JOURNAL OF DRUG DELIVERY SCIENCE AND TECHNOLOGY
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2026
·
IF 5.2
Zhouli Wang,Weibo Kong,Lingtong Ge,Xiaoqin Yu,Quanfang Li,Weijun Chen,Lipeng Qiu
The clinical application of doxorubicin (DOX) is severely limited by its off-target toxicities and the emergence of chemoresistance when used alone. Herein, we engineered a chondroitin sulfate (CS)-targeted Mn-Fe bimetallic metal-organic framework nanoparticle loaded with DOX (SMFDC) that integrates chemotherapy and chemodynamic therapy (CDT) within a single platform. SMFDC exhibited uniform spherical morphology with a particle size of 164.5 ± 3.2 nm and a zeta potential of −9.11 ± 0.26 mV. The DOX encapsulation efficiency was 52.9 ± 3.54%, the drug loading capacity was 24.05 ± 1.4%, and the hemolysis rate was 1.08 ± 0.12%. The nanoparticle enabled pH/glutathione (GSH) dual-responsive release, achieving 60.33 ± 3.09% cumulative release of DOX within 60 h under simulated tumor microenvironment (TME) conditions (pH 5.0, 10 mM GSH). The released Mn 2+ /Fe 2+ ions efficiently catalyzed the Fenton/Fenton-like reaction to convert H 2 O 2 into hydroxyl radicals (·OH), while markedly depleting intracellular GSH and inducing potent oxidative stress. CS modification significantly enhanced cellular uptake in HeLa cells. In vitro antitumor evaluation showed that the half-maximal inhibitory concentration (IC 50 ) of SMFDC (DOX-equivalent) was 5.708 μg/mL, which was significantly lower than that of the unmodified SMFD group (12.849 μg/mL). Unlike previously reported Mn-Fe bimetallic MOFs used solely for CDT or CS-modified MOFs used only for targeting, this work integrates DOX loading, Mn-Fe bimetallic CDT, and CS-mediated active targeting into a single nanoplatform. This integrated design achieved synergistic chemotherapy-CDT, carrier-based pH/GSH dual-responsive release, and active tumor targeting, thereby enhancing CDT efficacy while overcoming the off-target toxicity and chemoresistance associated with DOX monotherapy. This strategy not only offers a promising paradigm for synergistic therapy but also provides a generalizable design principle for developing next-generation CDT-based combination nanomedicines. Download: Download high-res image (307KB) Download: Download full-size image
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高影响因子
PHYTOMEDICINE
·
2023
·
IF 7.9
Shanshan Dai,Yunxuan Chen,Xiaoxi Fan,Jibo Han,Lingfeng Zhong,Yucong Zhang,Qingran Liu,Jiahui Lin,Weijian Huang,Lan Su,Zhouqing Huang,Bozhi Ye
Background Doxorubicin (Dox), which is an anticancer drug, has significant cardiac toxicity and side effects. Pyroptosis occurs during Dox-induced cardiotoxicity (DIC), and drug inhibition of this process is one therapeutic approach for treating DIC. Previous studies have indicated that emodin can reduce pyroptosis. However, the role of emodin in DIC and its molecular targets remain unknown. Hypothesis/Purpose We aimed to clarify the protective role of emodin in mitigating DIC, as well as the mechanisms underlying this effect. Methods The model of DIC was established via the intraperitoneal administration of Dox at a dosage of 5 mg/kg per week for a span of 4 weeks. Emodin at two different doses (10 and 20 mg/kg) or a vehicle was intragastrically administered to the mice once per day throughout the Dox treatment period. Cardiac function, myocardial injury markers, pathological morphology of the heart, level of pyroptosis and mitochondrial function were assessed. Protein microarray, biolayer interferometry and pull-down assays were used to confirm the target of emodin. Moreover, GSDMD-overexpressing plasmids were transfected into GSDMD −/− mice and HL-1 cells to further verify whether emodin suppressed GSDMD activation. Results Emodin therapy markedly enhanced cardiac function and reduced cardiomyocyte pyroptosis in mice induced by Dox. Mechanistically, emodin binds to GSDMD and inhibits the activation of GSDMD by targeting the Trp415 and Leu290 residues. Moreover, emodin was able to mitigate Dox-induced cardiac dysfunction and myocardial injury in GSDMD −/− mice overexpressing GSDMD, as shown by increased EF and FS, decreased serum levels of CK-MB, LDH and IL-1β and mitigated cell death and cell morphological disorder. Additionally, emodin treatment significantly reduced GSDMD-N expression and plasma membrane disruption in HL-1 cells overexpressing GSDMD induced by Dox. In addition, emodin reduced mitochondrial damage by alleviating Dox-induced GSDMD perforation in the mitochondrial membrane. Conclusion Emodin has the potential to attenuate DIC by directly binding to GSDMD to inhibit pyroptosis. Emodin may become a promising drug for prevention and treatment of DIC.
