Journal of Physical Chemistry C
·
2016
·
IF 4.509
Xiaojun Zhou,Liang Chen,Wei Nie,Weizhong Wang,Ming Qin,Xiumei Mo,Hongsheng Wang,Chuanglong He
The combination of chemotherapy and gene therapy could induce the enhanced therapeutic efficacy in the cancer therapy. To achieve this goal, a new mesoporous silica nanoparticles (MSNs)-based codelivery system was developed for targeted simultaneous delivery of doxorubicin (DOX) and Bcl-2 small interfering RNA (siRNA) into breast cancer cells. The multifunctional MSNs (MSNs-PPPFA) were prepared by modification of polyethylenimine–polylysine copolymers (PEI-PLL) via the disulfide bonds, to which a targeting ligand folate-linked poly(ethylene glycol) (FA-PEG) was conjugated. The multifunctional MSNs-PPPFA nanocarrier has the ability to encapsulate DOX into the mesoporous channels of MSNs, while simultaneously carrying siRNA via electrostatic interaction between cationic MSNs-PPPFA and anionic siRNA. The resulting MSNs-PPPFA nanoparticles were characterized with various techniques. The drug release results reveal that DOX released from DOX-loaded MSNs-PPPFA are both pH- and redox-responsive, and the results of cell viability and hemolysis assays show that the functional nanocarrier has excellent biocompatibility. Importantly, the folate-conjugated MSNs-PPPFA showed significantly enhanced intracellular uptake in the folate receptor overexpressed MDA-MB-231 breast cancer cells than nontargeted counterparts and thus results in more DOX and siRNA being codelivered into the cells. Furthermore, the delivery of Bcl-2 siRNA obviously downregulate the Bcl-2 protein expression, and thus targeted codelivery of DOX and Bcl-2 siRNA by DOX@MSNs-PPPFA/Bcl-2 siRNA in MDA-MB-231 cells could induce remarkable cell apoptosis as indicated by the results of cell viability and cell apoptosis assays. These results indicate that the constructed DOX@MSNs-PPPFA/Bcl-2 siRNA codelivery system is promising for targeted treatment of breast cancer.
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高影响因子
ANALYTICAL CHEMISTRY
·
2022
·
IF 8.008
Shanshan Qian,Ying Han,Yue Zhang,Yanan Du,Jing Li,Xin Yang,Jingwu Kang
Target identification is critically important for understanding the mechanism of action of drugs. Here, we reported a new strategy for deconvolution of drug targets (or off-targets) with photoaffinity labeling chemoproteomics in combination with untargeted metabolomics by using doxorubicin (DOX) as a model. The DOX-derived photoaffinity probes were prepared and applied to capture DOX-interacting proteins in living cells. The captured DOX-interacting proteins were then identified by label-free quantitative proteomics. Totally, 151 significant proteins were identified with high confidence (fold change >4, p-value < 0.005). The gene ontology enrichment analysis suggested that the proteins were mainly involved in carbon metabolism, citrate cycle, fatty acid metabolism, and metabolic pathways. Therefore, untargeted metabolomics was applied to quantify the significantly altered metabolites in cells upon drug treatment. The pathway enrichment analysis suggested that DOX mainly interrupted with the processes of pyrimidine and purine metabolism, carbon metabolism, methionine metabolism, and phosphatidylcholine biosynthesis. Integrative analysis of chemoproteomics and metabolomics indicated that adenosylhomocysteinase (AHCY) is a new target (off-target) of DOX leading to the accumulation of S-adenosyl homocysteine. This deduced DOX target was confirmed by the cellular thermal shift assay, affinity competitive pull-down assay, biochemical assay, and siRNA knock down experiments. Our result suggested that AHCY is the uncovered off-target of DOX.
