ACS Applied Materials & Interfaces
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2026
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IF 7.8
Xiaomeng Zou,Shiyu Li,Zhiying Jin,Sisi Huang,Ruilan Niu,Naiqin Fu,Wenqing Li,Jianbo Gao,Zhili Wang
Immunogenic cell death (ICD) represents a promising strategy to stimulate antitumor immunity. Doxorubicin (DOX) is one drug that can trigger ICD. However, DOX has limitations for treating triple-negative breast cancer (TNBC). Its ability to stimulate a strong immune response is weak. The drug also promotes an immunosuppressive tumor microenvironment. This suppression hinders the antitumor immune response. Since reactive oxygen species (ROS) generation is a pivotal ICD trigger, we therefore hypothesized that nintedanib, a triple tyrosine kinase inhibitor known to promote immune cell infiltration and activation within tumors, potentiates DOX-induced ICD by augmenting intratumoral ROS generation. To address this, we engineered a targeted nanoenhancer for TNBC by coencapsulating liquid nintedanib and perfluoropentane (PFP), within a peptide-functionalized (tLyp-1) liposomal shell, creating tLyp-1-Nintedanib-PFP Nanoparticles (tNP-NPs) for use in sonodynamic therapy. This tNP-NP platform is intended for combination therapy with DOX in a chemoimmunotherapeutic strategy. With the assistance of low-intensity focused ultrasound (LIFU), tNP-NPs exhibited potent targeting and penetrating capabilities toward 4T1 TNBC cells, enhanced drug cytotoxicity, ROS production, and ICD markers in vitro. Subsequently, for the in vivo study, to mitigate systemic toxicity, an injectable thermosensitive hydrogel coencapsulating tNP-NPs and DOX was applied for local peritumoral injection. In orthotopic 4T1 TNBC models, this combination elicited potent ICD, promoting dendritic cell (DC) cells maturation and cytotoxic T lymphocyte activation within tumors and draining lymph nodes. This approach achieved exceptional antitumor efficacy and systemic immunity while reversing the immunosuppressive tumor microenvironment, without observable organ toxicity, presenting a robust chemoimmunotherapeutic strategy for TNBC.
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JOURNAL OF PHARMACY AND PHARMACOLOGY
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2023
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IF 3.3
Zeng Xiangfeng,Liu Shengyao,Yang Hua,Jia Menglei,Liu Wei,Zhu Wenting
ObjectivesThe most common cause of osteosarcoma (OS) death is lung metastasis. Currently, doxorubicin is the primary chemotherapy drug used to treat OS, however, it is not effective in inhibiting metastasis, and it has obvious cardiotoxicity. The anticancer activity of ginsenoside Rg3 has been demonstrated in a variety of malignant tumours. The aim of this study was to determine the potential role of ginsenoside Rg3 and doxorubicin in OS and the possible mechanism.MethodsThe potential synergistic effects of ginsenoside Rg3 and doxorubicin on human osteosarcoma cells 143B and U2OS, human umbilical vein endothelial cells, and mice receiving 143B xenografts and lung metastases were investigated.Key findingsOur study demonstrated that the combination of ginsenoside Rg3 and doxorubicin significantly inhibited cell proliferation, metastasis and angiogenesis in vitro. Mechanically, the anti-tumour activity of ginsenoside Rg3 and doxorubicin by modulating mTOR/HIF-1α/VEGF and EMT signalling pathways. Furthermore, ginsenoside Rg3 combined with doxorubicin inhibits tumour growth and lung metastasis in 143B-derived murine osteosarcoma models. More importantly, ginsenoside Rg3 can effectively ameliorate doxorubicin-induced weight loss and cardiotoxicity in mice.ConclusionsConsequently, we concluded that the combination of ginsenoside Rg3 and doxorubicin displayed an evidently synergistic effect, which has the potential to be used as an effective and safe therapeutic approach for OS treatment.