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高影响因子
TOXICOLOGY AND APPLIED PHARMACOLOGY
·
2023
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IF 3.8
Yixin Sun,Danyang Guo,Saiding Yue,Mingyan Zhou,Dongxu Wang,Fengjiao Chen,Lingling Wang
Background Doxorubicin (DOX), a chemotherapeutic drug, could relieve the progressions of various diseases. However, its clinical application is limited due to its cardiotoxicity. This study aimed to investigate the effects of afzelin (a flavonol glycoside found in Houttuynia cordata ) on the cardiotoxicity induced by DOX. Methods In ex-vivo, H9C2 cells were incubated with 20, 40, or 80 μM afzelin for 12 h, followed by the treatment with 1 μM DOX for 12 h. In vivo, C57BL/6 J mice were intraperitoneally injected with 4 mg/kg/day DOX on days 1, 7, and 14. Meanwhile, starting from day 1, mice were intragastrically administrated with 5 mg/kg/day or 10 mg/kg/day afzelin for 20 days. The cardiac function of mice was evaluated by detecting hemodynamic parameters using the M-mode echocardiography. Results DOX decreased the cell survival rate, and elevated apoptotic rate, as well as induced the oxidative stress and mitochondrial dysfunction in H9C2 cells. All these changes were alleviated by afzelin treatment in a concentration-dependent manner. The results were further proven by the mitigation of cardiac injury in vivo, as evidenced by the elevation of fractional shortening, heart weight/tibia length, and the rate of the increase/decrease of left ventricular pressure in mice subjected to DOX-induced cardiotoxicity. Furthermore, afzelin upregulated the expression of p-AMP-activated protein kinase alpha (AMPKα) and sirtuin1 (SIRT1). Dorsomorphin (an AMPKα inhibitor) abrogated the anti-cardiotoxicity effects of afzelin in H9C2 cells induced by DOX. Conclusion Afzelin protected against DOX-induced cardiotoxicity by promoting the AMPKα/SIRT1 signaling pathway.
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高影响因子
Biomaterials Science
·
2021
·Vol. 9
·期 7
·2598-2607
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IF 6.843
Linhua Liao,Qiang Chu,Chao Fang,Xiang Li,Gaorong Han
In this study, fine hollow nanocapsules, consisting of NiFe hydroxides (denoted as H–NiFe(OH)x), are designed and synthesized for the delivery of an anticancer drug (Doxorubicin, DOX) and tumour depletion. Owing to its fascinating characteristics of “Fe2+ preservation and regeneration”, H–NiFe(OH)x presents considerable Fenton activity for hydroxyl radical (˙OH) induction. Efficient delivery of DOX is ensured due to its hollow microstructure, and a typical pH-responsive drug release is enabled. More importantly, the intracellular DOX, in addition to its intrinsic antitumour properties, induces extra exogenous H2O2 which favors the production of ˙OH by H–NiFe(OH)x in tumour cells. In consequence, remarkable in vitro and in vivo antitumour properties are successfully achieved. This drug delivery system is particularly inspirational to further studies in the exploration of intelligent therapeutic platforms for combinational tumour therapy.
