Advanced Healthcare Materials
·
2025
·
IF 9.6
Yiyin Ruan,Huijie Han,Xin Guan,Weiwei Feng,Xiaojuan Cui
Among the three primary gynecological malignancies, ovarian cancer has the highest mortality rate, and its onset is often insidious. Despite standard treatments, relapse and drug resistance remain major challenges. Doxorubicin (DOX) is known to induce immunogenic cell death (ICD); however, some patients still experience tumor resistance and recurrence owing to tumor-driven immunosuppression. Indoleamine 2,3-dioxygenase (IDO), which is highly expressed in tumor tissues, impairs T-cell function and differentiation, thereby promoting immunosuppression. Consequently, combining the IDO inhibitor indoximod (IND) with DOX may reverse immunosuppression and enhance both T-cell–mediated and ICD-driven anticancer effects. However, both drugs are limited by high systemic toxicity and poor tumor targeting, necessitating the use of nanocarriers to improve delivery efficiency and minimize toxicity. This study aims to develop novel cell membrane–camouflaged liposomes capable of co-delivering IND and DOX (DOX/IND@cmLPs) for ovarian cancer therapy and to evaluate its anticancer effects in vitro and in vivo. The particle size of DOX/IND@cmLPs is measured as 111.7 ± 2.7 nm using a Malvern Zetasizer Pro, with a zeta potential of −22.4 ± 4.00 mV. Entrapment efficiency (EE) is assessed using ultra-high performance liquid chromatography and ultraviolet spectrophotometry, yielding EE values of 85.1% ± 3.4% for DOX and 23.9% ± 1.3% for IND. At both pH 7.4 and pH 5.5, DOX release from DOX/IND@cmLPs is rapid during the first 24 hours, followed by a slower, more sustained release. Coomassie Brilliant Blue staining and Western Blot analysis confirmed successful encapsulation of the cell membrane in the liposomes. The potent antitumor effect of DOX/IND@cmLPs is demonstrated via CellTiter-Glo assays in vitro. Flow cytometry and immunofluorescence staining revealed an increased ratio of CD8 + T cells to Treg cells in tumor tissues, suggesting that DOX/IND@cmLPs may partially reverse local tumor-induced immunosuppression. Reduced Ki-67 expression and increased TdT-mediated dUTP nick-end labeling positive cell ratios in tumor sections indicated that DOX/IND@cmLPs treatment suppressed tumor proliferation and promoted apoptosis. Immunohistochemistry showed alterations in mammalian target of rapamycin (mTOR)-related pathway proteins in tumors. Furthermore, DOX/IND@cmLPs could induce an abscopal effect and provide long-lasting tumor suppression in a subcutaneous mouse model. In this study, a formulation of DOX/IND-loaded liposomes camouflaged with ovarian cancer cell membranes is successfully developed, and their stable physicochemical properties are confirmed. As an effective nanodrug delivery system, DOX/IND@cmLPs exhibited enhanced tumor-targeting and immune-mediated anticancer activity both in vitro and in vivo, indicating their potential as a platform for future combined chemotherapy and immunotherapy.
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Advanced Healthcare Materials
·
2025
·
IF 9.6
Yanan Fu,Huisong Hao,Yixuan Fang,Shengjie Sun,Simin Wen,Yuanqi Liu,Jia Tang,Tianqi Wang,Meiying Wu
The traditional copper ion carrier, elesclomol, relies on transporting extracellular copper ions into cells. However, the limited extracellular copper ions hinder the copper accumulation inside cells, limiting the cuproptosis effects and thus reducing its therapeutic efficacy in cancer treatment. Although metal peroxides are effective in transporting metals and inducing oxidative stress, their application is constrained by poor safety. To address these challenges, we develop a safe bicelle nanosystem for metal peroxide delivery. Typically, the assembly of lipid-based nanoparticles into non-spherical shapes requires stabilizing agents such as membrane-stabilizing proteins (MSPs). In this study, the hydrophobic effect within the bicelle cavities is leveraged to encapsulate copper peroxide (CP), ensuring efficient delivery. CP forms a stabilizing ring around the bicelle, mimicking the function of MSPs to reinforce bicelle stability. Furthermore, considering the inhibitory effect of reduced glutathione (GSH) on cuproptosis, a GSH-sensitive derivative of doxorubicin (cDOX) is designed to reduce intracellular GSH levels. In tumor cells, cDOX interacts with CP to preferentially induce cuproptosis and oxidative stress, facilitating chemoimmunotherapy. These interactions collectively address the challenges of cuproptosis in cancer treatment by promoting efficient copper ion accumulation, effective induction of oxidative stress, and robust immunogenic cell death, providing a promising strategy for cancer therapy.