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PubMed
高影响因子
Acta Biomaterialia
·
2022
·
IF 10.633
Daquan Wang,Ning Zhang,Tingting Yang,Yun Zhang,Xunan Jing,Yu Zhou,Jiangang Long,Lingjie Meng
On-demand designed theranostics nanoagents show promising applications for next-generation precision-and-personalized oncotherapy. Researchers have since aimed to develop nanoplatforms that can efficiently deliver drugs and contrast medium to tumor and release active ingredients in response to tumor microenvironment (TME) conditions. Herein, we propose a modular strategy, and develop a series of nanoplatforms based on metal-coordinated-polyprodrugs for cancer theranostics. The polyprodrugs were synthesized through a click-reaction between amino acid and doxorubicin (DOX) with dipropiolate. The backbones of the polyprodrugs had intrinsic sensitivities to pH and/or GSH, and provided abundant -COOH, -NH2, or -S-S- to chelate with functional metal ions and further self-assembled to form different morphologies. Dicysteine, which contains disulfide bond (-S-S-), was chosen to copolymerize with DOX and triethylene glycol dipropiolate (TEP) to prepare the pH/GSH dual-responsive polyprodrug poly(dicysteine-co-TEP-co-DOX) (pDTD), then separately coordinated with Gd3+, Fe3+, and Mn2+ to construct nanoplatforms [email protected] (M representing the metal ions). In vitro and in vivo investigations suggest the metal-coordinated-polyprodrug nanoplatforms have good magnetic resonance imaging (MRI) ability and efficient tumor-growth inhibition with high safety. The design strategy of nanoplatforms based on metal-coordinated-polyprodrugs provides a new idea for on-demand construction of promising theranostics agents. Statement of significance Compared to small molecule antitumor drugs, polymeric drugs have high drug loading ratio and are easily enriched at the tumor site to achieve improved therapy efficacy. This work utilizes click reactions to link amino acids with anticancer drugs to produce polymeric drugs that are degraded in response to tumor microenvironment and released small molecule antitumor drugs mainly in tumor sites, and subtly utilizes the coordination of amino acid to chelate MRI functional metal ion to realize enhanced MRI imaging mediated tumor therapy. This strategy provides a new idea for the convenient construction of polymeric drugs for tumor theranostics.
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高影响因子
International Journal of Nanomedicine
·
2023
·
IF 8
Chen Xu,Ri-jin Song,Pei Lu,Jian-chun Chen,Yong-qiang Zhou,Gang Shen,Min-jun Jiang,Wei Zhang
Aim To significantly promote cancer cell uptake and to achieve combination therapy and on-demand drug release, a pH-triggered charge-switchable and redox-responsive drug-release nanovehicle was developed in this study.Materials and methods The nanocarrier was constructed by conjugating 3,3′-dithiodipropionic acid-modified doxorubicin (DTPA-DOX) and 2,3-dimethylmaleic anhydride (DMA) to the side amino groups of poly(ethylene glycol)-b-poly(L-lysine) (PEG-b-PLL) and by encapsulating triptolide (TRI) into the hydrophobic core. The surface charge of the obtained nanocarriers (DA-ss-DT) can change from negative to positive in response to tumor extracellular acidity pH, and the nanocarriers capably release two drugs in response to intracellular high glutathione (GSH) environment.Results Compared to the control group, the in vitro cellular uptake of DA-ss-DT by human prostate cancer PC-3 cells was significantly promoted in slightly acidic conditions, and the drug could be rapidly released in the high concentration of GSH conditions. The in vitro and in vivo antitumor experiments exhibited that the DA-ss-DT nanoparticles have a great antitumor effect in comparison to the control group.Conclusion These findings demonstrated that the DA-ss-DT nanoparticles supply a useful strategy for promoting cellular uptake and synergetic anticancer therapy.
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PubMed
高影响因子
Nanoscale
·
2019
·Vol. 11
·期 12
·5717-5731
·
IF 6.97
Ruihao Yang,Mengmeng Hou,Ya Gao,Lei Zhang,Zhigang Xu,Yuejun Kang,Peng Xue
Hollow mesoporous structures with interior cavities and expanded surface area have attracted considerable interest as drug delivery systems. In this study, a multifunctional nanotheranostic agent was developed by conjugating indocyanine green (ICG) and loading doxorubicin (DOX) onto the surfaces or within the cavities of hollow mesoporous Prussian blue (HMPB) nanoparticles, known as HMPB@PEI/ICG/DOX or simply HPID NPs, which were investigated as phototheranostic agents for in vivo fluorescence imaging and light-induced chemotherapy, photothermal therapy (PTT) and photodynamic therapy (PDT). These original HPID NPs exhibited strong near infrared (NIR) absorbance, reactive oxygen species (ROS) yield, and controlled chemotherapeutic drug release behavior. After intravenous injection of HPID NPs, highly efficient solid tumor ablation effects were observed in 4T1 tumor-bearing mouse models under NIR laser irradiation. Additionally, there was insignificant low-term toxicity or damage to normal tissues, as evidenced by histopathological and hemocompatibility analyses, suggesting that this agent has reliable biosafety for systemic applications. Taken together, the results of this study suggest that HPID NPs can produce tumor-specific and stimuli-triggered theranostic effects under tri-modal combination therapy. These HPID NPs advantageously provide traceable accumulation and activation and therefore could be a capable mediator in nanomedicines for eliminating solid tumors.