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JOURNAL OF NATURAL PRODUCTS
·
2022
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IF 4.803
Qi Zeng,Xu Nie,Li Li,Hui-Fang Liu,Yang-Yao Peng,Wang-Ting Zhou,Xiao-Jia Hu,Xin-Yi Xu,Xue-Li Chen
Salidroside (Sal), the major active constituent of Rhodiola rosea L., is considered as a potential pro-drug with various activities; however, its role in tumor therapy is not clear. Here, we demonstrated in vitro and in vivo that Sal enhanced the inhibitory activity of doxorubicin (DOX) in drug-resistant cancer cell lines. Our results showed that combination drug treatment (Sal and DOX) significantly decreased cell proliferation, migration, and motility. Besides biological validation, a luciferase-labeled animal tumor xenograft model and bioluminescence imaging (BLI) were applied for assessing the tumor progression. Sal combined with DOX inhibited the growth of HeLa-ADR-luc cells in vivo and downregulated the DOX-induced high expression of MDR1. Also, Sal downregulated the Bcl-2, MMP-2, MMP-9, PI3K, and AKT and upregulated BAX proteins. Sal demonstrated high safety and cardiac protection activity. We discovered that Sal enhances DOX sensitivity through the regulation of PI3K/Akt/HIF-1α and DOX-induced resistance pathways. Our results suggest that Sal could be a novel chemosensitization agent for the treatment of multi-drug-resistance tumors.
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International Journal of Nanomedicine
·
2023
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IF 8
Guiqiang Qi,Guangyue Shi,Shengchao Wang,Haifeng Hu,Zhichen Zhang,Qiangqiang Yin,Zhongtao Li,Liguo Hao
Introduction This study developed a pancreatic cancer targeted drug delivery system that responds to changes in acidity. The system was based on iron oxide core-shell magnetic mesoporous silica nanoparticles (M-MSNs) to treat pancreatic cancer through combined chemotherapy and starvation therapy.Methods Glucose oxidase (Gox) was coupled to the cancer cell surface to reduce glucose availability for cancer cells, exacerbating the heterogeneity of the tumor microenvironment. Reduced pH accelerated the depolymerization of pH-sensitive polydopamine (PDA), thereby controlling the spatial distribution of Gox and release of doxorubicin (DOX) within tumor cells.Results Characterization results showed the successful synthesis of DG@M-MSN-PDA-PEG-FA (DG@NPs) with a diameter of 66.02 ± 3.6 nm. In vitro data indicated DG@NPs were highly effective and stable with good cellular uptake shown by confocal laser scanning microscopy (CLSM). DG@NPs exhibited high cytotoxicity and induced apoptosis. Additionally, in vivo experiments confirmed DG@NPs effectively inhibited tumor growth in nude mice with good biosafety. The combination of starvation therapy and chemotherapy facilitated drug release, suggesting DG@NPs as a novel drug delivery system for pancreatic cancer treatment.Conclusion This study successfully constructed a doxorubicin release system responsive to acidity changes for targeted delivery in pancreatic cancer, providing a new strategy for combination therapy.
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MOLECULAR PHARMACEUTICS
·
2021
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IF 4.939
Yupeng Liu,Fangying Yu,Suhuan Dai,Tingting Meng,Yun Zhu,Guoxi Qiu,Lijuan Wen,Xueqing Zhou,Hong Yuan,Fuqiang Hu
Stemness and metastasis are the two main challenges in cancer therapy and are related to disease relapse post-treatment. They both have a strong correlation with chemoresistance and poor prognosis, ultimately leading to treatment failure. It has been reported that chemotherapy can induce stemness and metastasis in many cancer types, especially treatment with the chemotherapeutic agent doxorubicin (DOX) in breast cancer. A combination treatment is an efficient and elegant approach in cancer therapy through simultaneous delivery of two or more drugs with a delivery system for its synergistic effect, which is not an additive of two individual drugs. Herein, we report a combinatorial system with DOX and all-trans retinoic acid (ATRA) to address both of the above issues. As a common critical regulatory factor for oncogenic signal transduction pathways, Pin1 is a specific isomerase highly expressed within various tumor cells. ATRA, a newly identified Pin1 inhibitor, can abolish several oncogenic pathways by effectively inhibiting and degrading overexpressed Pin1. We successfully developed a folic acid (FA)-modified chitosan (CSO)-derived polymer (FA-CSOSA) and obtained FA-CSOSA/DOX and FA-CSOSA/ATRA drug-loaded micelles. FA modification can improve the uptake of the nanoparticles in tumor cells and tumor sites via folate receptor-mediated cell internalization. Compared to treatment with DOX alone, the combined treatment induced 4T1 cell apoptosis in a synergistic manner. Reduced stemness-related protein expression and inhibited metastasis were observed during treatment with FA-CSOSA/DOX and FA-CSOSA/ATRA and were found to be associated with Pin1. Further in vivo experiments showed that treatment with FA-CSOSA/DOX and FA-CSOSA/ATRA resulted in 85.5% tumor inhibition, which was 2.5-fold greater than that of cells treated with DOX·HCl alone. This work presents a new paradigm for addressing chemotherapy-induced side effects via degradation of Pin1 induced by tumor-targeted delivery of DOX and ATRA.