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Polymers
·
2018
·Vol. 10
·期 3
·326
·
IF 2.935
Feng Ji,Hong Sun,Zhihui Qin,Ershuai Zhang,Jing Cui,Jinmei Wang,Shuofeng Li,Fanglian Yao
Multifunctional drug carriers have great applications in biomedical field. In this study, we introduced both polydopamine (PDA) and zwitterionic polymer of poly(3-(3-methacrylamidopropyl-(dimethyl)-ammonio)propane-1-sulfonate) (PSPP) onto the surface of mesoporous silica nanoparticles (MSNs) to develop a novel nanoparticle (MSNs@PDA-PSPP), which was employed as a new kind of drug carrier for the delivery of doxorubicin (DOX). The PDA coating, as a gatekeeper, could endow the drug carrier with pH-sensitive drug release performance. The outermost PSPP layer would make the drug carrier possess protein resistance performance. The chemical structure and properties were characterized by Fourier transform infrared spectroscopy (FTIR), transmission electron microscopy (TEM), dynamic light scattering (DLS) and thermogravimetric analysis (TGA). MSNs@PDA-PSPP could keep good colloidal stability within 72 h in phosphate buffered saline (PBS) and protein solutions. Meanwhile, MSNs@PDA-PSPP exhibited a high drug loading for DOX. In vitro drug release experiments suggested MSNs-DOX@PDA-PSPP exhibited pH-dependent drug release behaviors. Besides, MSNs@PDA-PSPP had no cytotoxicity to human hepatocellular carcinoma cells (HepG2 cells) even at a concentration of 125 µg/mL. More importantly, cellular uptake and in vitro anticancer activity tests suggested that MSNs-DOX@PDA-PSPP could be taken up by HepG2 cells and DOX could be successfully released and delivered into the cell nuclei. Taken together, MSNs@PDA-PSPP have great potential in the biomedical field.
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CARBOHYDRATE POLYMERS
·
2026
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IF 13.2
Yangyi Chen,Yue Wei,Qiao Li,Huajuan He,Hui Chen,Huajing Zhang,Xiaoqing Rong,Xiao Liang,Shiyuan Lin,Wei Zhang
A kind of novel pyrimidine nucleoside (PYN) and silybin (SB) conjugated chitosan (CS) (PYN-CS-SB) polymer micelles were designed for enhancing the oral absorption of doxorubicin (DOX) via the nucleoside transporters located at intestinal epithelial cell. The four types of endogenous PYNs selected respectively as the ligands of the transporter, along with SB, were conjugated to CS. The PYN-CS-SB were synthesized and identified by 1 H NMR and FT-IR. The drug-loaded micelles were prepared by ultrasound-assisted self-assembly, and their predominant characteristics, including the microscopic well-dispersed and regular globular shapes with the small particle sizes of 143 nm - 170 nm and the high loading capacities of 9–12%, the amorphous form of DOX encapsulated in micelles, the low critical micelle concentration of 23.1–31.6 μg/ml, and extremely sustained in-vitro release, were shown. Among them, the desoxycytidine (DCD) conjugated micelles (DCD-CS-SB@DOX) exhibited the highest oral bioavailability of 391% versus DOX·HCl. The enhanced absorption based on the nucleoside transporter-mediation, and the dual inhibition of PYN-CS-SB micelles on P-gp efflux and CYP3A4 enzyme, was confirmed by cellular uptake, immunofluorescence, enzyme activity inhibition test. The findings showed the extensive potential of intestinal nucleoside transporter mediated PYN-CS-SB micelles in oral drug delivery.