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PubMed
高影响因子
EUROPEAN JOURNAL OF INORGANIC CHEMISTRY
·
2017
·Vol. 2017
·期 15
·2236-2246
·
IF 2.444
Ying Yang,Yunlong Wang,Wanghua Xu,Xiuzhen Zhang,Yong Shang,Anjian Xie,Yuhua Shen
Graphical A multifunctional nanocomposite, reduced graphene oxide@mesoporous silica–doxorubicin/hydroxyapatite (rGO@mSiO 2 -DOX/HA), is fabricated by a simple method for synergistic chemotherapy and photothermal therapy. The introduction of biocompatible HA nanoparticles as a biodegradable pore-capping agent results in the controlled release of DOX under pH and near-infrared (NIR) dual stimulation. A new nanocomposite, reduced graphene oxide@mesoporous silica–doxorubicin/hydroxyapatite (rGO@mSiO 2 -DOX/HA), was prepared by a simple method under mild conditions. Owing to the relatively high loading capacity of the anticancer drug DOX, the biomimetic capping of nontoxic and pH-dependent biodegradable HA on the surface of rGO@mSiO 2 -DOX, and the efficient photothermal conversion effect of rGO under near-infrared (NIR) irradiation, the rGO@mSiO 2 -DOX/HA nanocomposite provides a lasting and pH–light dual-triggered drug release. Therefore, the excellent biocompatibility and drug-permeation ability of the nanocomposite are realized, and synergistic chemo-photothermal therapy is also achieved. The in vitro experimental results indicate that the chemotherapy of DOX and hyperthermia of rGO under NIR light irradiation killed HeLa cells effectively. Therefore, the new nanocomposite has promising prospects as a nano-drug-delivery system and in other biomedical applications because of the pH–light dual-factor sensitivity and chemo-photothermal synergistic therapy.
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高影响因子
Journal of Materials Chemistry B
·
2017
·Vol. 5
·期 7
·1380-1387
·
IF 4.543
Daquan Wang,Chen Hou,Lingjie Meng,Jiangang Long,Jiange Jing,Dongfeng Dang,Zhaofu Fei,Paul J. Dyson
Combining doxorubicin with thermal therapy in the clinic has led to startling results in the treatment of problematic cancers. Here, we describe a multimodal multi-walled carbon nanotube material that combines tumor targeting, doxorubicin delivery, and photothermal therapy for localized cancer treatment. The agent was constructed layer-by-layer from polypyrrole and gold nanoparticles on multi-walled carbon nanotubes. The gold surface was modified with tumor targeting folic acid terminated PEGylated chains, which also provide water-dispersibility, biocompatibility and should extend the half-life in blood. The material has a high loading/unloading capacity for the cytotoxic agent doxorubicin. Release of the doxorubicin, combined with the photothermal properties of the material that induces localized hyperthermia, leads to efficient cancer cell death.
