Cell Death & Disease
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2021
·Vol. 12
·期 5
·1-17
·
IF 8.469
Wang Ruoqin,Sun Linqing,Xia Suhua,Wu Hongya,Ma Yanchao,Zhan Shenghua,Zhang Guangbo,Zhang Xueguang,Shi Tongguo,Chen Weichang
Emerging evidence suggests that cellular senescence induced by chemotherapy has been recognized as a new weapon for cancer therapy. This study aimed to research novel functions of B7-H3 in cellular senescence induced by a low dose of doxorubicin (DOX) in colorectal cancer (CRC). Here, our results demonstrated that B7-H3 knockdown promoted, while B7-H3 overexpression inhibited, DOX-induced cellular senescence. B7-H3 knockdown dramatically enhanced the growth arrest of CRC cells after low-dose DOX treatment, but B7-H3 overexpression had the opposite effect. By RNA-seq analysis and western blot, we showed that B7-H3 prevented cellular senescence and growth arrest through the AKT/TM4SF1/SIRT1 pathway. Blocking the AKT/TM4SF1/SIRT1 pathway dramatically reversed B7-H3-induced resistance to cellular senescence. More importantly, B7-H3 inhibited DOX-induced cellular senescence of CRC cells in vivo. Therefore, targeting B7-H3 or the B7-H3/AKT/TM4SF1/SIRT1 pathway might be a new strategy for promoting cellular senescence-like growth arrest during drug treatment in CRC.
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Journal of Biomedical Nanotechnology
·
2016
·Vol. 12
·期 11
·1975-1986
·
IF 3.929
Zhang Min,Jiang Li
Mesoporous silica nanoparticles (MSNs) are widely used nanoparticles with a pore rich structure that is suitable for drug delivery. Here, we used MSNs to carry and deliver doxorubicin hydrochloride (DOX) in vivo to study the features of DOXloaded MSNs (MSNs@DOX). We used TEM
and zeta potential to illustrate that MSNs@DOX increase apoptosis and decrease metastasis of tumor cells. We used MTT, flow cytometry, Western blotting, wound healing, and transwell assays, as well as an in vivo metastasis model to explore the anti-carcinoma efficacy of MSNs@DOX. Our
results showed that DOX was efficiently loaded into MSNs measuring approximately 88±11 nm, which significantly increased the antitumor efficacy of DOX on lung cancer, both in vitro and in vivo, compared to a regular DOX treatment. MSNs@DOX markedly induced apoptosis through
cytochrome C release and the caspase family. Furthermore, cell migration and invasion were sharply inhibited, both in vitro and in vivo. We also found that the enhanced effect of MSNs@DOX might be due to an increased cellular uptake by tumor cells based on the enhanced permeability
and retention time of the nanoparticles. Matrigel plug assays and Western blotting assays revealed that the molecular mechanism behind the anti-metastasis effect might be attributed to the suppression of VEGF-mediated angiogenesis. Our results offer a new perspective on the application of
nanoparticles against metastasis.
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CARBOHYDRATE POLYMERS
·
2024
·
IF 10.7
Junmin Qian,Abdalrheem Jarelnaby Musa Aldai,Weijun Xu,Taibing Wang,Kunkun Zhao,Yaping Wang,Jingjing Fan,Aili Suo
Cuproptosis shows great prospects in cancer treatments. However, insufficient intracellular copper amount, low-level redox homeostasis, and hypoxic tumor microenvironment severely restrict cuproptosis efficacy. Herein, hydrazided hyaluronan-templated decorated CuO 2 -doxorubicin (CuDT) nanodot clusters (NCs) are developed for efficient doxorubicin (DOX)-sensitized cuproptosis therapy in breast cancer via a three-pronged strategy. The CuDT NCs with an average size of 56.2 nm are fabricated from 3,3′-dithiobis(propionohydrazide)-conjugated hyaluronan, Cu 2+ , and DOX through a one-pot mineralization process. The CuDT nanoparticles exhibit pH-responsive H 2 O 2 , Cu 2+ , and DOX release profiles and catalytic activity. Upon entrance into tumor cells, CuO 2 -based exogenous H 2 O 2 supply and DOX-augmented endogenous H 2 O 2 generation jointly elevate intracellular H 2 O 2 level, which can further be transformed into hydroxyl radicals and O 2 through Fenton-like reaction to achieve oxidative stress amplification and hypoxia relief, respectively. Moreover, the CuDT NCs can efficiently deplete intracellular overexpressed glutathione via Cu 2+ /Cu + cycle and abundant disulfide bonds, further enhancing cellular oxidative stress. These results demonstrate that the novel CuDT NCs achieve DOX-sensitized cuproptosis in breast cancer cells through elevating copper level, amplifying oxidative stress and alleviating hypoxia, and display prominent in vivo antitumor efficacy. Such a three-pronged strategy of targetedly boosting cuproptosis in cancer cells represents a novel approach for antitumor treatments.
