MOLECULAR PHARMACEUTICS
·
2015
·
IF 4.384
Tingjie Yin,Qu Wu,Lei Wang,Lifang Yin,Jianping Zhou,Meirong Huo
A redox-sensitive prodrug, octreotide(Phe)-polyethene glycol-disulfide bond-paclitaxel [OCT(Phe)-PEG-ss-PTX], was successfully developed for targeted intracellular delivery of PTX. The formulation emphasizes long-circulation-time polymer–drug conjugates, combined targeting based on EPR and OCT-receptor mediated endocytosis, sharp redox response, and programmed drug release. The nontargeted redox-sensitive prodrug, mPEG-ss-PTX, and the targeted insensitive prodrug, OCT(Phe)-PEG-PTX, were also synthesized as controls. These polymer–PTX conjugates, structurally confirmed by 1H NMR, exhibited approximately 23 000-fold increase in water solubility over parent PTX and possessed drug contents ranging from 11% to 14%. The redox-sensitivity of the objective OCT(Phe)-PEG-ss-PTX prodrug was verified by in vitro PTX release profile in simulated reducing conditions, and the SSTRs-mediated endocytosis was demonstrated by flow cytometry and confocal laser scanning microscopy analyses. Consequently, compared with mPEG-PTX and OCT(Phe)-PEG-PTX, the OCT(Phe)-PEG-ss-PTX exhibited much stronger cyotoxicity and apoptosis-inducing ability against NCI-H446 tumor cells (SSTRs overexpression), whereas a comparable cytotoxicity of these prodrugs was obtained against WI-38 normal cells (no SSTRs expression). Finally, the in vivo studies on NCI-H466 tumor-bearing nude mice demonstrated that the OCT(Phe)-PEG-ss-PTX possessed superior tumor-targeting ability and antitumor activity over mPEG-PTX, OCT(Phe)-PEG-PTX and Taxol, as well as minimal collateral damage. This targeted redox-sensitive polymer–PTX prodrug system is promising in tumor therapy.
研究领域:
药学
·
肿瘤学
✓ 已验证
DOI
PubMed
高影响因子
COLLOIDS AND SURFACES B-BIOINTERFACES
·
2018
·
IF 3.997
Min Yang,Houqiang Ding,Yixin Zhu,Yanxiu Ge,Lingbing Li
A strategy of preparing mixed micelles containing both DOX prodrug and PTX prodrug was developed, i.e., synthesizing a DOX conjugate and a PTX conjugate started with the same biocompatible amphiphilic copolymer, TPGS and DTDPA, a linker containing disulfide bond. The mixed micelles were prepared by co-assembling the two conjugates with a particle size about 98.5 nm. The mixed micelles could release anticancer drug DOX and PTX upon cellular reduction once they came into the cancerous cells. Moreover, the mixed micelles displayed synergistic effect in vitro and the combination therapy in micellar dosage-form led to reduced systematic toxicity and enhanced antitumor efficacy in vivo .
研究领域:
药剂学
·
肿瘤学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
International Journal of Nanomedicine
·
2017
·
IF 4.3
Yuling Liu,Sai Fu,Longfei Lin,Yuhong Cao,Xi Xie,Hua Yu,Meiwan Chen,Hui Li
Pluronic F127 (F127), an amphiphilic triblock copolymer, has been shown to have significant potential for drug delivery, as it is able to incorporate hydrophobic drugs and self-assemble into nanosize micelles. However, it suffers from dissociation upon dilution owing to the relatively high critical micelle concentration and lack of stimuli-responsive behavior. Here, we synthesized the α-tocopherol (TOC) modified F127 polymer (F127-SS-TOC) via a redox-sensitive disulfide bond between F127 and TOC, which formed stable micelles at relatively low critical micelle concentration and was sensitive to the intracellular redox environment. The particle size and zeta potential of the F127-SS-TOC micelles were 51.87±6.39 nm and -8.43±2.27 mV, respectively, and little changes in both particle size and zeta potential were observed within 7 days at room temperature. With 10 mM dithiothreitol stimulation, the F127-SS-TOC micelles rapidly dissociated followed by a significant change in size, which demonstrated a high reduction sensitivity of the micelles. In addition, the micelles showed a high hemocompatibility even at a high micelle concentration (1,000 μg/mL). Low cytotoxicity of the F127-SS-TOC micelles at concentrations ranging from 12.5 μg/mL to 200 μg/mL was also found on both Bel 7402 and L02 cells. Overall, our results demonstrated F127-SS-TOC micelles as a stable and safe aqueous formulation with a considerable potential for drug delivery.
