张学农教授课题组在ACS Appl. Mater. Interfaces等期刊上发表研究论文

 近日,张学农教授课题组在ACS Appl. Mater. Interfaces等期刊上发表研究论文

[1] Enhanced cellular internalization and on-demand intracellular release of doxorubicin by stepwise pH/reduction-responsive nanoparticles

Fang Li, Weiliang Chen, Bengang You, Yang Liu, Shudi Yang, Zhiqiang Yuan, Wenjing Zhu, Jizhao Li, Chenxi Qu, Yejuan Zhou, Xiaofeng Zhou, Chun Liu, and Xue-Nong Zhang 

ACS Appl. Mater. Interfaces, DOI: 10.1021/acsami.6b09604 一区 IF 7.145

The efficient delivery of anti-tumor agents to tumor sites faces numerous obstacles, such as poor cellular uptake and slow intracellular drug release. In this regard, smart NPs that respond to the unique microenvironment of tumor tissues have been widely used for drug delivery. In this study, novel charge-reversal and reduction-responsive histidine-grafted chitosan-lipoic acid NPs (HCSL-NPs) were selected for efficient therapy of breast cancer by enhancing cell internalization and intracellular pH- and reduction-triggered doxorubicin (DOX) release. The surface charge of HCSL-NPs presented as negative at physiological pH and reversed to positive at the extracellular and intracellular pH of the tumor. In vitro release investigation revealed that DOX/HCSL-NPs demonstrated a sustained drug release under the physiological condition, whereas rapid DOX release was triggered by both endo-lysosome pH and high-concentration reducing glutathione (GSH). These NPs exhibited enhanced internalization at extracellular pH, rapid intracellular drug release and improved cytotoxicity against 4T1 cells in vitro. Excellent tumor penetrating efficacy was also found in 4T1 tumor spheroids and solid tumor slices. In vivo experiments demonstrated that HCSL-NPs exhibited excellent tumor targeting ability in tumor tissues as well as excellent anti-tumor efficacy and low systemic toxicity in breast tumor-bearing BALB/c mice. These results indicated that the novel charge-reversal and reduction-responsive HCSL-NPs have great potential for targeted and efficient delivery of chemotherapeutic drugs in cancer treatments.

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[2] Tumor microenvironment-responsive micelles for pinpointed intracellular release of doxorubicin and enhanced anti-cancer efficiency

Wei-liang Chen ,Shu-di Yang, Fang Li, Ji-zhao Li, Zhi-qiang Yuan, Wen-jing Zhu, Yang Liu, Xiao-feng Zhou, Chun Liu, Xue-nong Zhang

Int J Pharm. 2016,511: 728–740.  二区,IF 3.994

Internal stimuli, such as intracellular lysosomal pH, enzyme, redox and reduction, can be applied to improve biological specificity of chemotherapeutic drugs for cancer therapy. Thus, functionalized copolymers based on their response to specific microenvironment of tumor regions have been designed as smart drug vesicles for enhanced anti-cancer efficiency and reduced side effects. Herein, we reported dually pH/reduction-responsive novel micelles based on self-assembly of carboxymethyl chitosan-cysteamine-N-acetyl histidine (CMCH-SS-NA) and doxorubicin (DOX). The tailor-made dually responsive micelles demonstrated favorable stability innormal physiological environment and triggered rapid drug release in acidic and/or reduction environment. Additionally, the nanocarriers responded to the intracellular environment in an ultra-fast manner within several minutes, which led to the pinpointed release of DOX in tumor cells effectively and ensured higher DOX concentrations within tumor areas with the aid of targeted delivery, thereby leading to enhanced tumor ablation. Thus, this approach with sharp drug release behavior represented a versatile strategy to provide a promising paradigm for cancer therapy.

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[3] Liposomes coated with N-trimethyl chitosan to improve the absorption of harmine in vivo and in vitro.

Wei-liang Chen,Zhi-Qiang Yuan1,,Yang Liu,Shu-di Yang,Chun-ge Zhang,Ji-zhao Li1,Wen-jing Zhu,Fang Li1Xiao-feng Zhou,Yi-mei Lin,Xue-nong Zhang 

 Int J Nanomed. 2016, 11:325-336, 二区,IF 4.32

In this study, harmine liposomes (HM-lip) were prepared through the thin-film hydration–pH-gradient method and then coated with N-trimethyl chitosan (TMC). Particle size, zeta potential, entrapment efficiency, and in vitro release of HM-lip and TMC-coated harmine liposomes (TMC-HM-lip) were also determined. Sprague Dawley rats were further used to investigate the pharmacokinetics in vivo. Retention behavior in mouse gastrointestinal tract (GIT) was studied through high-performance liquid chromatography and near-infrared imaging. Degradation was further evaluated through incubation with Caco-2 cell homogenates, and a Caco-2 monolayer cell model was used to investigate the uptake and transport of drugs. HM-lip and TMC-HM-lip with particle size of 150–170 nm, an entrapment efficiency of about 81%, and a zeta potential of negative and positive, respectively, were prepared. The release of HM from HM-lip and TMC-HM-lip was slower than that from HM solution and was sensitive to pH. TMC-HM-lip exhibited higher oral bioavailability and had prolonged retention time in GIT. HM-lip and TMC-HM-lip could also protect HM against degradation in Caco-2 cell homogenates. The uptake amount of TMC-HM-lip was higher than that of HM and HM-lip. TMC-HM-lip further demonstrated higher apparent permeability coefficient (Papp) from the apical to the basolateral side than HM and HM-lip because of its higher uptake and capability to open tight junctions in the cell monolayers. TMC-HM-lip can prolong the retention time in the GIT, protect HM against enzyme degradation, and improve transport across Caco-2 cell monolayers, thus enhancing the oral bioavailability of HM.