International Journal of Nanomedicine
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2015
·
IF 4.383
Liang Qiu,Chun-Yan Hong,Cai-Yuan Pan
Redox-and pH-sensitive branched star polymers (BSPs), BP(DMAEMA-co-MAEBA-co-DTDMA)(PMAIGP)ns, have been successively prepared by two steps of reversible addition–fragmentation chain transfer (RAFT) polymerization. The first step is RAFT polymerization of 2-(N,N-dimethylaminoethyl)methacrylate (DMAEMA) and p-(methacryloxyethoxy) benzaldehyde (MAEBA) in the presence of divinyl monomer, 2,2′-dithiodiethoxyl dimethacrylate (DTDMA). The resultant branched polymers were used as a macro-RAFT agent in the subsequent RAFT polymerization. After hydrolysis of the BSPs to form BP(DMAEMA-co-MAEBA-co-DTDMA)(PMAGP)ns (BSP-H), the anticancer drug doxorubicin (DOX) was covalently linked to branched polymer chains by reaction of primary amine of DOX and aldehyde groups in the polymer chains. Their compositions, structures, molecular weights, and molecular weight distributions were respectively characterized by nuclear magnetic resonance spectra and gel permeation chromatography measurements. The DOX-loaded micelles were fabricated by self-assembly of DOX-containing BSPs in water, which were characterized by transmission electron microscopy and dynamic light scattering. Aromatic imine linkage is stable in neutral water, but is acid-labile; controlled release of DOX from the BSP-H-DOX micelles was realized at pH values of 5 and 6, and at higher acidic solution, fast release of DOX was observed. In vitro cytotoxicity experiment results revealed low cytotoxicity of the BSPs and release of DOX from micelles in HepG2 and HeLa cells. Confocal laser fluorescence microscopy observations showed that DOX-loaded micelles have specific interaction with HepG2 cells. Thus, this type of BSP micelle is an efficient drug delivery system.
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PubMed
高影响因子
LANGMUIR
·
2014
·
IF 4.384
Xubo Zhao,Lei Liu,Xiaorui Li,Jin Zeng,Xu Jia,Peng Liu
A facile strategy was established to develop a drug delivery system (DDS) based on the graphene oxide nanoparticles (GON) with suitable size and shape to deliver drug effectively, by grafting the biocompatible PEGylated alginate (ALG-PEG) brushes onto the GON via the disulfide bridge bond. TEM analysis and drug-loading performance revealed that the 3-D nanoscaled, biocompatible, reduction-responsive nanocarriers (GON-Cy-ALG-PEG) were spherical in shape with diameters of 94.73 ± 9.56 nm. They possessed high doxorubicin (DOX)-loading capacity and excellent encapsulation efficiency, owing to their unique 3-D nanoscaled structure. They also had excellent stability in simulated physiological conditions and remarkable biocompatibility. Importantly, the in vitro release showed that the platform could not only prevent the leakage of the loaded DOX under physiological conditions but also detach the cytamine (Cy) modified PEGylated alginate (Cy-ALG-PEG) moieties, response to glutathione (GSH). Confocal microscopy and WST-1 assays provided clear evidence of the DOX-loaded GON-Cy-ALG-PEG endocytosis, whereas the drug-loaded nanocarriers exhibited high cytotoxicity to model cells. Furthermore, the cell apoptosis also was monitored via Flow cytometry. The results indicated that the DOX-loaded nanocarriers presented favorable efficiency of cell apoptosis. So these findings demonstrate that the accelerated release of the loaded DOX was realized in the presence of an elevated GSH that simulate the acidic endosomal compartments.