研究领域:
药剂学
·
生物材料学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
POLYMER
·
2015
·
IF 3.562
Lin Wang,Yin Wang,Qiao Jin,Fan Jia,Haibo Wang,Jian Ji
Biomimic hyaluronic acid (HA) prodrug micelles with pH and reduction responsiveness were prepared by chemical graft of phosphorylcholine and doxorubicin (DOX) to the backbone of HA. DOX was conjugated to HA by pH-sensitive hydrazone bonds which could be hydrolyzed under acidic conditions and thus resulted in controlled release of DOX. Besides, the HA prodrug micelles were cross-linked via reduction-responsive disulfide bonds to improve the stability of the micelles. The HA prodrug can form remarkable core–shell micelles with a quite narrow size distribution which was confirmed by dynamic light scattering (DLS) and transmission electron microscopy (TEM). The in vitro drug release studies showed that there was a dramatic release under endosome pH (pH = 5.0) and reductive environment (10 mM of dithiothreitol) than that at normal physiological environment (pH = 7.4). Greater uptake of DOX from HA prodrug micelles was observed in the CD44 receptor highly expressed MDA-MB-231 cell line, compared to the results from the CD44-negative cell line, NIH3T3, which was demonstrated by the flow cytometry and fluorescence microscopy . The glutathione (GSH)-responsive behaviors were studied as well. The micelles showed higher cellular proliferation inhibition against glutathione monoester (GSH-OEt) pretreated MDA-MB-231 cells than that of the non-pretreated and buthionine sulfoximine (BSO) pretreated ones. These results suggested that such pH/reduction dual-responsive prodrug micelles may enhance the selective inhibition to cancer cells which exhibit higher levels of GSH concentration and provide favorable platforms for cancer therapy.
研究领域:
药剂学
·
肿瘤学
·
生物材料
✓ 已验证
DOI
高影响因子
PHARMACEUTICAL RESEARCH
·
2017
·Vol. 34
·期 10
·2172-2184
·
IF 3.002
Yin Xuelei,Chi Yingying,Guo Chuanyou,Feng Shuaishuai,Liu Jinhu,Sun Kaoxiang,Wu Zimei
Purpose To investigate the potential of a reduction-sensitive and fusogenic liposomes, enabled by surface-coating with chotooligosaccharides (COS) via a disulfide linker, for tumor-targeted cytoplasmic drug delivery. Methods COS (MW2000-5000) were chemically tethered onto the liposomes through a disulfide linker (-SS-) to cholesterol (Chol). Doxorubicin (DOX) was actively loaded in the liposomes. Their reduction-sensitivities, cellular uptake, cytotoxicity, pharmacokinetics and antitumor efficacy were investigated. Results The Chol-SS-COS/DOX liposomes (100 nm) had zeta potential of 33.9 mV and high drug loading (13% w /w). The liposomes were stable with minimal drug leakage under physiological conditions but destabilized in the presence of reducing agents, dithiothreitol (DTT) or glutathione (GSH) at 10 mM, the cytosolic level. MTT assay revealed that the cationic Chol-SS-COS/DOX liposomes had higher cytotoxicity to MG63-osteosarcoma cells than non-reduction sensitive liposome (Chol-COS/DOX). Flow cytometry and confocal microscopy revealed that Chol-SS-COS/DOX internalized more efficiently than Chol-COS/DOX with more content to cytoplasm whereas Chol-COS/DOX located around the cell membrane. Chol-SS-COS/DOX preferentially internalized into MG63 cancer cell over LO2 normal liver cells. In rats both liposomes produced a prolonged half-life of DOX by 4 - 5.5 fold ( p < 0.001) compared with the DOX solution. Chol-SS-COS/DOX exhibited strong inhibitory effect on tumor growth in MG63 cell-bearing nude mice ( n = 6), and extended animal survival rate. Conclusions Reduction-responsive Chol-SS-COS liposomes may be an excellent platform for cytoplasmic delivery of anticancer drugs. Conjugation of liposomes with COS enhanced tumor cell uptake, antitumor effect and survival rate in animal models.