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高影响因子
Journal of Materials Chemistry B
·
2015
·Vol. 3
·期 13
·2685-2697
·
IF 4.726
Xinyu Hu,Wei Wei,Xiaoliang Qi,Hao Yu,Liandong Feng,Junjian Li,Shiming Wang,Jianfa Zhang,Wei Dong
Salecan is a novel water-soluble extracellular β-glucan produced by a salt-tolerant strain Agrobacterium sp. ZX09. Salecan is suitable for the fabrication of hydrogels for biomedical applications due to its excellent physicochemical and biological properties. In this paper, a series of pH-sensitive hydrogels were prepared in aqueous solution by the graft copolymerization of Salecan and acrylic acid (AA) using N,N′-methylene diacrylamide as a crosslinker for controlled drug delivery. The structure and thermal stability of the resulting hydrogels were characterized by FT-IR, XRD and TGA. By SEM analysis, freeze-dried hydrogels displayed an interconnected porous structure with tunable pore size in the range of 23.2–90.3 μm. The swelling behavior of the hydrogels was shown to be highly dependent on the environmental pH, salt type and concentration, as well as the contents of Salecan and BAAm. They are almost unswellable at pH 1.2 and swollen extensively at pH 6.86. Meanwhile, the increase in the content of hydrophilic Salecan could enhance the swelling ratio, whereas the presence of more BAAm reduced the swelling capacity but promoted the water retention to some extent. Rheological tests revealed that storage modulus G′ was strongly influenced by the crosslink density of the obtained hydrogel network. Especially, doxorubicin (DOX) as a model anti-cancer drug was very efficiently loaded into the negatively charged hydrogels (up to 69.4 wt%) through electrostatic interactions. More importantly, the release of DOX from this intelligent system exhibited pH-responsive behavior and a sustained release pattern. For SPA2, the cumulative release profile showed a low level of drug release (about 12.3 wt% in 24 h) at pH 7.4, and was significantly accelerated at pH 4.0 (over 40 wt% in 6 h). Cytotoxicity experiments confirmed that all blank hydrogels were non-toxic to A549 cells, while DOX released from the drug-loaded hydrogels remained biologically active and had the capability to kill cancer cells. The preliminary results clearly suggested that the Salecan-g-PAA hydrogels may be promising carriers for controlled drug delivery.
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高影响因子
JOURNAL OF NANOSCIENCE AND NANOTECHNOLOGY
·
2016
·Vol. 16
·期 7
·7530-7538
·
IF 1.338
Wang Yang,Nie Jinshan,Wang Wei,Gu Zhun
In this work, redox and pH responsive vesicles of PEGylated hyperbranched poly(amidoamine)-doxorubicin (PPCD) conjugates were prepared for the improvement of cancer therapy. The PPCD 3/1 and PPCD 6/1 conjugates were respectively prepared by the acid sensitive cis-aconityl linkage
between doxorubicin and differently PEGylated hPAMAM (PEG3-g-hPAMAM and PEG6-g-hPAMAM). The PPCD vesicles were prepared by disulfide-crosslinking the micelles formed in THF and then transferring them from THF into water. The crosslinked
PPCD vesicle with a higher PEGylated degree showed a measurable decrease in size and zeta potential. Both the crosslinked PPCD vesicles could be disassembled into small-sized conjugates under the redox condition. The drug release profiles showed that the both vesicles presented stimuli-triggered
drug release in acidic and reducing environment and lower DOX leakage under neutral condition. The cytotoxicity assay reflected that both the PPCD vesicles could effectively kill the gastric cancer MGC803 cells, and PPCD 6/1 vesicle with smaller size presented higher cytotoxicity than PPCD
3/1 vesicle. Considering the more applicable size (about 100 nm), higher capacity of killing tumor cells and better compatibility, the PPCD-6 vesicle with higher PEGylation degree is more favorable to promote the therapeutic effect of cancer, and will be more suitable as drug delivery system
for solid tumor treatment.
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高影响因子
RSC Advances
·
2015
·Vol. 5
·期 90
·73416-73423
·
IF 3.84
Yanan Xue,Xiaoyang Xia,Bo Yu,Xiaogang Luo,Ning Cai,Sihui Long,Faquan Yu
A surfactant-free and organic solvent-free one-pot method was utilized for the preparation of a pH-responsive alginate nanogel (pH-AN). Simply by mixing anionic sodium alginate (SA) with cationic doxorubicin (DOX) through electrostatic interactions, followed by in situ crosslinking with ionic calcium under ultrasound, a DOX-loaded pH-AN was obtained. The sizes of the nanogels can be tailored by varying the concentration of SA, the ratio of SA to ionic calcium and DOX. The nanogel was measured with a size range of 210 nm, and a polydispersity index of 0.208, as confirmed by transmission electron microscopy and dynamic light scattering. In vitro release profiles showed a significantly higher accumulative release at pH 5.0 than at pH 7.4, exhibiting apparent acid responsiveness. In vitro cytotoxicity tests clearly illustrated the remarkable inhibition to the growth of HeLa cells with an IC50 value of 0.26 μg mL−1. In contrast, NIH 3T3 cells displayed high tolerance. The plain nanogel exclusive of DOX was practically non-toxic. Confocal laser scanning microscopy observation demonstrated that DOX was efficiently internalized into HeLa cells through endocytosis, released into the cytoplasm, and then principally entered the nuclei. It is clearly suggested that a green and facile method was proposed to achieve a pH-responsive nanogel carrier for the delivery of drugs.