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高影响因子
Science China-Chemistry
·
2014
·Vol. 57
·期 4
·624-632
·
IF 1.516
Zhang Yu,Xiao ChunSheng,Li MingQiang,Ding JianXun,Yang ChenGuang,Zhuang XiuLi,Chen XueSi
A series of well-defined amphiphilic linear-dendritic block copolymers (telodendrimers, MPEG- b -PAMAM-cholesterol) with 1,2,4 or 8 cholesteryl groups (named as P1 , P2 , P4 , P8 , respectively) were synthesized. Their chemical structures were characterized with 1 H NMR and mass spectrum (MALDI-TOF MS). The telodendrimers could self-assemble into micelles in aqueous solution, and encapsulate chemotherapeutic drug doxorubicin (DOX) and paclitaxel (PTX) for combination therapy. All the telodendrimers could encapsulate DOX with similar capability. However, their drug-loading capability of PTX is increased with the increasing number of cholesteryl groups. P8 exhibited much higher PTX loading efficiency than its counterparts. Thus, P8 was selected for further application of drug delivery in the paper. The drug-loading micellar nanoparticles (NPs) of P8 were spherical in shape and their diameters were less than 150 nm which were determined by dynamic light scattering measurements (DLS) and transmission electron microscope (TEM). In vitro drug release experiment demonstrated that P8 exhibited a controlled release manner for both DOX and PTX, and the two drugs were released simultaneously. In vitro cytotoxicity experiment further demonstrated that the co-delivery of DOX and PTX in P8 exhibited better anti-cancer efficiency than the delivery systems encapsulated with single drug (DOX or PTX). This indicates a synergistic effect. The co-delivery system showed potential in future anti-cancer treatment.
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高影响因子
COLLOIDS AND SURFACES B-BIOINTERFACES
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2015
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IF 4.152
Tingxian Liu,Mingfang Wang,Tianqi Wang,Yao Yao,Na Zhang
The greatest challenge in combining chemotherapy and gene therapy is the construction of a suitable platform for the co-delivery of the drug and the therapeutic gene. In this study, a simplified and effective system for the co-loading and intracellular co-delivery of doxorubicin (Dox) and siRNA was developed. Oligodeoxynucleotides with CGA repeating units (CGA-ODNs) were introduced to load Dox. The loading mechanism was based on the ability of Dox to intercalate within double-stranded 5′-GC-3′ or 5′-CG-3′ sequences. Poly(ethyleneimine) (PEI) was used to condense siRNA and Dox loaded CGA-ODNs (CGA-ODNs-Dox) to obtain Dox and siRNA co-loaded nanocomplexes (PEI/CGA-ODNs-Dox&siRNA, PDR). The cellular uptake of PDR in A549 and HepG2 cells was 39.52% and 36.78%, respectively, indicating that the co-loading and co-delivery effect was achieved through the mono-loading method. An in vitro drug release study indicated that CMCS-poly(ethylene glycol) (PEG)-NGR (CPN) modified PDR (CPN-PDR) displayed a pH-triggered drug release property due to the reversed surface charge of CMCS in an acidic environment. Cellular uptake studies also confirmed that the disassembly of CPN-PDR was induced by an acidic pH in the extracellular matrix. Moreover, lysosomal escape of both Dox and siRNA was observed. Successful accumulation of Dox in the cell nucleus and siRNA in the cytoplasm was also demonstrated. Consequently, the novel construction of a simplified loading method and high co-delivery efficiency was proven to be a promising platform for the co-delivery of drug and siRNA.
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高影响因子
JOURNAL OF NANOPARTICLE RESEARCH
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2014
·Vol. 16
·期 7
·1-14
·
IF 2.278
Ma Xiaona,Shu Chang,Guo Jing,Pang Lili,Su Lin,Fu Degang,Zhong Wenying
