BIOCHEMICAL PHARMACOLOGY
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2023
·
IF 5.8
Xinyu Guo,Mengqing Liu,Bing Han,Yeqing Zheng,Kaina Zhang,Gaowa Bao,Chenying Gao,Hongwen Shi,Qiang Sun,Zhenghang Zhao
The clinic application of doxorubicin (DOX) is severely limited by its severe cardiotoxicity. Tripartite motif-containing protein 16 (TRIM16) has E3 ubiquitin ligase activity and is upregulated in cardiomyocytes under pathological stress, yet its role in DOX-induced cardiotoxicity remains elusive. This study aims to investigate the role and mechanism of TRIM16 in DOX cardiotoxicity. Following TRIM16 overexpression in hearts with AAV9-TRIM16, mice were intravenously administered DOX at a dose of 4 mg/kg/week for 4 weeks to assess the impact of TRIM16 on doxorubicin-induced cardiotoxicity. Transfection of OE-TRIM16 plasmids and siRNA-TRIM16 was performed in neonatal rat cardiomyocytes (NRCMs). Our results revealed that DOX challenge elicited a significant upregulation of TRIM16 proteins in cardiomyocytes. TRIM16 overexpression efficiently ameliorated cardiac function while suppressing inflammation, ROS generation, apoptosis and fibrosis provoked by DOX in the myocardium. TRIM16 knockdown exacerbated these alterations caused by DOX in NRCMs. Mechanistically, OE-TRIM16 augmented the ubiquitination and degradation of p-TAK1, thereby arresting JNK and p38MAPK activation evoked by DOX in cardiomyocytes. Furthermore, DOX enhanced the interaction between p-TAK1 and YAP1 proteins, resulting in a reduction in YAP and Nrf2 proteins in cardiomyocytes. OE-TRIM16 elevated YAP levels and facilitated its nuclear translocation, thereby promoting Nrf2 expression and mitigating oxidative stress and inflammation. This effect was nullified by siTRIM16 or TAK1 inhibitor Takinib. Collectively, the current study elaborates that upregulating TRIM16 mitigates DOX-induced cardiotoxicity through anti-inflammation and anti-oxidative stress by modulating TAK1-mediated p38 and JNK as well as YAP/Nrf2 pathways, and targeting TRIM16 may provide a novel strategy to treat DOX-induced cardiotoxicity.
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Journal of Functional Biomaterials
·
2023
·Vol. 14
·期 11
·546
·
IF 4.8
Qingfeng Guo,Jie Li,Jing Mao,Weijun Chen,Meiyang Yang,Yang Yang,Yuming Hua,Lipeng Qiu
Multidrug resistance (MDR) is a key factor in chemotherapy failure and tumor recurrence. The inhibition of drug efflux and autophagy play important roles in MDR therapy. Herein, a multifunctional delivery system (HA-MIL-125@DVMA) was prepared for synergistically reverse tumor MDR. Tumor-targeted hollow MIL-125-Ti nanoparticles were used to load the doxorubicin–vitamin E succinate (DV) prodrug and 3-methyladenine (3-MA) to enhance reverse MDR effects. The pH-sensitive DV can kill tumor cells and inhibit P-gp-mediated drug efflux, and 3-MA can inhibit autophagy. HA-MIL-125@DVMA had uniformly distributed particle size and high drug-load content. The nanoparticles could effectively release the drugs into tumor microenvironment due to the rapid hydrazone bond-breaking under low pH conditions, resulting in a high cumulative release rate. In in vitro cellular experiments, the accumulation of HA-MIL-125@DVMA and HA-MIL-125@DV in MCF-7/ADR cells was significantly higher than that in the control groups. Moreover, the nanoparticles significantly inhibited drug efflux in the cells, ensuring the accumulation of the drugs in cell cytoplasm and causing drug-resistant cells’ death. Importantly, HA-MIL-125@DVMA effectively inhibited tumor growth without changes in body weight in tumor-bearing mice. In summary, the combination of the acid-sensitive prodrug DV and autophagy inhibitor 3-MA in a HA-MIL-125 nanocarrier can enhance the antitumor effect and reverse tumor MDR.Keywords:hyaluronic acid;metal-organic framework;multidrug resistance;doxorubicin;3-methyladenine