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Chemical Engineering Journal Advances
·
2023
·
IF 0
Yun-Da Yue,Yuan-Yuan Cui,Cheng-Xiong Yang
Rational design and fabrication of effective drug delivery systems (DDS) are crucial for improving the therapeutic effectiveness and overcoming the shortcomings of chemotherapy. Herein, we report the construction of a novel cyclodextrin microporous organic network (CD-MON)-based DDS via a convenient thiol‑yne click reaction and dehydration condensation modification for the controllable release and targeted delivery of doxorubicin (DOX), a typical chemotherapy drug. The constructed DDS afforded multiple hydrophobic, hydrogen-bonding, and host-guest interaction sites, allowing for the efficient loading of DOX. The obtained DDS also exhibited good sustained and long-term release of DOX. Additionally, the proposed DDS offers good biocompatibility and exhibits an obvious aggregation-induced emission. Furthermore, the introduction of folic acid (FA) into the CD-MON-based DDS provided excellent targeting capacity for FA receptor-positive NCI-H226 cells. This study proved the universality of the design, synthesis, and application of CD-MON-based DDS, revealing the great potential of CD-MONs in drug delivery.
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COLLOIDS AND SURFACES B-BIOINTERFACES
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2015
·
IF 4.152
Baocheng Tian,Yuanyuan Ding,Jian Han,Jing Zhang,Yuzhen Han,Jingtian Han
A novel targeting drug delivery system containing poly(styrene-alt-maleic anhydride) 58 -b-polystyrene 130 (P(St-alt-MA) 58 -b-PSt 130 ) as a copolymer backbone, N -acetyl glucosamine (NAG) as a targeting moiety was designed and synthesized. The NAG grafted copolymer (NAG-P(St-alt-MA) 58 -b-PSt 130 ) was characterized by FTIR and 1 H NMR. The NAG-P(St-alt-MA) 58 -b-PSt 130 nanoparticles exhibited spherical shapes with an average diameter about 56.27 ± 0.43 nm, low critical micelle concentration of 0.028 mg/mL, negative zeta potential −41.46 ± 0.99 mV, high drug loading 25.83 ± 1.09% and encapsulation efficiency 69.69 ± 3.98%. In vitro cell cytotoxicity was conducted to confirm the safety of the NAG-P(St-alt-MA) 58 -b-PSt 130 nanoparticles. Confocal laser scanning microscopy (CLSM) and flow cytometry (FCM) results showed that the NAG targeting moiety enhanced the internalization and targeting ability of NAG-P(St-alt-MA) 58 -b-PSt 130 nanoparticles. Anticancer activity toward MCF-7 cells and HT29 cells showed that DOX-loaded NAG-P(St-alt-MA) 58 -b-PSt 130 nanoparticles exhibited a higher antitumor activity compared to DOX-loaded P(St-alt-MA) 58 -b-PSt 130 nanoparticles, which could attribute to NAG receptor-mediated endocytosis. These results suggest that the biocompatible and non-toxic NAG-P(St-alt-MA) 58 -b-PSt 130 nanoparticles may be used as an effective targeting drug delivery system for cancer therapy.