Abstract A new targeted drug delivery system (DDS) based on oxidized single-wall carbon nanohorns (oxSWCNHs) was developed. Sodium alginate (SA) was used to modify oxSWCNHs to improve its dispersibility and biocompatibility, the first time such a modification to oxSWCNHs was reported. The humanized anti-vascular endothelial growth factor (anti-VEGF) monoclonal antibody was bound to the SA as targeting group to selectively kill the tumor cells. Doxorubicin hydrochloride (DOX) was conjugated to oxSWCNHs in basic pH solution by π–π stacking, and its release was triggered by the lower pH as the micro-environment of the tumor. Quantitative analyses showed that the DOX@oxSWCNHs/SA complexes contained 1 g DOX per gram of oxSWCNHs. Cell experiment showed that the DOX@oxSWCNHs/SA-mAb effectively targeted the human breast adenocarcinoma (MCF-7) cells and rarely adhered to the human embryonic kidney 293 (HEK293) cells. And the anticancer effects of the complexes were higher than those of the free DOX. Pharmaceutical efficiency in vivo showed that the relative tumor volumes (RTV) of normal saline (NS) group, oxSWCNH/SA-mAb (2.5 mg/kg) group, DOX (2.5 mg/kg) group, and DOX@oxSWCNHs/SA-mAb (2.5 mg/kg) group were approximately 61, 56, 14, and 7.2, respectively. In addition, higher drug dose (5 mg/kg) of DOX@oxSWCNHs/SA-mAb resulted in a better antitumor activity. Histopathological studies in mice confirmed that the DOX@oxSWCNHs/SA-mAb complexes did not demonstrate any detectable hepatotoxicity, cardiotoxicity, and nephrotoxicity. Graphical abstract
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Oncotarget
·
2016
·
IF 5.008
Li Lv,Chunxia Liu,Chuxiong Chen,Xiaoxia Yu,Guanghui Chen,Yonghui Shi,Fengchao Qin,Jiebin Ou,Kaifeng Qiu,Guocheng Li
The combination of a chemotherapeutic drug with a chemosensitizer has emerged as a promising strategy for cancers showing multidrug resistance (MDR). Herein we describe the simultaneous targeted delivery of two drugs to tumor cells by using biotin-decorated poly(ethylene glycol)-b-poly(ε-caprolactone) nanoparticles encapsulating the chemotherapeutic drug doxorubicin and the chemosensitizer quercetin (BNDQ). Next, the potential ability of BNDQ to reverse MDR in vitro and in vivo was investigated. Studies demonstrated that BNDQ was more effectively taken up with less efflux by doxorubicin-resistant MCF-7 breast cancer cells (MCF-7/ADR cells) than by the cells treated with the free drugs, single-drug–loaded nanoparticles, or non-biotin–decorated nanoparticles. BNDQ exhibited clear inhibition of both the activity and expression of P-glycoprotein in MCF-7/ADR cells. More importantly, it caused a significant reduction in doxorubicin resistance in MCF-7/ADR breast cancer cells both in vitro and in vivo , among all the groups. Overall, this study suggests that BNDQ has a potential role in the treatment of drug-resistant breast cancer.
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高影响因子
Advanced Healthcare Materials
·
2016
·Vol. 5
·期 19
·2517-2527
·
IF 5.76
Xiaoman Mao,Jingxing Si,Qian Huang,Xuanrong Sun,Qianzhi Zhang,Youqing Shen,Jianbin Tang,Xiangrui Liu,Meihua Sui
Doxorubicin (DOX) is a widely used chemotherapeutic drug to treat a range of cancers. However, its unfavorable effects, particularly the cardiotoxicity and the induction of multidrug resistance (MDR), significantly limit its clinical applications. Herein, a novel doxorubicin prodrug, PEG 2K -DOX, is synthesized by conjugating a deprotonated doxorubicin molecule with the polyethylene glycol (PEG, MW: 2K) chain via pH-responsive hydrazone bond, and its potential as a better alternative than doxorubicin is evaluated. The data show that the amphiphilic PEG 2K -DOX can self-assemble into stable nanoparticles with a high and fixed doxorubicin loading content (≈20 wt%), a favorable size of 91.5 nm with a narrow polydispersity (PDI = 0.14), good stability, and pH-dependent release behavior due to the acid-cleavable linkage between PEG and doxorubicin. Although doxorubicin hardly accumulates in MDR cells, PEG 2K -DOX nanoparticles significantly increase the cellular uptake and cell-killing activity of doxorubicin in two MDR cancer cell lines MCF-7/ADR and KBv200, with the IC 50 values dropped to 1.130% and 42.467% of doxorubicin, respectively. More impressively, PEG 2K -DOX nanoparticles exhibit significantly improved plasma pharmacokinetics, increased in vivo therapeutic efficacy against MDR xenograft tumors, and better in vivo safety compared with doxorubicin. PEG 2K -DOX nanoparticles hold the promise to become a better alternative than doxorubicin for cancer treatment, especially for MDR tumors.