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NAUNYN-SCHMIEDEBERGS ARCHIVES OF PHARMACOLOGY
·
2026
·
IF 4
Liu Jie,Chen Jun,Zhang Lei,Xia Chunyong
Doxorubicin (DOX) efficacy in breast cancer is limited by dose-dependent cardiotoxicity and the development of multidrug resistance, while celastrol (Cel) suffers from poor solubility, low bioavailability and systemic toxicity. Their combination offers synergistic potential, but effective co-delivery remains challenging. We designed a protein-based nanoplatform via ferric ion-mediated biomimetic mineralization co-assembly of DOX, Cel, and human serum albumin (HSA) for enhanced antitumor therapy. HSA-Fe(III)-Cel-DOX nanoparticles were characterized by dynamic light scattering (DLS) and transmission electron microscopy (TEM). Drug loading and encapsulation efficiencies were determined by high-performance liquid chromatography (HPLC). In vitro drug release was evaluated with or without glutathione (GSH). Cytotoxicity against 4T1 murine breast cancer cells was assessed by CCK-8 assay. The optimized HSA-Fe(III)-Cel-DOX NPs (8 mM Fe 3 ⁺) exhibited uniform spherical morphology with an average diameter of approximately 64.6 nm and narrow size distribution (PDI = 0.103). The nanoparticles demonstrated exceptionally high drug encapsulation efficiencies (96.7 ± 1.9% for DOX and 94.5 ± 1.4% for Cel) and drug loading capacities (19.7 ± 0.5% for DOX and 17.3 ± 0.4% for Cel). The formulation exhibited excellent colloidal stability over 28 days of storage. In vitro release studies revealed remarkable GSH-responsive behavior, with cumulative release reaching 77.0 ± 3.3% for DOX and 64.0 ± 2.9% for Cel at 12 h under reducing conditions, while negligible release (< 5%) under non-reducing conditions was observed in the absence of GSH. Cytotoxicity assays demonstrated that HSA-Fe(III)-Cel-DOX NPs exerted significantly enhanced antitumor effect against 4T1 cells compared to free DOX or free Cel alone. At an equivalent DOX concentration of 0.5 μg/mL, the nanoparticles reduced cell viability to 29.2 ± 1.2%, substantially lower than free DOX (89.7 ± 2.0%) or free Cel (100.4 ± 2.2%). We successfully constructed a ferric ion-mediated biomimetic nanoplatform via co-assembly of DOX, Cel, and HSA. This nanoplatform offers facile preparation, excellent stability, GSH-responsive drug release, and significantly enhanced in vitro cytotoxicity, representing a promising strategy for synergistic breast cancer therapy.
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Redox Biology
·
2026
·
IF 16.2
Yan Chen,Bo Zhang,Yufan Wei,Yanfa Dai,Baoyue Zhang,Jing Li,Ke-Jia Wu,Ning Sun,Chenwen Shao
Doxorubicin (DOX)-induced cardiotoxicity remains a major limitation of cancer chemotherapy, largely due to the lack of sensitive approaches for early detection and effective cardioprotective interventions. This study investigated whether cysteine depletion represents an early redox event during DOX cardiotoxicity and evaluated a cysteine-activatable fluorescent probe, termed the cardiotoxicity-responsive cysteine probe (CCP), for in vivo redox imaging and therapeutic discovery. Cardiac imaging revealed a significant reduction in intracellular cysteine levels three weeks after DOX administration, preceding systolic dysfunction detected by echocardiography at four weeks. Mechanistically, cysteine depletion was accompanied by impaired glutathione-dependent antioxidant defense, iron accumulation, lipid peroxidation, and ferroptosis. Through probe-guided screening, gnetol (a naturally occurring polyphenolic stilbene) was identified as a potent regulator of intracellular cysteine homeostasis. Gnetol restored cysteine and glutathione levels, reduced lipid peroxidation, and suppressed ferroptosis by modulating the SMAD–hepcidin–FPN1 axis and preserving glutathione peroxidase 4 activity. In the mouse model of DOX-induced cardiomyopathy, gnetol significantly improved cardiac function, attenuated myocardial injury and fibrosis, and reduced oxidative stress without evident systemic toxicity. Collectively, these findings establish cysteine depletion as an early redox feature of DOX cardiotoxicity and demonstrate that cysteine-targeted redox imaging enables mechanism-guided discovery of cardioprotective agents. This study highlights gnetol as a promising ferroptosis-suppressing candidate and provides a mechanistic framework for early detection and intervention in redox-driven cardiac injury.