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INTERNATIONAL JOURNAL OF PHARMACEUTICS
·
2020
·
IF 4.845
Dianlong Jia,Yujiao Yang,Fengjiao Yuan,Qing Fan,Feifei Wang,Yujiao Huang,Hao Song,Ping Hu,Rui Wang,Guangyong Li,Renmin Liu,Jun Li
Epidermal growth factor receptor (EGFR) is overexpressed in a wide range of solid tumors . In this study, we exploited a high-affinity EGFR-antagonistic affibody (Z EGFR ) coupled to a doxorubicin loaded pegylated liposome (LS-Dox) for concurrent passive and active targeting of EGFR + A431 tumor cells in vitro and in vivo . The in vitro studies revealed that the Dox liposomes coupled with Z EGFR (AS-Dox) showed a higher Dox uptake than LS-Dox in EGFR + A431 cells but not in EGFR − B16F10 cells, resulting in a selectively enhanced cytotoxicity. In vivo , AS-Dox confirmed its long circulation time and efficient accumulation in tumors. This targeted chemotherapy achieved greater tumor suppression. Further, this low-dose but effective targeted treatment reduced systemic toxicity such as body weight loss and organ injury demonstrated by H&E staining. Thus, selective targeting of LS-Dox coupled with Z EGFR enhanced antitumor effects and improved systemic safety. These results demonstrated that LS-Dox coupled with Z EGFR might be developed as a potential tool for therapy of EGFR + tumors.
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RSC Advances
·
2020
·Vol. 10
·期 56
·33894-33902
·
IF 3.119
Feng Tian,Chen Xu,Mingyue Xu,Haiqing Gao,Ziyi Xiao,Ling Li,Yingxi Wang
Drug resistance is a major obstacle in cancer treatment, and designing a material that monitors real-time drug release remains a top priority. In this study, metal–organic frameworks doped with lanthanum and thulium were synthesized and then coated with aminated silica to form La/Tm-MOF@d-SiO2 as a drug carrier. Doxorubicin hydrochloride (DOX) was selected as a drug model, and the drug loading and release were investigated. It was found that the release of DOX under acidic conditions reached an optimal level, indicating the pH-responsiveness of La/Tm-MOF@d-SiO2. Under acidic conditions (pH = 5.8), upconversion fluorescence was generated after loading DOX on La/Tm-MOF@d-SiO2. At pH = 5.8, the longer the drug released, the stronger the upconversion fluorescence. It was found that the upconversion fluorescence intensity is directly proportional to the amount of drug released; thus, the real-time monitoring of DOX release in tumor cells can be performed based on the upconversion fluorescence.
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Scientific Reports
·
2025
·Vol. 15
·期 1
·40205
·
IF 3.9
Tang Cheng,Zou Yangyang,Meng Hao,Xu Jin,Long Fang,Chen Xiaoli,Xiao Qingling,Su Kelei,Nan Zhang,Guo Yaoyao,Li Chaojuan
To develop excipient-free carrier-free nanoparticles (DE NPs) via self-assembly of doxorubicin (DOX) and emodin (EMO) for enhanced combination chemotherapy against non-small cell lung cancer (NSCLC). DE NPs were fabricated through non-covalent interactions between DOX and EMO using a self-assembly method. The nanoparticles were characterized for morphology, stability, encapsulation efficiency, and cellular uptake. In vitro cytotoxicity and in vivo antitumor efficacy of free drugs (EMO, DOX), DOX/EMO mixture, and DE NPs were evaluated on A549 NSCLC cells. Mechanistic studies explored the role of DE NPs in suppressing efflux pump proteins via modulation of p65 activation and nuclear translocation. DE NPs formed rod-like nanostructures with high encapsulation efficiency (> 90%) and stability. They exhibited enhanced cellular uptake and intracellular drug accumulation compared to free drugs or the mixture. In vitro studies demonstrated significantly stronger cytotoxicity in A549 cells (IC50 reduction of ~ 50%) and a synergistic antitumor effect (combination index < 0.5). In vivo studies further confirmed the superior antitumor efficacy of DE NPs over individual DOX or EMO monotherapy (72.67 ± 7.20% tumor inhibition rate). Mechanistically, DE NPs inhibited p65 activation and nuclear translocation, downregulating efflux pump protein expression and prolonging drug retention in cancer cells. The excipient-free DE NPs provide a promising carrier-free nanomedicine platform for NSCLC treatment, achieving synergistic antitumor efficacy through enhanced drug delivery and suppression of drug resistance mechanisms. This strategy highlights the potential of self-assembled dual-drug nanoparticles to improve therapeutic outcomes in combination.