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Frontiers in Pharmacology
·
2023
·
IF 5.6
Zhenxiong Zhao,Shenglu Jiang,Qing Fan,Kuo Xu,Yubin Xu,Feiqiang Wu,Xihong Zhang,Ting Wang,Zhelin Xia
Apocynum venetum leaf is commonly utilized for its beneficial effects in reducing blood pressure, inducing sedation, promoting diuresis, anti-aging, and cardioprotection, which also exhibit positive effects on the gut microbiota. The gut microbiota plays a role as an endocrine organ by producing bioactive metabolites that can directly or indirectly impact host physiology, specifically cardiovascular diseases. In this study, main chemical components of A. venetum leaf extract (AVLE) were identified by LC-MS, and an orally administered AVLE was employed to treat mice with doxorubicin (Dox)-induced cardiotoxicity. The results showed that AVLE contained hyperoside and oganic acids. The pharmacological findings revealed that AVLE regulated the gut microbiota, resulting in a significant increase in the levels of two organic acids, indole-3-propionic acid (IPA) and acetic acid (AA). Both IPA and AA exhibited the ability to reduce BNP, CK, and LDH levels in mice with Dox-induced cardiotoxicity. Moreover, IPA demonstrated an improvement in Dox-induced cardiac injury by inhibiting apoptosis, while AA promoted increased secretion of ghrelin through the parasympathetic nervous system, subsequently reducing cardiac fibrosis by decreasing collagen I, collagen III, and activin A. Hence, our study demonstrates that AVLE exerts a beneficial cardioprotective effect by modulating the gut microbiota, providing a potential novel target for the treatment and prevention of Dox-induced cardiotoxicity.
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Pharmaceutics
·
2026
·Vol. 18
·期 9
·1155
·
IF 6.9
Li Wang,Ning Yang,Yina Sa,Zhenghua Li,Yanlong Qiao,Yanxin Yang,Lixue Chen,Xiangyu Liu,Lei Li
Background: combination chemotherapy employing agents with complementary mechanisms of action can enhance therapeutic efficacy and overcome resistance, but mismatched pharmacokinetics and systemic toxicity limit benefit.Methods: We designed reductant-responsive squalene prodrugs of doxorubicin (DOX) and exatecan (EXA) that co-assemble with DSPE-PEG2kinto approximately 76 nm dual-prodrug nanoparticles (doxorubicin prodrug–exatecan prodrug nanoparticles, DP-EP NPs) at a predefined synergistic ratio 1:2.Results: The minimalist, drug-as-carrier formulation achieved high effective loadings with minimal leakage under normoxia, yet synchronously liberated both drugs in reductive, hypoxia-mimicking media (24 h release: DOX ~65% and EXA ~58% at 1 mM Na2S2O4vs. ~8–11% at 0 mM Na2S2O4). In MCF-7 and 4T1 cells, the nanoparticles enhanced intracellular accumulation, intensified the disruption of DNA damage repair, as evidenced by increased colocalization of 53BP1 and enhanced γ-H2AX foci, and induced markers of immunogenic cell death, including increased CRT-associated cellular fluorescence and reduced intracellular HMGB1 staining. Furthermore, they partially reversed drug resistance in MCF-7/ADR cells. In rats, the formulation prolonged circulation and increased exposure (DOX t½~9×, AUC ~1.8×; EXA t½~5×, AUC ~14.9×) relative to the free-drug mixture. In 4T1 tumor-bearing mice, the nanoparticles produced the greatest tumor-growth inhibition with improved tolerability, supported by stable body weight and benign histopathology.Conclusions: These findings establish a scalable, excipient-lean platform that aligns pharmacokinetics with microenvironment-triggered pharmacodynamics to deliver synchronized Topo II/I inhibition for synergistic chemotherapy.