研究领域:
药剂学
·
肿瘤学
·
生物材料学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Nanomaterials
·
2015
·Vol. 5
·期 4
·1571-1587
·
IF 2.076
Bing Han,Yanli Wang,Lan Wang,Zuhui Shang,Shuang Wang,Jin Pei
During the chemotherapy of cancer, drug resistance is the first issue that chemotherapeutic drugs cannot be effectively used for the treatment of cancers repeatedly for a long term, and the main reason for this is that tumor cell detoxification is mediated by GSH (glutathione) catalyzed by GST (glutathione-S-transferase). In this study, a GST inhibitor, ethacrynic acid (ECA), was designed to be coupled with methoxy poly(ethylene glycol)-poly(lactide) (MPEG–PLA) by disulfide bonds to prepare methoxy poly(ethylene glycol)-poly(lactide)-disulphide bond-mthacrynic acid (MPEG–PLA–SS–ECA) as a carrier material of the nanoparticles. Nanoparticles of pingyangmycin (PYM) and carboplatin (CBP) were prepared, respectively, and their physicochemical properties were investigated. The ECA at the disulfide could be released in the presence of GSH, the pingyangmycin, carboplatin and ECA were all uniformly released, and the nanoparticles could release all the drugs completely within 10 days. The half maximal inhibitory concentration (IC50) of the prepared MPEG–PLA–SS–ECA/CBP and MPEG–PLA–SS–ECA/PYM nanoparticles in drug-resistant oral squamous cell carcinoma cell lines SCC15/CBP and SCC15/PYM cells was 12.68 μg·mL−1and 12.76 μg·mL−1, respectively; the resistant factor RF of them in the drug-resistant cells were 1.51 and 1.24, respectively, indicating that MPEG–PLA–SS–ECA nanoparticles can reverse the drug resistance of these two drug-resistant cells.Keywords:nanoparticle;GST inhibitor;redox-sensitive;self-assembly
研究领域:
药学
·
肿瘤学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
COLLOIDS AND SURFACES B-BIOINTERFACES
·
2017
·
IF 3.887
Jilian Wu,Huiyuan Zhang,Xu Hu,Ruiling Liu,Wei Jiang,Zhonghao Li,Yuxia Luan
Clinically, codelivery of chemotherapeutics has been limited by poor water-solubility and severe systemic toxicity. In this work, we developed a new reduction-sensitive mixed micellar system for self-codelivery of doxorubicin (DOX) and docetaxel (DTX). Biodegradable methoxy poly(ethylene glycol)-poly(ε-caprolactone) (mPEG-PCL) was coupled with DOX and DTX by a reduction-sensitive disulfide bond, resulting in mPEG-PCL-SS-DOX and mPEG-PCL-SS-DTX, respectively. mPEG-PCL-SS-DOX was mixed with mPEG-PCL-SS-DTX at a mole ratio of 1:1 in water, forming a mixed micellar system. The mixed micelles had a diameter of 223.7 nm and a low critical micelle concentration. Reductive-triggered drug release revealed a “smart” characteristic of the mixed micelles. A cellular uptake and cytotoxicity assay in vitro showed that the mixed micelles could efficiently accumulate in MCF-7 cells and suppress the growth of tumour cells. The proposed reduction-sensitive mixed micelles assembled from amphiphilic prodrugs can be used as a promising drug codelivery system for cancer therapy.