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高影响因子
Pharmaceuticals
·
2021
·Vol. 14
·期 2
·101
·
IF 5.863
Lin-Song Li,Bin Ren,Xiaojing Yang,Zhong-Chao Cai,Xue-Jie Zhao,Mei-Xia Zhao
Functionalized gold nanoparticles (AuNPs) have been successfully used in many fields as a result of having low cytotoxicity, good biocompatibility, excellent optical properties, and their ability to target cancer cells. Here, we synthesized AuNP carriers that were modified by hyaluronic acid (HA), polyethylene glycol (PEG), and adipic dihydrazide (ADH). The antitumor drug doxorubicin (Dox) was loaded into AuNP carriers and attached chemically. The Au nanocomposite AuNPs@MPA-PEG-HA-ADH-Dox was able to disperse uniformly in aqueous solution, with a diameter of 15 nm. The results of a 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyltetrazolium bromide (MTT) assay indicated that AuNP carriers displayed very little toxicity toward cells in high doses, although the antitumor properties of Au nanocomposites were significantly enhanced. Cellular uptake experiments demonstrated that AuNPs modified with hyaluronic acid were more readily ingested by HepG2 and HCT-116 cells, as they have a large number of CD44 receptors. A series of experiments measuring apoptosis such as Rh123 and annexin V-FITC staining, and analysis of mitochondrial membrane potential (MMP) analysis, indicated that apoptosis played a role in the inhibition of cell proliferation by AuNPs@MPA-PEG-HA-ADH-Dox. Excessive production of reactive oxygen species (ROS) was the principal mechanism by which the Au nanocomposites inhibited cell proliferation, leading to apoptosis. Thus, the Au nanocomposites, which allowed cell imaging in real-time and induced apoptosis in specific cell types, represent theragnostic agents with potential for future clinical applications in bowel cancer.Keywords:hyaluronic acid;gold nanoparticles;drug carriers;theragnostic agents;imaging
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高影响因子
Asian Journal of Pharmaceutical Sciences
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2021
·
IF 6.598
Yinxian Yang,Shiyi Zuo,Linxiao Li,Xiao Kuang,Jinbo Li,Bingjun Sun,Shujun Wang,Zhonggui He,Jin Sun
Ferroptosis is a new mode of cell death, which can be induced by Fenton reaction-mediated lipid peroxidation. However, the insufficient H 2 O 2 and high GSH in tumor cells restrict the efficiency of Fenton reaction-dependent ferroptosis. Herein, a self-supplying lipid peroxide nanoreactor was developed to co-delivery of doxorubicin (DOX), iron and unsaturated lipid for efficient ferroptosis. By leveraging the coordination effect between DOX and Fe 3+ , trisulfide bond-bridged DOX dimeric prodrug was actively loaded into the core of the unsaturated lipids-rich liposome via iron ion gradient method. First, Fe 3+ could react with the overexpressed GSH in tumor cells, inducing the GSH depletion and Fe 2+ generation. Second, the cleavage of trisulfide bond could also consume GSH, and the released DOX induces the generation of H 2 O 2, which would react with the generated Fe 2+ in step one to induce efficient Fenton reaction-dependent ferroptosis. Third, the formed Fe 3+ /Fe 2+ couple could directly catalyze peroxidation of unsaturated lipids to boost Fenton reaction-independent ferroptosis. This iron-prodrug liposome nanoreactor precisely programs multimodal ferroptosis by integrating GSH depletion, ROS generation and lipid peroxidation, providing new sights for efficient cancer therapy.
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JOURNAL OF MAGNETISM AND MAGNETIC MATERIALS
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2020
·
IF 2.717
Lihua He,Rong Zheng,Jie Min,Fulin Lu,Changqiang Wu,Yunfei Zhi,Shaoyun Shan,Hongying Su
Hydrogel nanocomposites incorporated with magnetic nanoparticles (MNPs) were widely researched as promising candidate for environment-responsive drug delivery, due to their unique magnetic properties and quick response to an external magnetic field. In this study, dextran-coated iron oxide nanoparticles (Fe 3 O 4 ) with various particle size were prepared and embedded physically into dextran microgels formed via Schiff base reactions between aldehyded dextran and diamine in W/O inverse microemulsion, leading to a series of magnetic microgels with MNPs content of 3, 6, 9% by weight percentage. Similar superparamagnetic properties of as prepared microgels with Fe 3 O 4 nanoparticles were proved, and their saturation magnetization increased with the increasing particle size or content of the MNPs. Antitumor drug doxorubicin (DOX) was encapsulated into the magnetic dextran microgels, and pH/magnetic field dual-responsive release profiles of DOX were demonstrated. Moreover, the release rate of DOX decreased obviously with the increasing MNPs content, probably due to the diffusion barrier for drug movement resulted from the reduced pore size of hydrogel matrix in respond to external magnetic field. These results indicate that the magnetic dextran microgels can serve as stimuli-sensitive drug delivery systems.
