analysis identified 707 proteins that were differentially expressed after artemether treatment. We focused on phosphoglycerate dehydrogenase and phosphoserine aminotransferase in the serine biosynthesis pathway because of their importance to the growth and proliferation of protozoan and cancer cells. The expression of these proteins in Acanthamoeba was validated using quantitative real-time PCR and Western blotting after artemether treatment. The changes in the expression levels of phosphoserine aminotransferase were consistent with those of phosphoglycerate dehydrogenase. Therefore, the downregulation of phosphoserine aminotransferase may be due to the downregulation of phosphoglycerate dehydrogenase. Furthermore, exogenous serine might antagonize the activity of artemether against Acanthamoeba trophozoites. These results indicate that the serine biosynthesis pathway is important to amoeba survival and that targeting these enzymes would improve the treatment of Acanthamoeba infections. Artemether may be used as a phosphoglycerate dehydrogenase inhibitor to control or block Acanthamoeba infections.


Su K.,Zhejiang University | Zou Q.,Zhejiang University | Li H.,Zhejiang University | Wang T.,Zhejiang University | And 4 more authors.
Sensor Letters | Year: 2015

Drug-induced cardiovascular toxicity is a principal reason for drug recall and production termination. Early and wide screening and assessment methods are demanded in the medical and pharmaceutical fields. In vitro rapid bioassay is one of the effective methods to evaluate cardiovascular function by characteristics of beating rate, contractility, and toxicity. In this study, the cardiomyocyte-based biosensors were established by impedance sensor technology and CCD imaging for drug analysis. The basic performance and drug analysis function of cardiomyocyte-based biosensor established by cell impedance sensor were tested by two Ca2+ channel compounds with contrary effects (Ca2+ channel inhibitor and agonist). From the results, cardiomyocyte-based biosensor had stable performance to sensitively reflect the drug effects. Also, another detection method of cardiomyocyte beating was developed by CCD imaging analysis. Both impedance sensor and CCD methods were tested by drug experiments, and they will open new opportunities for predicting cardiotoxicity and studying cardiac biology. Copyright © 2015 American Scientific Publishers


Wang T.,Zhejiang University | Wang T.,ACEA Bio Hangzhou Co. | Hu N.,Zhejiang University | Cao J.,Zhejiang University | And 3 more authors.
Biosensors and Bioelectronics | Year: 2013

Drug-induced cardiotoxicity greatly endangers the human health and results in resource waste. Also, it is a leading attribution to drug withdrawal and late-stage attrition in pharmaceutical industry. In the study, a dual function cardiomyocyte-based biosensor was introduced for rapid drug evaluation with xCELLigence RTCA Cardio system. The cardiomyocyte-based biosensor can monitor the cardiomyocyte growth and beating status simultaneously under the drug effects. Two typical cardiovascular drug, verapamil and flecainide were selected as treatment agents to test the performance of this biosensor. The experiment results showed that the performance of cardiomyocyte-based biosensor verified the basic drug effects by beating status and also tested the drug cytotoxicity by the cell index curves of cardiomyocyte growth. Based on the advanced sensor detection technology and cell culture technology, this cardiomyocyte-based biosensor will be a utility platform for the drug preclinical assessment. © 2013 Elsevier B.V.


Hu N.,Zhejiang University | Wang T.,Zhejiang University | Wang T.,ACEA Bio Hangzhou Co. | Cao J.,Zhejiang University | And 4 more authors.
Sensors and Actuators, B: Chemical | Year: 2013

Electrical cell-substrate impedance sensor (ECIS) and light-addressable potentiometric sensor (LAPS) are becoming powerful tools for monitoring the cell growth status and cell metabolism. This work describes the ECIS- and LAPS-type cardiomyocyte-based biosensors. The working principle and detection systems of transducers were presented. In particular, our investigation is devoted to some basic characteristic tests of these transducers for the purpose of comparing their performance related to cardiomyocyte-based biosensors evaluation. Finally, cardiomyocyte-based biosensors performance was displayed and analyzed. From the results, both of transducers are promising tools to establishing the cardiomyocyte-based biosensors. © 2013 Elsevier B.V.


Wang Q.,Zhejiang University | Wang Q.,ACEA Bio Hangzhou Co. | Su K.,Zhejiang University | Hu L.,Zhejiang University | And 8 more authors.
Sensors and Actuators, B: Chemical | Year: 2015

Saxitoxin (STX) and tetrodotoxin (TTX) are highly toxic marine toxins targeting site 1 of α subunit of voltage-dependent sodium channels (VDSCs). Both of them disturb sodium channels’ function by inhibition of ion current through the channels. And they are probably involved in some ion channel diseases, such as cardiovascular diseases and neurodegenerative diseases. The present work described a novel and functional method for detecting the pharmacological effects of STX and TTX using the cardiomyocyte-based biosensor. This biosensor was based on impedance technology through a label-free and real-time detection system which could monitor the cardiomyocyte growth and beating status simultaneously. The parameters of the cardiomyocyte-based biosensor, cell index, beating rate, and amplitude were analyzed to determine the biosensor performance under the treatment of toxins. The results showed that beating rate of this biosensor was a sensitive parameter to STX and TTX, and the detection limit of this biosensor was 0.087 and 89 ng/ml for STX and TTX, respectively. It could be concluded that the cardiomyocyte-based impedance biosensor would be a promising tool for quantitative analysis of the pharmacological effects of these two toxins. © 2014 Elsevier B.V.


Hu N.,Zhejiang University | Zhou J.,Zhejiang University | Su K.,Zhejiang University | Zhang D.,Zhejiang University | And 4 more authors.
Biomedical Microdevices | Year: 2013

The study presented a novel integrated cell-based biosensor with light-addressable potentiometric sensor (LAPS) and electrical cell-substrate impedance sensor (ECIS). The integrated cell-based biosensor was fabricated in order to monitor the cellular metabolism and growth status by LAPS and ECIS. Moreover, the specific instrument was established for controlling the detection processes. Sensor test and cell experiments were carried out to determine the performance of integrated sensor. The result showed that integrated biosensor can monitor the change of cell electrical impedance and extracellular acidification simultaneously which can be used for drug evaluation by monitoring cell growth status (e.g. cell number, adhesion, and morphology) and cell energy metabolism status (e.g. extracellular acidification) in real time. With the development of sensor technology, the integrated cell-based biosensor will be a utility platform to study the mechanism of cellular metabolism and in vitro drug analysis. © 2013 Springer Science+Business Media New York.

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