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Aggregate
·
2023
·Vol. 5
·期 1
·e434
·
IF 18.8
Lianxue Zhang,Jianxiang Huang,Damiano Buratto,Panli Han,Zaixing Yang,Ruhong Zhou
The efficacy of nanoparticle (NP)-based drug delivery technology is hampered by aberrant tumor stromal microenvironments (TSMs) that hinder NP transportation. Therefore, the promotion of NP permeation into deep tumor sites via the regulation of tumor microenvironments is of critical importance. Herein, we propose a potential solution using a dihydralazine (HDZ)-loaded nanoparticle drug delivery system containing a pH-responsive, cyclic RGD peptide-modified prodrug based on doxorubicin (cRGD-Dex-DOX). With a combined experimental and theoretical approach, we find that the designed NP system can recognize the acid tumor environments and precisely release the encapsulated HDZ into tumor tissues. HDZ can notably downregulate the expression levels of hypoxia-inducible factor 1α (HIF1α), α-smooth muscle actin, and fibronectin through the dilation of tumor blood vessels. These changes in the TSMs enhance the enrichment and penetration of NPs and also unexpectedly promote the infiltration of activated T cells into tumors, suggesting that such a system may offer an effective “multifunctional therapy” through both improving the chemotherapeutic effect and enhancing the immune response to tumors. In vivo experiments on 4T1 breast cancer bearing mice indeed validate that this therapy has the most outstanding antitumor effects over all the other tested control regimens, with the lowest side effects as well.
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CARBOHYDRATE POLYMERS
·
2023
·
IF 11.2
Xiaoping Zhao,Qin Wang,Ning Wang,Ge Zhu,Jingzhi Ma,Ning Lin
Cellulose nanocrystals (CNCs) have shown immense promise in medical applications, especially in cancer treatment, owing to their excellent biocompatibility and potential for functional modifications. Considering the crucial role of the protein reduced glyceraldehyde-phosphate dehydrogenase (GAPDH) in cancer progression, we embarked to immobilize CNCs with GAPDH and fluorescent molecules FITC , creating FCNC-G through regioselective modifications. Furthermore, an accelerated proliferation of cancer cells was observed in the presence of FCNC-G. To evaluate the therapeutic potential of FCNC-G, we loaded it with doxorubicin (DOX) to create FCNC-G-D and tested its effect on Hepg2. We observed a significant inhibition of Hepg2 cells exposed to low concentrations of FCNC-G-D. Additionally, mitochondrial dysfunction was detected in Hepg2 and Cal27 cells, treated with FCNC-G-D, but not in A375 cells, further highlighting its selective impact on cancer cells. Given the limitations of DOX in clinical applications, our findings establish a strong foundation for further research on the potential of CNCs grafted with GAPDH as a novel cancer-targeted biocarrier with high affinity. The combination of CNCs unique properties with targeted delivery strategies holds tremendous promise for the development of more effective and safer cancer therapies.
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ACS Omega
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2021
·
IF 3.512
Yinghua Tao,Dan Zheng,Jingyang Zhao,Kefeng Liu,Jing Liu,Jiandu Lei,Luying Wang
Pharmaceutical science based on biological nanotechnology is developing rapidly in parallel with the development of nanomaterials and nanotechnology in general. Pectin is a natural polysaccharide obtainable from a wide range of sources. Here, we show that doxorubicin (DOX)-conjugated hydrophilic pectin (PET) comprising an amphiphilic polymer loaded with hydrophobic dihydroartemisinin (DHA) self-assemble into nanoparticles. Importantly, conjugated DOX and DHA could be released quickly in a weakly acidic environment by cleavage of the acid-sensitive acyl hydrazone bond. Confocal microscopy and flow cytometry confirmed that these PET-DOX/DHA nanoparticles efficiently delivered DOX into the nuclei of MCF-7 cells. Significant tumor growth reduction was monitored in a female C57BL/6 mouse model, showing that the PET-DOX/DHA nanoparticle-mediated drug delivery system inhibited tumor growth and may improve therapy. Thus, we have demonstrated that pectin may be useful in the design of materials for biomedical applications.