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JOURNAL OF DRUG DELIVERY SCIENCE AND TECHNOLOGY
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2019
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IF 2.606
Jiahui He,Wei Wang,Huicong Zhou,Pan She,Pantian Zhang,Yi Cao,Xuefei Zhang
A novel cytocompatible and pH-sensitive amphiphilic polymeric prodrug named as mPEG- b -norbornene functional PLA-graft-Doxorubicin (mPEG- b -PLA- g -DOX) was synthesized by ROP (ring-opening polymerization), then condensation and followed by click reaction. The polymeric carriers were grafted with triazo group. Doxorubicin (DOX) was modified by the cyclooctyne via condensation reaction and conjugated to the polymeric carriers through the SPAAC (Strain-Promoted Alkyne-Azide Cycloaddition) click reaction. There was a Schiff base between the DOX and cyclooctyne which could result in the pH stimuli-responsiveness for controlled release of anti-cancer drug. The resultant mPEG- b -PLA- g -DOX prodrug was characterized by the 1 H NMR, GPC and HPLC. The content of DOX in prodrug reached 17.4% as measured by the UV spectrum. The amphiphilic polymeric prodrug could self-assemble into micelle which was characterized by the dynamic light scattering (DLS) and scanning electron microscope (SEM). The profile of in vitro drug release exhibited enhanced drug release at acidic pH (pH = 5.3) compared with neutral pH (pH = 7.4). The results of MTT assay showed that the amount of DOX required for MCF-7 cells was reduced after DOX molecules were prepared into polymer prodrug, which was conducive to reducing side effects under the premise of ensuring inhibitory effect.
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Acta Biomaterialia
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2014
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IF 5.684
Junmin Qian,Minghui Xu,Aili Suo,Weijun Xu,Ting Liu,Xuefeng Liu,Yu Yao,Hongjie Wang
To minimize the side effects and enhance the efficiency of chemotherapy, a novel folate-decorated hydrophilic cationic star-block terpolymer , [poly( l -glutamic acid γ-hydrazide)- b -poly(N,N-dimethylaminopropyl methacrylamide)] 3 - g -poly(ethylene glycol) ((PGAH- b -PDMAPMA) 3 - g -PEG), with disulfide linkages between the PEG and PDMAPMA blocks, was developed for targeted co-delivery of doxorubicin and Bcl-2 small interfering RNA (siRNA) into breast cancer cells. The terpolymer was synthesized by a combination of ring-opening polymerization, reversible addition–fragmentation chain transfer polymerization, PEGylation and hydrazinolysis. The chemical structures of the polymers were confirmed by 1 H-NMR analysis. The terpolymer could conjugate doxorubicin via an acid-labile hydrazone linkage and simultaneously efficiently complex siRNA through electrostatic interaction at N/P ratios of ⩾4:1 to form “two-in-one” nanomicelleplexes, which displayed a spherical shape and had an average size of 101.3 nm. The doxorubicin loading efficiency and content were 61.0 and 13.23%, respectively. The cytotoxicity, drug release profile, targeting ability, cellular uptake and intracellular distribution of the nanomicelleplexes were evaluated in vitro. We found that the release behaviors of doxorubicin and siRNA had a pH/reduction dual dependency. They were released faster under reductive acidic conditions (pH 5.0, glutathione : 10 mM) than under physiological conditions (pH 7.4). The folate-decorated nanomicelleplexes could deliver doxorubicin and Bcl-2 siRNA more efficiently into the same MCF-7 cell and exhibited a higher cytotoxicity than non-targeted nanomicelleplexes. These results indicate that the terpolymer could act as an efficient vehicle for targeted intracellular co-delivery of doxorubicin and therapeutic siRNA in cancer therapy.