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JOURNAL OF NANOBIOTECHNOLOGY
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2021
·Vol. 19
·期 1
·1-16
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IF 10.435
Xu Jiangkang,Yang Xiaoye,Ji Jianbo,Gao Yuan,Qiu Na,Xi Yanwei,Liu Anchang,Zhai Guangxi
Background Glioblastoma is a lethal neoplasm with few effective therapy options. As a mainstay in the current treatment of glioma at present, chemotherapeutic agents usually show inadequate therapeutic efficiency due to their low blood brain barrier traversal and brain targeting, together with tumor multidrug resistance. Novel treatment strategies are thus urgently needed to improve chemotherapy outcomes. Results Here, we report that nanomedicines developed by functionalizing the neurotropic rabies virus-derived polypeptide, RVG, and loading reduction-sensitive nanomicelles (polymer and doxorubicin) enable a highly specific and efficacious drug accumulation in the brain. Interestingly, curcumin serves as the hydrophobic core of the polymer, while suppressing the major efflux proteins in doxorubicin-resistant glioma cells. Studies on doxorubicin-resistant rat glioma cells demonstrate that the RVG-modified micelles exhibit superior cell entry and antitumor activity. In vivo research further showed that RVG modified nanomicelles significantly enhanced brain accumulation and tumor inhibition rate in mice, leading to a higher survival rate with negligible systemic toxicity. Moreover, effective suppression of recurrence and pulmonary metastatic nodules were also determined after the RVG-modified nanomicelles treatment. Conclusions The potential of RVG-modified nanomicelles for glioma was demonstrated. Brain accumulation was markedly enhanced after intravenous administration. This unique drug delivery nanoplatform to the brain provides a novel and powerful therapeutic strategy for the treatment of central nervous system disorders including glioma. Graphic abstract
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高影响因子
DRUG DELIVERY
·
2020
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IF 4.902
Renna Qiu,Denghua Sun,Yuzhuo Bai,Jiannan Li,Lizhe Wang
Osteosarcoma is the most common primary malignant bone tumor in childhood and adolescence. Currently, surgery combined with chemotherapy is the main treatment for osteosarcoma. However, the long-term survival of patients with metastatic osteosarcoma is unsatisfactory. Therefore, new treatment methods to improve the prognosis of patients with osteosarcoma are required. The present study aimed to develop nanocarriers with both tumor targeting and reduction responsiveness abilities, and to improve the therapeutic effect and reduce toxicity by loading traditional small molecule antitumor drugs. The tumor targeting peptide-decorated, doxorubicin (DOX)-loaded mPEG-P(Phe-co-Cys) nanoparticles were developed successfully through the ring-opening polymerization of amino acids. The peptide VATANST (STP) can specifically bind with vimentin, which is highly expressed on the osteosarcoma cell surface, resulting in tumor targeting effects. The nanoparticle is core–shell structured to protect the loaded DOX during blood flow. The disulfide bonds within the nanoparticles are sensitive to the osteosarcoma microenvironment, which has high glutathione (GSH) levels. Under the enhanced permeability and retention and active tumor targeting effects, the STP-decorated DOX-loaded nanoparticles accumulated in tumor tissues. High GSH levels can rupture disulfide bonds, resulting in the controlled release of DOX, which will cause necrosis of tumor cells. The characteristics of the synthesized nanoparticles, DOX release profiles in vitro and in vivo, cytotoxicity analysis, animal study, and safety evaluation were performed. The nanoparticles could increase the tumor inhibition efficiency against osteosarcoma and reduce the side effects of DOX to major organs. The STP-decorated mPEG-P(Phe-co-Cys) nanoparticles might be a suitable drug delivery system for DOX to treat osteosarcoma.