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ACS Applied Materials & Interfaces
·
2021
·
IF 9.229
Yao Peng,Jiaqi Lu,Ru Li,Yi Zhao,Li Hai,Li Guo,Yong Wu
Glioma is one of the most lethal and complex tumors, and thus, an effective drug delivery system must selectively target the tumor sites and release its cargos in a controlled manner. For the first time, we combined chemotherapeutic agent doxorubicin (DOX) and chemosensitizer lonidamine (LND) to synergistically treat glioma. We also designed and prepared multitargeted redox-sensitive liposomes (Lip-SPG) co-modified with glucose and triphenylphosphonium (TPP) to effectively deliver DOX and LND for anti-glioma therapy. The anti-glioma evaluation shows that DOX and LND have a synergistic effect and Lip-SPG could further enhance their cooperation. In vitro, Lip-SPG could increase the cellular uptake and mitochondrial uptake on bEnd.3 cells and C6 cells with multitargeting ability on the brain, tumor, and mitochondria mediated by glucose and TPP. Lip-SPG can also escape from lysosomes before entering the mitochondria. The anti-glioma efficacy in vitro shows that Lip-SPG can inhibit tumor cell proliferation and induce apoptosis. In addition, Lip-SPG have a remarkable interference to mitochondria, such as reducing intracellular ATP production, inducing ROS generation, and promoting mitochondrial membrane potential depolarization. Furthermore, in vivo, the introduction of PEGylation via glutathione-sensitive disulfide bonds endows Lip-SPG with favorable pharmacokinetic properties, brain targeting ability, low toxicity to normal tissues, and great anti-glioma efficacy with the survival time extended from 19 to 39 days. In conclusion, Lip-SPG are an effective delivery system for synergistically treating glioma with DOX and LND.
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Translational Oncology
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2021
·
IF 4.243
Qiuli Wang,Dong Liang,Peng Shen,Yang Yu,Yuan Yan,Wei You
Previous study has confirmed that hsa_circ_0092276 is highly expressed in doxorubicin (DOX)-resistant breast cancer cells, indicating that hsa_circ_0092276 may be involved in regulating the chemotherapy resistance of breast cancer. Here we attempted to investigate the biological role of hsa_circ_0092276 in breast cancer. We first constructed DOX-resistant breast cancer cells (MCF-7/DOX and MDA-MB-468/DOX). The 50% inhibiting concentration of MCF-7/DOX and MDA-MB-468/DOX cells was significantly higher than that of their parental breast cancer cells, MCF-7 and MDA-MB-46. MCF-7/DOX and MDA-MB-468/DOX cells also exhibited an up-regulation of drug resistance-related protein MDR1. Compared with MCF-7 and MDA-MB-46 cells, hsa_circ_0092276 was highly expressed in MCF-7/DOX and MDA-MB-468/DOX cells. Hsa_circ_0092276 overexpression enhanced proliferation and the expression of LC3-II/LC3-I and Beclin-1, and repressed apoptosis of breast cancer cells. The effect of hsa_circ_0092276 up-regulation on breast cancer cells was abolished by 3-methyladenine (autophagy inhibitor). Hsa_circ_0092276 modulated autophagy-related gene 7 (ATG7) expression via sponging miR-384. Hsa_circ_0092276 up-regulation promoted autophagy and proliferation, and repressed apoptosis of breast cancer cells, which was abolished by miR-384 overexpression or ATG7 knockdown. In addition, LV-circ_0092276 transfected MCF-7 cell transplantation promoted autophagy and tumor growth of breast cancer in mice. In conclusion, our data demonstrate that hsa_circ_0092276 promotes autophagy and DOX resistance in breast cancer by regulating miR-348/ATG7 axis. Thus, this article highlights a novel competing endogenous RNA circuitry involved in DOX resistance in breast cancer.