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CHEMICAL ENGINEERING JOURNAL
·
2025
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IF 13.2
Xin Ding,Ya Zhang,Qian Zhou,Guoyin Zheng,Yan Qiao,Yang Zhang,Junli Liang,Hongrui Ma,Xiaofei Chen,Guangguo Tan
Radix Aconiti Lateralis Preparata (Fuzi in Chinese) is an efficient Chinese herbal medicine (CHM) against doxorubicin (DOX)-induced cardiomyopathy (DIC), but the cardioprotective compounds and targets of Fuzi remain unclear. In this work, a novel two-dimensional (2D) polyamidoamine (PAMAM)-modified cardiac mitochondrial membrane chromatography (CMMC) system, with the characteristic of high-density mitochondrial membrane coating and longer column lifespan, was developed for the identification of bioactive components from Fuzi to counteract DIC. Three compounds with strong retention were screened out to have cardioprotective effects against DOX-induced cardiotoxicity in different cardiomyocytes, and one promising compound songorine with the highest affinity was selected for further in vitro and in vivo pharmacodynamic validation and target identification. Hadha, involved in fatty acid oxidation (FAO) and apoptosis, was identified as the functional target of songorine by cardiac mitochondria proteomics, drug affinity responsive target stability (DARTS), cellular thermal shift assay (CETSA), surface plasmon resonance (SPR) and molecular docking assays. siRNA experiments have also demonstrated that songorine can affect the function of Hadha. It was concluded that songorine could directly bind to the Hadha protein to alleviate the functional impairment of the mitochondrial FAO and oxidative phosphorylation (OXPHOS) and regulate the Bcl-2 family proteins in mice to treat DIC.
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JOURNAL OF PHYSIOLOGY AND PHARMACOLOGY
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2026
·Vol. 77
·期 1
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IF 2.5
Y Yang,J H Liu,D K Gui
Adriamycin (ADR)-induced nephrotic syndrome (NS) is a common renal disease model characterized by proteinuria, glomerular damage, and inflammatory responses. Baicalin, a bioactive flavonoid derived from Scutellaria baicalensis, demonstrates anti-inflammatory and anti-fibrotic properties. This study aims to investigate whether baicalin alleviates ADR-induced NS by regulating the transforming growth factor-beta (TGF-β)/Smad signaling pathway and the NOD-like receptor family, pyrin domain-containing protein 3 (NLRP3) inflammasome. A murine NS model in vivo was established by administering 10 mg/kg ADR to male C57BL/6J mice. Experimental groups were treated orally with 20 mg/kg or 40 mg/kg baicalin for 6 weeks. The following parameters were measured in each group: 24-h urinary protein, serum creatinine (Scr), blood urea nitrogen (BUN), total protein, albumin, total cholesterol, and triglycerides. In vitro, a cellular NS model was established by treating mouse podocyte cells (MPC5) with 0.75 µmol/L ADR, and the protective effects of baicalin were evaluated. Protein expression levels of the TGF-β/Smad signaling pathway and NLRP3 inflammasome were analyzed by Western blot. The secretion levels of interleukin-4 (IL-4), interleukin-8 (IL-8), interleukin-1β (IL-1β), and interleukin-18 (IL-18) were assessed by enzyme-linked immunosorbent assay, and the activity of superoxide dismutase (SOD) and the content of malondialdehyde (MDA) were measured in cells. ADR reduced MPC5 cell viability to below 50% and increased MDA levels (≥6 nmol/mg prot). The expression of NLRP3 (upregulated by 4-fold), α-smooth muscle actin (upregulated by 3-fold), N-cadherin (upregulated by 3-fold), and IL-8/IL-1β/IL-18 (all upregulated by more than 1-fold) was significantly elevated. Treatment with 12.5 µmol/L baicalin markedly reversed these changes, restoring cell viability to over 85% and bringing pathway protein and cytokine levels close to those of the control group. In vivo , ADR-induced NS mice exhibited doubled 24-h urinary protein, Scr, and BUN levels, along with renal interstitial inflammatory infiltration and a 60% downregulation of podocin expression. Treatment with 40 mg/kg of baicalin restored these indicators to levels comparable to those in untreated mice, with effects similar to irbesartan ( P <0.05). We concluded that baicalin demonstrated significant renoprotective effects in both in vivo and in vitro models of ADR-induced NS by regulating the TGF-β/Smad pathway and NLRP3 inflammasome, mitigating renal injury and inflammation. These results offer experimental support for the potential use of baicalin as a therapeutic agent for NS.