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RSC Advances
·
2015
·Vol. 5
·期 95
·77986-77995
·
IF 3.84
Nuannuan Li,Pei Zhang,Chunzhi Huang,Yunmei Song,Sanjay Garg,Yuxia Luan
In this paper, we synthesized the pH-sensitive and biodegradable amphiphilic polypeptide-based block copolymer methoxy-poly(ethylene glycol)2K-poly(ε-caprolactone)4K-poly(glutamic acid)1K (mPEG2K-PCL4K-PGA1K). mPEG2K-PCL4K-PGA1K had low critical aggregation concentration and could self-assemble into polymersomes in aqueous solution revealed by transmission electron microscopy. Therefore, two hydrophilic drug doxorubicin hydrochloride (DOX) and verapamil hydrochloride (VER) were encapsulated into the mPEG2K-PCL4K-PGA1K polymersomes to form poly(DOX + VER) co-delivery system to reverse the multidrug resistance by inhibiting the expression of P-glycoprotein and improve the anti-cancer effect of DOX. The in vitro cytotoxicity experiments indicated the obviously higher inhibition ratio to MCF-7/ADR resistant cells of poly(DOX + VER) compared with that of free DOX solution and polyDOX. The release rate of the two drugs from poly(DOX + VER) were much slower than that from the free drug solutions, and their release behaviors exhibited high pH-sensitive character. Furthermore, the low hemolysis ratio of mPEG2K-PCL4K-PGA1K confirmed that the copolymer could be applied for intravenous injection safely. Therefore, all these findings indicated that the co-delivery of DOX and VER by mPEG2K-PCL4K-PGA1K polymersomes is very promising for cancer therapy.
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Current Drug Delivery
·
2024
·Vol. 22
·期 10
·1414-1429
·
IF 2.8
Houlin Su,Zhiqiang Tu,Lin Jing,Yanling Huang,Xu Liu,Mingqing Yuan
BackgroundCombining Doxorubicin (DOX) with sorafenib (SF) is a promising strategy for treating Hepatocellular Carcinoma (HCC). However, strict dosage control is required for both drugs, and there is a lack of target selectivity.ObjectiveThis study aims to develop a novel nano-drug delivery system for the combined use of DOX and SF, aiming to reduce their respective dosages, enhance therapeutic efficacy, and improve target selectivity.MethodsDOX/SF co-loaded liposomes (LPs) were prepared using the thin-film hydration method. The liposomes were modified with 1,2-distearoyl-sn-glycero-3-phospho-ethanolamine (DSPE)-polyethylene glycol (PEG2000), DSPE-PEG1000-cell penetrating peptide TAT, and Glycyrrhetinic Acid (GA). The basic properties of the liposomes were characterized. CCK-8 cell viability assays were conducted using HepG2, MHCC97-H, and PLC cell models, and apoptosis experiments were performed using HepG2 cells to determine if this delivery system could reduce the respective dosages of DOX and SF and enhance HCC cytotoxicity. Liposome uptake experiments were performed using HepG2 cells to validate the target selectivity of this delivery system.ResultsA GA/TAT-DOX/SF-LP liposomal nano drug delivery system was successfully constructed, with a particle size of 150 nm, a zeta potential of -7.9 mV, a DOX encapsulation efficiency of 92%, and an SF encapsulation efficiency of 88.7%. Cellular experiments demonstrated that this delivery system reduced the required dosages of DOX and SF, exhibited stronger cytotoxicity against liver cancer cells, and showed better target selectivity.ConclusionA simple and referenceable liposomal nano drug delivery system has been developed for the combined application of DOX and SF in hepatocellular carcinoma treatment.