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高影响因子
JOURNAL OF CELLULAR AND MOLECULAR MEDICINE
·
2025
·Vol. 29
·期 2
·e70358
·
IF 4.2
Jiangfang Lian,Hui Lin,Zuoquan Zhong,Yongfei Song,Xian Shao,Jiedong Zhou,Lili Xu,Zhenzhu Sun,Yongyi Yang,Jufang Chi,Ping Wang,Liping Meng
The clinical application of doxorubicin (DOX) is limited due to its cardiotoxicity, which is primarily attributed to its interaction with iron in mitochondria, leading to lipid peroxidation and myocardial ferroptosis. This study aimed to investigate the role of the gut microbiota‐derived metabolite, indole‐3‐lactic acid (ILA), in mitigating DOX‐induced cardiotoxicity (DIC). Cardiac function, pathological changes, and myocardial ferroptosis were assessed in vivo. The cardioprotective effects and mechanisms of ILA were explored using multi‐omics approaches, including single‐nucleus RNA sequencing (snRNA‐seq) and bulk RNA‐seq, and were further validated in Nrf2 knockout mice. The findings revealed that DOX treatment disrupted gut microbiota, significantly reducing the levels of the tryptophan metabolite ILA. In DIC models, ILA supplementation markedly improved cardiac function, reduced collagen deposition, and mitigated cardiac atrophy. The bulk and snRNA‐seq analyses indicated that myocardial ferroptosis played a crucial role in the cardioprotective effects of ILA. Experimental data demonstrated that ILA decreased DOX‐induced ferroptosis in both DIC mice and DOX‐treated H9C2 cells, evidenced by restoration of GPX4 and SLC7A11 levels and reduction of ACSL4. Mechanistically, ILA functions as a ligand for the aryl hydrocarbon receptor (AhR), leading to the upregulation of Nrf2 expression. The protective effects of ILA against ferroptosis were abolished by silencing AhR. Moreover, the beneficial effects of ILA on DIC were eliminated in Nrf2‐deficient mice. In conclusion, ILA exerts therapeutic effects against DIC by inhibiting ferroptosis through activation of the AhR/Nrf2 signalling pathway. Identifying the cardioprotective role of the microbial metabolite ILA could offer viable therapeutic strategies for DIC.
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高影响因子
TOXICOLOGY
·
2024
·
IF 4.8
Mingyang Chen,Yaodong Yi,Binxin Chen,Hengbin Zhang,Minlei Dong,Luexiang Yuan,Hui Zhou,Huidi Jiang,Zhiyuan Ma
Doxorubicin (DOX) is a widely used antitumor agent; however, its clinical application is limited by dose-related organ damage. Because organic cation/carnitine transporters (OCTN1 and OCTN2), which are critical for DOX uptake, are highly expressed in hepatocytes, we aimed to elucidate the role of these transporters in hepatic DOX uptake. The results indicated that inhibitors and RNA interference both significantly reduced DOX accumulation in HepG2 and HepaRG cells, suggesting that OCTN1/2 contribute substantially to DOX uptake by hepatocytes. To determine whether metformin (MET, an inhibitor of OCTN1 and OCTN2) ameliorates DOX-induced hepatotoxicity, we conducted in vitro and in vivo studies. MET (1–100 μM) inhibited DOX (500 nM) accumulation and cytotoxicity in vitro in a concentration-dependent manner. Furthermore, intravenous MET administration at 250 or 500 mg/kg or by gavage at 50, 100, or 200 mg/kg reduced DOX (8 mg/kg) accumulation in a dose-dependent manner in the mouse liver and attenuated the release of alanine aminotransferase, aspartate aminotransferase, and carboxylesterase 1. Additionally, MET reduced the distribution of DOX in the heart, liver, and kidney and enhanced the urinary elimination of DOX; however, it did not increase the nephric toxicity of DOX. In conclusion, our study demonstrated that MET alleviates DOX hepatotoxicity by inhibiting OCTN1- and OCTN2-mediated DOX uptake in vitro (mouse hepatocytes and HepaRG or HepG2 cells) and in mice.
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高影响因子
ACS Applied Nano Materials
·
2018
·
IF 0
Yan-Ping Wu,Jing Yang,Hua-Ying Gao,Yan Shen,Lingxiang Jiang,Changren Zhou,Yi-Fang Li,Rong-Rong He,Mingxian Liu
To carry doxorubicin (DOX) on breast cancer site effectively, halloysite nanotubes conjugated with poly(ethylene glycol) and folate (HNTs-PEG-FA) is designed as a targeted drug delivery system. Halloysite nanotubes (HNTs) are shortened to ∼200 nm by ultrasonic scission and functionalized with amide groups to conjugate with N-hydroxylsuccinimide-polyethylene glycol carboxylic acid (NHS-PEG-COOH) and folate (FA). DOX@HNTs-PEG-FA is prepared by loading DOX on HNTs-PEG-FA via physical adsorption. The sustained and controlled release of DOX from DOX@HNTs-PEG-FA is up to 35 h in an acidic environment (pH 5.3). DOX@HNTs-PEG-FA, performed as a new nanodelivery system, shows significant inhibition of proliferation and induction of death in MCF-7 cells with positive FA receptor but not in L02 cells with negative FA receptor. Results of acridine orange/ethidium bromide and flow cytometric assay indicate that DOX@HNTs-PEG-FA induces cell death through apoptosis. Compared to the same dose of DOX, DOX@HNTs-PEG-FA generates more reactive oxygen species (ROS) in MCF-7 cells, which lead to mitochondrial damage and apoptosis. Furthermore, with fluorescence images and transmission electron microscopy, uptake of DOX@HNTs-PEG-FA by tumor cells is both through endocytosis and direct penetration mechanism. The in vivo antibreast cancer activity of DOX@HNTs-PEG-FA is further confirmed in 4T1-bearing mice. In contrast to DOX, DOX@HNTs-PEG-FA effectively reduces heart toxicity and inhibits solid tumor growth with higher cleaved caspase-3 protein level in tumor tissue of 4T1-bearing mice. DOX@HNTs-PEG-FA reveals a higher DOX fluorescence intensity in tumor tissue than in other normal tissues including heart, spleen, lung, and kidney at different time points. All these results suggest that FA-conjugated HNTs may be designed to be a novel drug delivery system for targeted therapy of breast cancer via intravenous injection.