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Bioactive Materials
·
2020
·
IF 8.724
Lin An,Peng Zhang,Wei Shen,Xuan Yi,Weitian Yin,Rihua Jiang,Chunsheng Xiao
Melanoma, as the most aggressive and treatment-resistant skin malignancy, is responsible for about 80% of all skin cancer mortalities. Prone to invade into the dermis and form distant metastases significantly reduce the patient survival rate. Therefore, early treatment of the melanoma in situ or timely blocking the deterioration of metastases is critical. In this study, a sulfur dioxide (SO 2 ) polymer prodrug was designed as both an intracellular glutathione (GSH)-responsive SO 2 generator and a carrier of doxorubicin (DOX), and used for the treatment of subcutaneous and metastatic melanoma. Firstly, chemical conjugation of 4- N -(2,4-dinitrobenzenesulfonyl)-imino-1-butyric acid (DIBA) onto the side chains of methoxy poly (ethylene glycol) grafted dextran (mPEG- g -Dex) resulted in the synthesis of the amphiphilic polymer prodrug of SO 2 , mPEG- g -Dex (DIBA). The obtained mPEG- g -Dex (DIBA) could self-assemble into stable micellar nanoparticles and exhibited a glutathione-responsive SO 2 release behavior. Subsequently, DOX was encapsulated into the core of mPEG-g-Dex (DIBA) micelles to form DOX-loaded nanoparticles (PDDN-DOX). The formed PDDN-DOX could be internalized by B16F10 cells and synchronously release DOX and SO2 into the tumor cells. As a result, PDDN-DOX exerted synergistic anti-tumor effects in B16F10 melanoma cells because of the oxidative damage properties of SO 2 and toxic effects of DOX. Furthermore, in vivo experiments verified that PDDN-DOX had great potential for the treatment of subcutaneous and metastasis melanoma. Collectively, our present work demonstrates that the combination of SO 2 -based gas therapy and chemotherapeutics offers a new avenue for inhibiting melanoma progression and metastases.
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ANALYTICAL AND BIOANALYTICAL CHEMISTRY
·
2020
·Vol. 413
·期 2
·469-478
·
IF 3.637
Yu Xiao,Yu Wanxiang,Han Xiufen,Chen Zuanguang,Wang Shumei,Zhai Haiyun
Doxorubicin has been extensively used to treat cancers, and there are recent findings that the anticancer activities can be enhanced by curcumin. Although the two compounds have native fluorescence, they can hardly be quantified directly simultaneously using the laser-induced fluorescence (LIF) detection method. To avoid complex fluorescence derivatization and introduction of interfering components, a highly sensitive double wavelength excitation source LIF (D-W-Ex-LIF) detector composed of a 445-nm and 488-nm commercial laser diode was constructed to detect them simultaneously. Rhodamine 6G was selected as an internal standard, because its fluorescence can be excited at 445 nm and 488 nm. The native fluorescence of doxorubicin and curcumin and their resolution were enhanced by introducing mixed micelles. The optimal electrophoretic separation buffer was 10 mM borate buffer containing 20 mM Triton X-100, 5 mM sodium dodecyl sulfate, and 30% (v/v) methanol at pH 9.00. Therefore, the developed method was specific, accurate, and easily operable. Its limits of detection for doxorubicin and curcumin in human urine samples were 4.00 × 10 −3 and 1.00 × 10 −2 μg/mL, respectively, and the limits of quantification were 1.00 × 10 −2 and 3.00 × 10 −2 μg/mL, respectively. The recoveries were 94.9–109.1%.
Graphical abstract
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Drug Delivery and Translational Research
·
2021
·Vol. 12
·期 1
·167-179
·
IF 4.617
Wang Shuanghu,Tan Xueying,Zhou Quan,Geng Peiwu,Wang Jinhui,Zou Ping,Deng Aiping,Hu Jingbo
Multidrug resistance (MDR) is considered as a critical limiting factor for the successful chemotherapy, which is mainly characterized by the overexpression of ATP-binding cassette (ABC) transporter ABCB1 or ABCG2. In this study, folate-targeted polymeric micellar carrier was successfully constructed to co-delivery of doxorubicin (DOX) and SIS3 (FA/DOX/SIS3 micelles), a specific Smad3 inhibitor which sensitizes ABCB1- and ABCG2-overexpressing cancer cells to chemotherapeutic agents. The ratio of DOX to SIS3 in polymeric micelles was determined based on the anti-tumor activity against resistant breast cells. In addition, FA/DOX/SIS3 micelles exhibited a much longer circulation time in blood and were preferentially accumulated in resistant tumor tissue. Pharmacodynamic studies showed that FA/DOX/SIS3 micelles possessed superior anti-tumor activity than other DOX-based treatments. Overall, FA/DOX/SIS3 micelles are a promising formulation for the synergistic treatment of drug-resistant tumor. Graphical abstract
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