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COLLOIDS AND SURFACES A-PHYSICOCHEMICAL AND ENGINEERING ASPECTS
·
2026
·
IF 5.4
Xin Dang,Haiping Zhou,Hui Qi,Ruoru Qian,Jieru Xu
Insufficient therapeutic response in cervical cancer is closely associated with enhanced redox buffering, mitochondrial metabolic adaptation, and drug damage repair, which collectively weaken the sustained cytotoxicity of conventional chemotherapy. Herein, we developed a poly(2-ethyl-2-oxazoline) (PEOz)-modified Cu 2+ /Ca 2+ -coordinated doxorubicin (DOX)-loaded nanoplatform, D/CCP-P, to integrate chemotherapy, oxidative stress remodeling, cuproptosis sensitization, and photothermal amplification. In this system, Cu/Ca-doped mesoporous polydopamine served as both a drug-loading scaffold and photothermal converter, while PEOz enabled weakly acidic charge-reversal to enhance tumor cell uptake. The Cu/Ca dual-ion design was designed to disrupt intracellular redox and mitochondrial homeostasis: Cu 2+ was associated with glutathione depletion and reactive oxygen species accumulation, whereas Ca 2+ was associated with mitochondrial perturbation and metabolic stress, thereby weakening cellular tolerance to therapeutic insults. D/CCP-P exhibited efficient DOX loading, with a drug loading content of 42.64%. The nanoplatform also showed favorable photothermal performance, with a photothermal conversion efficiency of 41.43%, and enabled stimuli-responsive DOX release under acidic, reductive, and near-infrared (NIR) irradiation conditions. Mechanistically, D/CCP-P increased ROS-associated stress and altered NDUFS8/HSP70 expression, while time-course and Cu-MPDA/CCP comparisons supported progressive, Cu/Ca-amplified cuproptosis-related changes; HUVECs retained relatively high viability under non-irradiated conditions. Overall, this cascade nanotherapeutic strategy may enhance DOX-mediated cervical cancer therapy through redox remodeling–cuproptosis sensitization–photothermal amplification. Download: Download high-res image (237KB) Download: Download full-size image
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Advanced Healthcare Materials
·
2026
·
IF 11
Yunan Yuan,Yijun Wu,Jiaxuan Yang,Fujiang Li,Ruonan Huang,Qian Cheng,Yan Rong,Chaoliang He
The therapeutic efficacy of melanoma immunochemotherapy is severely limited by insufficient intratumoral drug retention, systemic toxicity, and immunosuppressive tumor microenvironment (TME). Thus, we developed a single-dose injectable localized chemo-immunotherapy platform that enables sustained tumor-restricted delivery and synergistic immune remodeling. This hybrid system integrates doxorubicin-loaded tumor-derived exosome-coated hollow mesoporous silica nanoparticles (DeH) with a mannose-modified β-cyclodextrin-polyethyleneimine carrier co-delivering dual Toll-like receptor agonists (RC-MCP) within a thermoresponsive polypeptide hydrogel (mPEG- b -PELG). The biomimetic exosome coating provides an exosome-sheathed nanostructure and amplifies doxorubicin-induced immunogenic cell death. Mannose-mediated targeting facilitates preferential uptake by antigen-presenting cells and enhances endosomal Toll-like receptor signaling, leading to robust dendritic cell maturation. Following intratumoral injection, the hydrogel undergoes in situ sol-gel transition to form a stable drug depot, enabling sustained and coordinated release while minimizing systemic exposure. As a result, a single intratumoral administration elicits potent antitumor immune responses, significantly suppresses tumor growth, alleviates TME immunosuppression, and exhibits favorable biocompatibility in murine melanoma model. Collectively, this work presents a rationally designed single-dose localized chemo-immunotherapy strategy for melanoma treatment.
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