研究领域:
药剂学
·
肿瘤学
·
生物材料学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
CHEMISTRY AND PHYSICS OF LIPIDS
·
2023
·
IF 3.4
Jie Hu,Yongsheng Zheng,Zhijie Wen,Hudie Fu,Xuedan Yang,Xuexin Ye,Shengpeng Zhu,Li Kang,Xiaojun Li,Xinzhou Yang,Yan Hu
The aim of this study was to construct a bifunctional liposome with hepatic-targeting capacity by modifying with a targeting ligand and an intracellular tumor reduction response functional group to deliver drugs precisely to focal liver tissues and release them in large quantities in hepatocellular carcinoma cells. This could improve drug efficacy and reduce toxic side effects at the same time. First, the bifunctional ligand for liposome was successfully obtained by chemically synthesizing it from the hepatic-targeting glycyrrhetinic acid (GA) molecule, cystamine , and the membrane component cholesterol. Then the ligand was used to modify the liposomes. The particle size, PDI and zeta potential of the liposomes were determined with a nanoparticle sizer, and the morphology was observed by transmission electron microscopy . The encapsulation efficiency and drug release behavior were also determined. Further, the stability in vitro of the liposomes and the changes in the simulated reducing environment were determined. Finally, the antitumor activity in vitro and cellular uptake efficiency of the drug-loaded liposomes were investigated by performing cellular assays. The results showed that the prepared liposomes had a uniform particle size of 143.6 ± 2.86 nm with good stability and an encapsulation rate of 84.3 ± 2.1 %. Moreover, the particle size of the liposomes significantly increased and the structure was destroyed in a DTT reducing environment. Cellular experiments showed that the modified liposoes had better cytotoxic effects on hepatocarcinoma cells than both normal liposomes and free drugs. This study has great potential for tumor therapy and provides novel ideas for the clinical use of oncology drugs in dosage forms.
研究领域:
药剂学
·
肿瘤学
·
生物医学工程
✓ 已验证
产品关联
DOI
PubMed
高影响因子
ChemistrySelect
·
2024
·Vol. 9
·期 42
·e202401655
·
IF 1.9
Yang Lin,Ju Liang,Wenlan Wu,Yunyun Zhang,Fuqing Yan
Graphical In this study, the reduction responsive prodrug folic acid-polyethylene glycol-disulfide bond-curcumin (FA-PEG-SS-CUR) was synthesized. The prodrug could self-assemble into micelles in an aqueous solution. The chemical structure of the prodrug was determined using FTIR and NMR. Subsequently, the properties of the micelles were evaluated through TEM, particle size analysis, cell experiments, and in vitro drug release assessment. In order to improve the delivery performance of curcumin (CUR) in liver cancer cells, we prepared a targeted and reduction-sensitive prodrug, folic acid-polyethylene glycol-disulfide bond-curcumin (FA-PEG-SS-CUR). The synthesis involved the conjugation of CUR with NH 2 -PEG-NH 2 through a disulfide bond, followed by the connection of CUR-SS-PEG-NH 2 to FA-COOH via acylation. The resultant FA-PEG-SS-CUR prodrug self-assembled into nano micelles in aqueous solutions, displaying excellent dispersibility with an approximate particle size of 119 nm. In vitro drug release studies demonstrated the sensitivity of FA-PEG-SS-CUR to glutathione (GSH), displaying sustained release performance. After 72 h, FA-PEG-SS-CUR exhibited a drug release rate of 38% at low GSH concentration and 59% at high GSH concentration. Notably, FA-PEG-SS-CUR micelles exhibited favorable biocompatibility. The hemolysis rate resulting from co-incubation with red blood cells remained below 3%. Furthermore, cytotoxicity experiments unveiled the substantial cytotoxicity of FA-PEG-SS-CUR micelles against HepG2 tumor cells. Cellular uptake studies confirmed the greater internalization of FA-PEG-SS-CUR by HepG2 cells compared to the non-targeted PEG-SS-CUR. The findings highlight the potential of FA-PEG-SS-CUR as an ideal drug delivery system for CUR due to its facile synthesis and strong self-assembly performance.
研究领域:
药学
·
癌症研究
·
纳米技术
✓ 已验证
产品关联
DOI
高影响因子
INTERNATIONAL JOURNAL OF BIOLOGICAL MACROMOLECULES
·
2019
·
IF 4.784
Cihui Tian,Sajid Asghar,Ziyi Hu,Yue Qiu,Jingwei Zhang,Feng Shao,Yanyu Xiao
The gliomas treatment is challenging due to the limits imposed by blood-brain barrier to the distribution of the drugs in the brain. Therefore, we designed a brain glioma targeting redox-sensitive hyaluronic acid (HA)-ss-curcumin (CUR) micelles . HA was conjugated to CUR through a disulfide bond , which could form micelles independently in aqueous solution. And we further increased the drug loading by loading free CUR. Brain penetration was achieved with Tween 80, whereas glioma-targeting was inclined by CD44-mediated endocytosis . Compared to the disulfide-free group, the redox-sensitive micelles exhibited rapid in vitro drug release under high glutathione conditions, significantly enhanced cell apoptosis and cellular uptake in G422 glioma cells. Redox-sensitive micelles displayed about 4.70-fold higher area under the curve in rats after intravenous injection in comparison to the free CUR and effectively accumulated in the brain. These findings suggest that redox-sensitive micelles could be a promising candidate to achieve brain targeted CUR delivery.