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MICROCHEMICAL JOURNAL
·
2024
·
IF 4.9
Wen-Juan Wang,Kai-Qi Liu,Jia-Lou Chen,Gang Wang,Feng Li,Yu-Qin Wang,Fen-Ying Kong,Wei Wang,Zhong-Xia Wang
Cancer is currently one of the deadliest diseases in the world. As one of the most common anti-cancer drugs, monitoring the amount of doxorubicin (Dox) with high sensitivity in serum can not only guide the dosage of Dox and minimize their toxicity, but also guarantee the effectiveness of treatment and the safety of patient’s life. Here, a green luminescent probe of the sulfur-enrichment, nitrogen-deficiency carbon nanodots (SCDs) was synthesized by melamine and 3-mercaptopropionic acid as nitrogen-sulfur-oxygen sources. The optical properties and surface functional groups of the SCDs have tremendously changed owing to the enrichment of the sulfur atoms. Interestingly, the SCDs luminescence can be suppressed by Dox through effective inner filter effect, which was permitted to construct high sensing platform for Dox determination. With the help of this mechanism, a wide linear range from 0.1 μM to 300 μM with a low limit of detection of 78.4 nM by utilizing SCDs-based constructed sensing platform were obtained. More importantly, this sensing platform has been successfully used to detect Dox in serum samples, and achieved satisfactory results with the recoveries between 97.7 and 104.2 %. This study conduces to the design of surface sulfur-containing carbon dots and broaden the utilization of functional SCDs in anthraquinone drugs detection.
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高影响因子
JOURNAL OF MATERIALS CHEMISTRY
·
2012
·Vol. 22
·期 30
·15206-15214
·
IF 5.968
Wan-Fu Ma,Ke-Yi Wu,Jing Tang,Dian Li,Chuan Wei,Jia Guo,Shi-Long Wang,Chang-Chun Wang
A smart magnetic targeting drug carrier (MCNC/PAA) comprising an approximately 100 nm sized magnetic colloid nanocrystal cluster (MCNC) core and a pH-responsive cross-linked poly(acrylic acid) (PAA) shell is reported. The abundant carboxyl groups in the shell enable the resultant MCNC/PAA to easily load a large amount of doxorubicin (DOX) (up to 44.6%) via the strong interaction between the DOX and the carboxyl group in a neutral solution. Interestingly, a synergistic pH-responsive effect derived from the entrapped DOX and PAA network was found to effectively manipulate the drug releasing behavior at 37 °C. It was found that the premature release was highly restricted at a pH of 7.4, and upon reduction in pH from 7.4 to 5.0 or 4.0, a large amount of drug was rapidly released. Compared with the synthesized MCNC/PNIPAM, MCNC/PHEMA and MCNC/PDMAPMA nanocarriers, the MCNC/PAA was preferably suited to drug delivery. In addition, the composite nanocarriers could be tracked by magnetic resonance imaging (MRI). The cytotoxicity assay of MCNC/PAA to normal cells indicated that the composite nanospheres were biocompatible and suitable as drug carriers. Meanwhile, the DOX-loaded composite nanospheres had more potent cytotoxicity than free DOX to HeLa cells. These results clearly imply that the MCNC/PAA nanocarrier is a promising platform that can be applied to construct a smart drug delivery system with magnetic targeting and pH-stimulation, as well as tracking by MRI.
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