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JOURNAL OF COLLOID AND INTERFACE SCIENCE
·
2016
·
IF 3.782
Hui Zhang,Jiangkang Xu,Liang Xing,Jianbo Ji,Aihua Yu,Guangxi Zhai
Doxorubicin (DOX) is one of the most common chemotherapeutic agents for the treatment of various cancers, but its clinical usage is limited by dose-dependent cardiotoxicity. We have recently synthesized a series of Chondroitin sulfate/poly ( d , l -lactideco-glycolide) block copolymers (Chs- b -PLGA) with different length of hydrophobic block by an end-to-end coupling strategy. The structure of the amphiphilic block copolymers with low critical micelle concentration (∼28 mg/L) were confirmed by 1 H NMR. The copolymers could self-assemble into stable micelles in aqueous environment with homogeneous size distribution and negative zeta potential . The hemolytic study indicated their excellent blood compatibility and potential application for intravenous administration. DOX can be efficiently encapsulated by the Chs- b -PLGA micelles. The DOX-loaded micelles showed a sustained and pH dependent drug release behavior. The cytotoxicity assay showed no associated toxicity with blank micelles while concentration-related cell inhibition with DOX-loaded micelles. Moreover, fast cellular uptake of DOX-loaded micelles was observed by fluorescent microscope. In vivo pharmacokinetics study showed that the Chs- b -PLGA micelles could significantly prolong the blood circulation time of DOX. The maximum tolerated dose (MTD) of DOX-loaded micelles in Kunming mice was about 2-fold higher of the MTD of free DOX, indicating a high tolerance of the DOX-loaded micelles. In conclusion, the Chs- b -PLGA micelles would be a potentially useful drug delivery system for cancer therapy.
研究领域:
药剂学
·
药物递送
·
纳米医学
·
高分子科学
·
癌症治疗
·
生物医学工程
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Asian Journal of Pharmaceutical Sciences
·
2022
·
IF 9.273
Linping Jiang,Kesi Wang,Liyan Qiu
Drug resistance is accountable for the inadequate outcome of chemotherapy in clinics. The newly emerging role of nitric oxide (NO) to conquer drug resistance has been recognized as a potential strategy. However, it remains a great challenge to realize targeted delivery as well as accurate release of NO at desired sites. Herein, we developed a PEGylated indocyanine green (mPEG-ICG) integrated nanovesicle system (PIDA) to simultaneously load doxorubicin hydrochloride (DOX⋅HCl) and the NO donor L-arginine (L-Arg), which can produce NO triggered by NIR light irradiation and exert multimodal therapy to sensitize drug-resistant cancers. Upon 808 nm irradiation, the NO released from PIDA led to a decrease in mitochondrial membrane potential, an increase in ROS and significant ATP depletion in K562/ADR cells, thus inhibiting cell growth and resolving the problem of drug resistance. Consequently, the in vivo experiment on K562/ADR-bearing nude mice indicated that PIDA nanovesicles achieved significant anticancer efficacy with a tumor inhibition rate of 80.8%. Above all, PIDA nanovesicles offer guidance for designing nanoplatforms for drug-resistant cancer treatment.
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AAPS PHARMSCITECH
·
2022
·Vol. 24
·期 1
·1-14
·
IF 4.026
Wang Xiaoling,Du Jiangyue,Zhou Feng,Ye Qing,Chen Ying,Sun Dujuan,Chen Haimin,Lv Yuanyuan,Sun Xiaoyi
Adequate delivery of therapeutic agents to their intended molecular targets is crucial in tumor therapy. Versatile drug carriers need to overcome the challenges coming from the systemic circulation, membrane barriers, and endo-lysosomal degradation. Herein, hyaluronic acid-conjugated polydopamine (HA-PDA)-shelled mesoporous silica nanoparticles encapsulated with doxorubicin (MSNs-DOX) were successfully fabricated for targeted tumor therapy. Compared with reported studies focusing on the pH-sensitive release in tumors, we especially revealed the significant role of lysosomal release in DOX nuclear accumulation. After active targeting and CD44-mediated endocytosis in tumor cells, the PDA layer of the nanoparticles would be peeled off to trigger drug release owing to MSNs gatekeeper in acidic lysosomes. Subsequently, DOX molecules passively diffused into nuclei. The intracellular DOX transportation was evidenced by DOX accumulation in nuclei, lysosomal location of nanoparticles, and lysosome acidification inhibition test. After discharging of the cargoes from nanoparticles, PDA shells from residual nanoparticles were able to produce localized hyperthermia under NIR irradiation entrapped in lysosomes, inducing synergistic chemo-photothermal effect. Under NIR treatment, HA-PDA@MSNs-DOX presented a prominent tumor inhibition rate without obvious side effects. This study indicated the potent nuclear delivery and synergetic chemo-photothermal therapy achieved by HA-PDA-shelled MSNs. Graphical Abstract
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Biomaterials Science
·
2022
·Vol. 10
·期 6
·1544-1553
·
IF 7.59
Peng Ji,Xianglong Wang,Jiabing Yin,Yansheng Yao,Wangqi Du
Despite the remarkable tumor inhibition effect of doxorubicin (DOX), its cardiotoxicity severely limits the clinical dosage and further impairs the chemotherapy efficacy. To improve the biosafety and effectiveness of conventional chemotherapy, we propose a strategy to co-deliver DOX and ART to supplement apoptosis with ferroptosis. To this end, ART and DOX were incorporated into ferrous LiMOFs to develop a nanoreactor, utilizing ferrous ions as a catalyst to decompose ART into radicals and thus to induce efficient ferroptosis. Further, DOX can induce another form of death, apoptosis, which in combination enhances tumor inhibition. The synthesized nanoreactor (DOX/ART@LiMOFs) possesses a size of ∼100 nm and maintains a regular crystal structure. The pH-responsive disassociation endows it with acid-sensitive drug-releasing kinetics, and the liposomal bilayers bring about a sustained release feature (up to 12 h). The cellular ROS assay indicated that the supply of ferrous ions dramatically increased the ROS mediated by ART and led to markedly enhanced tumor inhibition in animal tests accompanied by the apoptosis of DOX. Consequently, this work presents an innovative strategy to synchronously induce potent ferroptosis and apoptosis, promoting conventional cancer chemotherapy.