研究领域:
药剂学
·
肿瘤学
·
神经科学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Biomaterials Science
·
2017
·Vol. 5
·期 10
·2169-2178
·
IF 4.21
Shengcai Yang,Zhaohui Tang,Dawei Zhang,Mingxiao Deng,Xuesi Chen
A pH and redox dual-sensitive biodegradable polysaccharide, succinic acid-decorated dextran-g-phenylalanine ethyl ester-g-cysteine ethyl ester (Dex-SA-L-Phe-L-Cys), was synthesized to load doxorubicin hydrochloride (DOX·HCl). The DOX-loaded nanoparticles, which were prepared in aqueous solution and free of organic solvent, could spontaneously self-assemble into uniform sizes. When loading DOX·HCl, mercapto Dex-SA-L-Phe-L-Cys was oxidized into a crosslinked disulfide linkage to form pH and redox dual-sensitive nanoparticles (DOX-S-NPs). The amphiphilic polymer loaded DOX·HCl into the core through electrostatic and hydrophobic interactions, meanwhile the crosslinked disulfide bond could stabilize the drug loaded nanoparticles. As a control with similar polymer structure, succinic acid decorated dextran-g-phenylalanine ethyl ester (Dex-SA-L-Phe) was prepared to obtain pH-sensitive DOX-loaded micelles (DOX-N-NPs). The controlled pH and redox-dependent release profiles of the DOX-S-NPs in vitro were certified in different releasing mediums. Furthermore, the cellular uptake of the DOX-S-NPs was comparable with that of free DOX·HCl, determined by confocal laser scanning microscopy (CLSM) and flow cytometry. Cytotoxicity assay in vitro showed that the DOX-S-NPs and free DOX·HCl were similar in inhibiting the proliferation of non-small cell lung carcinoma A549 and breast cancer MCF-7 cell lines. DOX-S-NPs displayed similar antitumor efficiency compared with free DOX·HCl, but lower toxicity by body weight. These dual-sensitive DOX-S-NPs provide a useful strategy for anti-tumor therapy.
研究领域:
药剂学
·
生物医学工程
·
肿瘤学
✓ 已验证
DOI
PubMed
高影响因子
INTERNATIONAL JOURNAL OF BIOLOGICAL MACROMOLECULES
·
2025
·
IF 8.5
Qiao Qiao,Jie Li,Chunying Tao,Meiyang Yang,Weijun Chen,Lipeng Qiu,Huiming Tu
Studies have shown that inflammation is closely linked to the cancer development, and the patients with inflammatory bowel disease (IBD) have a higher risk of colon cancer. Celecoxib (CXB) and camptothecin (CPT) showed potential treatment for IBD and colon cancers, respectively. However, their applications are limited by synchronous delivery, water insolubility, and off-target side effects. Herein, a glutathione (GSH) responsive chondroitin sulfate A (CSA)-SS-CXB micelle loaded with CPT (CSA-SS-CXB@CPT) was prepared as a targeted system to treat colon cancer by anti-inflammatory and antitumor synergistic effect. Specifically, CSA had tumor tumor-targeting effect due to colon cancer lesion-high expression of CD44 receptors. In vitro results verified that CSA-SS-CXB@CPT selectively internalized into colon cancer HT-29 cells and had strong reactive oxygen species (ROS) elimination ability. The CSA-SS-CXB@CPT could rapidly release CXB and CPT in the tumor microenvironment for playing an anti-tumor role. In vivo experiments illustrated that CSA-SS-CXB@CPT significantly targeted tumor tissues and suppressed tumor growth without producing serious side effects in tumor-bearing nude mice. Therefore, this work provides an opportunity for targeted co-delivery of anti-inflammatory and chemotherapy drugs to treat colon cancer.
研究领域:
药学
·
肿瘤学
·
生物医学工程
✓ 已验证
产品关联
DOI
PubMed
高影响因子
危险品化学品经营许可证（带存储）