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Materials Express
·
2021
·Vol. 11
·期 10
·1619-1627
·
IF 0
Zhang Yue,Liu Yuanfen,Hu Yumin,Pan Lei
In this study, we developed an active targeting nano-immunoplatform of doxorubicin (DOX)-loaded bovine serum albumin (BSA) modified with the humanized antibody cetuximab, which can target the epidermal growth factor receptor (EGFR) of EGFR-overexpressing colon cancer, and subjected
it to a series of in vitro evaluation. The obtained cetuximab-modified nanoparticles (cetuximab-DOX-immuno-NPs) had an average particle size of 218.2±2.2 nm, a polydispersity index of 0.162±0.023, a zeta potential of −23.28±0.75 mV, and a cetuximabloading
efficiency of 33.6%±3.5%. The results of 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide cytotoxicity experiments showed that the cytotoxic of cetuximab-DOX-immuno-NPs in EGFR-overexpressing RKO colon cancer cells was significantly higher than it was in EGFR-under-expressing
LS174 T cells. The results of flow cytometry showed that when DOX-immuno-NPs were used, DOX was eliminated soon after entering the cells, whereas when cetuximab-DOX-immuno-NPs were used, DOX efflux was reduced. Confocal laser-scanning microscopy was used to visualize the endocytosis of nanoparticles,
and revealed that the fluorescence intensity of cetuximab-DOX-immuno-NPs was significantly higher than that of non-specific IgG-DOX-immuno-NPs in RKO cells. Moreover, in EGFR-under-expressing LS174 T cells, both cetuximab-DOXimmuno-NPs and Immunoglobulin G-DOX-immuno-NPs showed weak DOX fluorescence
intensity, reflecting the specificity and selectivity of cetuximab-modified nanoparticles toward EGFR-overexpressing cancer cells. This study demonstrated that cetuximab modification of DOX-loaded BSA nanoparticles can increase their selectivity and reduce their toxicity. As this would decrease
the side effects of these treatments in patients, this study shows that cetuximab-modified doxorubicin-loaded bovine serum albumin nanoparticles are promising candidates for targeted colon cancer therapy.
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Biomaterials Advances
·
2025
·
IF 6
Chen Wang,Yin Li,Xiaoxue Shen,Shiwei Xiao,Huiying Du,Qianye Zhao,Ying Wang,Qiangtao Zhang,Shuxin Wen
Background Patients with locally advanced head and neck squamous cell carcinoma (HNSCC) exhibit poor survival due to tumor microenvironment (TME) barriers and systemic toxicity of chemo-immunotherapy associated with chemo-immunotherapy. Methods An injectable thermoresponsive hydrogel was engineered by crosslinking D-α-tocopheryl polyethylene glycol succinate (TPGS) with Na₂CO₃ (15 % w/v TPGS: 9 % w/v Na₂CO₃). This platform co-encapsulated doxorubicin-loaded nanoparticles (DOX NP) synthesized via PEI-cis-aconitic acid conjugation and CpG-loaded adjuvant nanoparticles (CpG NP) prepared through genipin-mediated PEI crosslinking. The hydrogel exhibited rapid temperature-triggered gelation, shear-thinning injectability, and a macroporous architecture that enabled dual drug retention and immune cell infiltration. Results In vitro , the hydrogel provided the sustained release of DOX NP with pH-responsive acceleration in acidic TME. In vivo , localized delivery of Gel-DOX NP-CpG NP significantly suppressed tumor growth ( p < 0.05) and enhanced cytotoxic CD8 + T-cell infiltration in TME (3.1-fold) and spleens (2.4-fold). RNA sequencing revealed 88 immune-related differentially expressed genes, including downregulated immunosuppressors and enriched cytokine pathways. Conclusion This TPGS/Na₂CO₃ hydrogel platform coordinates chemotherapy-induced immunogenic cell death (DOX NP) with CpG-driven innate immunity, overcoming TME barriers to enhance localized and systemic anti-tumor responses in HNSCC.
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