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Marine Drugs
·
2022
·Vol. 20
·期 5
·278
·
IF 6.085
Yingqi Mi,Jingjing Zhang,Wenqiang Tan,Qin Miao,Qing Li,Zhanyong Guo
In this study, chitosan nanoparticles (HF-CD NPs) were synthesized by an ionic gelation method using negatively charged carboxymethyl-β-cyclodextrin and positively charged 2-hydroxypropyltrimethyl ammonium chloride chitosan bearing folic acid. The surface morphology of HF-CD NPs was spherical or oval, and they possessed relatively small particle size (192 ± 8 nm) and positive zeta potential (+20 ± 2 mV). Meanwhile, doxorubicin (Dox) was selected as model drug to investigate the prepared nanoparticles’ potential to serve as a drug delivery carrier. The drug loading efficiency of drug-loaded nanoparticles (HF-Dox-CD NPs) was 31.25%. In vitro release profiles showed that Dox release of nanoparticles represented a pH-sensitive sustained and controlled release characteristic. At the same time, the antioxidant activity of nanoparticles was measured, and chitosan nanoparticles possessed good antioxidant activity and could inhibit the lipid peroxidation inside the cell and avoid material infection. Notably, CCK-8 assay testified that the nanoparticles were safe drug carriers and significantly enhanced the antitumor activity of Dox. The nanoparticles possessed good antioxidant activity, pH-sensitive sustained controlled release, enhanced antitumor activity, and could be expected to serve as a drug carrier in future with broad application prospects.Keywords:chitosan nanoparticles;cyclodextrin;antioxidant activity;antitumor activity;drug release
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EUROPEAN JOURNAL OF PHARMACEUTICS AND BIOPHARMACEUTICS
·
2022
·
IF 5.589
Qiangwei Liang,Yang Lan,Yifan Li,Yongjin Cao,Juan Li,Yanhua Liu
Chemotherapeutic agents can trigger the immune response via inducing immunogenic cell death (ICD), but the weak ICD effect induced by chemotherapy alone limits its lasting antitumor immunotherapy effect. A Cro polymerized prodrug carriers (POEG- b -PCro) with immunostimulatory by ICD induction was developed and co-delivered DOX to generate synergistic ICD induction for chemo-immunotherapy on breast cancer. DOX/POEG- b -PCro micelles displayed prolonged circulation in blood, efficient accumulation in tumors, internalization and then co-released DOX&Cro in tumor cells. Moreover, the DOX/POEG- b -PCro micelles synergistically triggered ICD induction by releasing the nuclear high mobility group box 1 (HMGB1) and down-regulation of c-Met level for generating chemo-immune anti-tumor actions. Importantly, the DOX/POEG- b -PCro micelles synergistically enhanced the tumor cytotoxic T lymphocytes infiltration , concomitant decreasing the immunosuppressive regulatory T (Treg) cells, accompanied with the increased cytokines secretion of IFN-γ and TNF-α, consequently displaying an improved anti-tumor activity in 4 T1 breast cancer mice. Overall, POEG- b -PCro prodrug micelles co-delivered DOX could be served as a promising nano drug delivery system for synergistic ICD induction on breast cancer chemo-immunotherapy.
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