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MOLECULAR PHARMACEUTICS
·
2023
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IF 4.9
Jie Li,Yubin Yang,Peng Liu
Carbon quantum dots (CDs) have attracted more and more attention in the field of biological imaging, while their applications are restricted due to their nonspecific fluorescence and small particle size. Herein, two pH-responsive carbon quantum dot–doxorubicin (DOX) conjugates were designed with maleic acid (MA, cis-butenedioic acid) and fumaric acid (FA, trans-butenedioic acid) as linker, respectively, which could self-assemble into unique hybrid micelles as tumor-specific carrier-free nanotheranostics. Owing to the acid-labile covalent modification with conjugated groups and the interaction with the surrounding DOX molecules, the fluorescence of CDs was completely quenched, while it could be recovered in the tumor intracellular microenvironment by acid-triggered cleavage of the fluorophore–drug conjugates, showing excellent turn-on fluorescence for effective cellular imaging. Especially, the trans conjugate with FA as linker possessed higher drug content, better drug release behavior and stronger inhibition of tumor cells than the cis one with MA as linker, demonstrating its promising potential as carrier-free nanotheranostics for future tumor treatment.
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COLLOIDS AND SURFACES B-BIOINTERFACES
·
2022
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IF 5.999
Yongli Shi,Xueyan Hou,ShaSha Yu,Xiaofei Pan,Mingbo Yang,Jie Hu,Xiao Wang
Doxorubicin (DOX) is widely used in the treatment of many tumors, but the dose-dependent toxicity limits its further application. In this study, a unique strategy was developed to improve the anti-tumor effects of free DOX and lower its in vivo toxicity by constructing novel glutathione (GSH)-sensitive poloxamer188-b-polycaprolactone-S-S-doxorubicin nanoparticles (PPSSD NPs). After uptake by tumor cells, the disulfide bonds in the PPSSD NPs would be cloven by reacting with GSH. Then, a lethal dose of DOX was released in tumor cells. The uptake of PPSSD NPs by 4T1 cells was proved using fluorescence microscopy by co-localization of PPSSD NPs and 4′, 6-diamidino-2-phenylindole (DAPI). Cell tests suggested that the PPSSD NPs showed high anti-tumor cells (4T1) activity but low cytotoxicity against normal cells (293 t). The in vivo toxicity and anti-tumor effects of the PPSSD NPs were studied with Kunming and Balb/c mice as models, respectively. The H&E slices, blood routine and biochemistry indexes of the PPSSD NPs treated mice indicated that the PPSSD NPs did not induce obvious in vivo toxicity. The PPSSD NPs showed higher in vitro anti-4T1 cells activity than free DOX. Furthermore, the in vivo anti-tumor study, TUNEL and H&E slices suggested that the PPSSD NPs exhibited excellent anti-tumor effects. In a word, the novel PPSSD NPs did not only improve the anti-tumor effect of DOX, but also decrease its cytotoxicity to normal tissues.
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Molecular Medicine Reports
·
2023
·Vol. 28
·期 2
·1-11
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IF 3.4
Qiao Lu,Xueyang Gong,Guangtao Jia,Jingliang Wu,Siwei Liu,Ke Song,Guixiang Tian
All‑trans retinoic acid (ATRA) has been implicated in the differentiation of hepatic stellate cells (HSCs). In the present study, the liver‑targeting hyaluronic acid micelles (ADHG) were prepared for co‑delivery of ATRA and doxorubicin (DOX) to block the HSC‑hepatoma interrelation. To simulate the tumor microenvironment, an in vitro dual‑cell model and an in vivo co‑implantation mouse model were established for anticancer studies. The experimental methods involved the MTT assay, wound‑healing assay, cellular uptake, flow cytometry and and in vivo antitumor study. The results revealed that the HSCs in the research models notably promoted tumor proliferation and migration. Furthermore, ADHG were readily internalized by cancer cells and HSCs simultaneously, and widely distributed in cancer regions. The in vivo antitumor studies demonstrated that ADHG could notably decrease HSC activation and extracellular matrix deposition, as well as constrain tumor growth and metastasis. Therefore, ATRA could facilitate DOX‑induced anti‑proliferation and anti‑metastasis effects, and ADHG are a promising nano‑sized formulation for the combination therapy of hepatocellular carcinoma.
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