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高影响因子
EUROPEAN JOURNAL OF PHARMACOLOGY
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2019
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IF 3.17
Jiamao Lin,Lijun Fang,Hui Li,Zhenxiang Li,Linmao Lyu,Haiyong Wang,Jun Xiao
Doxorubicin (DOX) is a classic anti-tumor chemotherapeutic used to treat a wide range of tumors. One major downfall of DOX treatment is it can induce fatal cardiotoxicity. Astragaloside IV (AS-IV) is one of the primary active ingredients that can be isolated from the traditional Chinese herbal medicine, Astragalus membranaceus . This study uses both in vitro and in vivo tools to investigate whether AS-IV alleviates DOX induced cardiomyopathy . We found that AS-IV supplementation alleviates body weight loss, myocardial injury , apoptosis of cardiomyocytes, cardiac fibrosis and cardiac dysfunction in DOX-treated mice. Also, DOX-induced cardiomyocyte injury and apoptosis were effectively improved by AS-IV treatment in vitro . NADPH oxidase (NOX) plays an important role in the progress of the oxidative signal transduction and DOX-induced cardiomyopathy. In this study, we found that AS-IV treatment relieves DOX-induced NOX2 and NOX4 expression and oxidative stress in cardiomyocytes. In conclusion, AS-IV, an antioxidant, attenuates DOX-induced cardiomyopathy through the suppression of NOX2 and NOX4.
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JOURNAL OF DRUG DELIVERY SCIENCE AND TECHNOLOGY
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2019
·
IF 2.606
Mengzhu Kong,Yaling Huang,Ruilin Yu,Juqun Xi
Multistimuli-responsive vehicles that deliver drugs in temporal-, spatial- and dosage-controlled manners have developed as a potential platform in tumor therapy. However, how to integrate these functions in one single carrier effectively still presents a lot of challenge. Here, we developed a strategy to construct a photothermal and pH responsive platform based on Zn 2+ coordination with doxorubicin (DOX) and polydopamine (PDA) on the surface of magnetic nanoparticles (Fe 3 O 4 @PDA-Zn 2+ -DOX NPs). In this architecture, Fe 3 O 4 @PDA nanoparticles triggered photothermal effects for tumor hyperthermia, and Zn 2+ coordinated DOX was released in responding to the thermal effect to achieve chemotherapy simultaneously. Moreover, DOX release was further promoted at acidic environment due to the pH sensitivity of Zn 2+ coordination. Therefore, our system possesses multiple effects in tumor treatment: photothermal therapy with near infrared lighting (NIR), thermosensitive DOX release for chemotherapy, and pH-responsive DOX release to enhance deeper therapy in tumor acidic microenvironment. Our in vivo results provide the evidence that Fe 3 O 4 @PDA-Zn 2+ -DOX NPs upon laser exposure have effective anti-tumor therapeutic activity, indicating this platform is suitable for enhanced chemo-photothermal synergistic tumor therapy.
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高影响因子
JOURNAL OF BIOMATERIALS SCIENCE-POLYMER EDITION
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2018
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IF 1.911
Nahla Rahoui,Bo Jiang,Nadia Taloub,Mohammad Hegazy,Yu Dong Huang
The accuracy of spatiotemporal control cargo delivery and release are primordial to enhance the therapeutic efficiency and decrease the undesirable effects, in this context a novel prodrug were developed based on biocompatible polyvinyl alcohol (PVA) substrate. PVA was conjugated to doxorubicin (PVA-DOX) via an acid-labile hydrazone linkage. PVA was first functionalized with acidic groups, then reacted with hydrazine hydrate to form an amide bond. The amine group of PVA hydrazide was linked to carbonyl group (C = O) of DOX to form a pH sensitive hydrazone bond. The molecular structure of the PVA-DOX was confirmed by FTIR, XPS, and 1H-NMR analysis methods. The degree of grafting were evaluated by TGA and confirmed by XPS, which reveals the successful bond attachment of DOX to PVA. Our findings confirm pH dependent DOX release from PVA-DOX prodrug with faster release rate in acidic environment (pH 5.0, pH 6.0) and slower release rate in neutral pH environment (pH 7.4). Compared to the primary DOX, our synthesized PVA-DOX conjugates could exhibit a promising therapeutic effect, high biocompatibility and zero premature release. The results prove the successful synthesis of PVA-DOX conjugates with high efficiency.
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高影响因子
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