INTERNATIONAL IMMUNOPHARMACOLOGY
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2024
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IF 4.8
Yichen Hu,Jingzhi Yu,Wanxian He,Yang Qiao,Xie Cheng,Huang Huang,Songqing Lai,Dong Yin,Huan He
The clinical use of doxorubicin has been severely limited by doxorubicin-induced cardiotoxicity (DIC). Its mechanism is extremely complex and involves reactive oxygen species overgeneration, DNA damage, and aberrant inflammatory activity, which also involves multi-regulatory cell death mechanisms, including apoptosis, autophagy, and pyroptosis. These mechanisms overlap and crosstalk, resulting in the poor intervention of DIC injury. Astragaloside IV (Ast) has polybioactivity and mitigates DIC damage; however, the underlying mechanisms remain unknown. This study aimed to investigate whether Ast pretreatment (Ast-pre) could protect the myocardium against DIC damage and the underlying mechanisms. In particular, the relationship between Ast-pre, AMPKα2 activity, autophagy, apoptosis, and pyroptosis was explored. Firstly, DIC injury models were established using neonatal rat cardiomyocytes (NRCMs) and mice. And then the effects of adaptive autophagy, anti-pyroptosis and anti-apoptosis of Ast-pre were detected using multi-relevant indexes in NRCMs. Further, how does Ast-pre in AMPKα2 phosphorylation was explored. Finally, these results were validated by DIC injury in mice. Ast-pre, similar to disulfiram (pyroptosis inhibitor), effectively alleviated the inflammatory response, inhibited oxidative and energy stress, prevented mitochondrial dysfunction, and protected the myocardium resisting DIC damage, as demonstrated using multi-indexes. The protection of Ast-pre to DIC damage was almostly canceled by paclitaxel (pyroptosis inducer), 3-methyladenine (autophagy inhibitor), and pAD/AMPKα2-shRNA or compound C (AMPK inhibitor) to varying degrees. In conclusion, Ast-pre could upregulate and activate AMPKα2, enhance adaptive autophagy, and improve energy metabolism and mitochondrial function, thereby alleviate DIC-induced pyroptosis and apoptosis in NRCMs and mice.
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JOURNAL OF CONTROLLED RELEASE
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2025
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IF 11.5
Zhaoming Guo,Yi Zhang,Yuwei Gong,Guqing Li,Jiawei Pan,Danni Dou,Kun Ma,Changhao Cui,Yubo Liu,Xudong Zhu
Conventional cancer treatments often induce a sustained DNA damage response (DDR) in tumor cells, leading to therapy-induced senescence (TIS), characterized by permanent cell cycle arrest and resistance to apoptosis. These senescent cells secrete senescence-associated secretory phenotypes (SASP), which can promote tumor progression and create an immunosuppressive microenvironment. This study introduces a novel approach to enhance chemotherapy efficacy by using functionalized curcuma-derived extracellular vesicles (DR5-CNV/DOX) to target and eliminate senescent tumor cells and inhibit their SASP. Curcuma-derived extracellular vesicles (CNV) were loaded with the chemotherapeutic drug doxorubicin (DOX) and surface-modified with an antibody targeting death receptor 5 (DR5), which is overexpressed on senescent tumor cells. In vitro experiments demonstrated that DR5-CNV/DOX effectively targeted senescent tumor cells, promoting apoptosis and suppressing SASP production. In vivo studies confirmed the inhibition of epithelial-mesenchymal transition (EMT) initiation, angiogenesis, and modulation of the tumor immune microenvironment, enhancing chemotherapy efficacy and demonstrating promising biocompatibility. This study highlights the potential of plant-derived extracellular vesicles as a novel drug delivery system to overcome senescent tumor cells and their SASP.
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JOURNAL OF BIOMATERIALS APPLICATIONS
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2017
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IF 2.31
Liangping Li,Ruisong Tao,Mingming Song,Yue Zhang,Kuanmin Chen,Hui Wang,Renmin Gong
In this paper, the starch was firstly modified by quaternary reagent to obtain cationic starch. Then self-assembled folate–biotin-quaternized starch nanoparticles were prepared by a one-pot synthesis via N,N′-dicyclohexylcarbodiimide/N-hydroxysuccinimide/4-dimethylaminopyridine-mediated esterification reaction. The physicochemical properties of the prepared folate–biotin-quaternized starch nanoparticles were characterized. The average diameter of folate–biotin-quaternized starch nanoparticles was 109 nm with polydispersity index of 0.183 and zeta potential of 28.59 mV. The folate–biotin-quaternized starch nanoparticles were used as co-carrier of siRNA and doxorubicin with satisfactory drug loading capacity (6.98%) and encapsulation efficiency (69.66 %), and siRNA could be efficiently encapsulated at 40/1 weight ratio of doxorubicin/folate–biotin-quaternized starch nanoparticles to siRNA. The folate–biotin-quaternized starch nanoparticles could effectively protect siRNA from degradation of serum RNAase for up to 48 h. The release characteristics of doxorubicin and siRNA from folate–biotin-quaternized starch nanoparticles were studied in different pH environment and the release behaviors of two drugs were all pH sensitive. The folate–biotin-quaternized starch nanoparticles as a potential co-carrier of anticancer agents and gene drugs was expected to achieve future practical application in vitro and in vivo.
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Oncotarget
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2017
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IF 5.168
Chen Zhu,Yi Wang,Hua Liu,Haiman Mu,Yue Lu,Jiayi Zhang,Jianhua Huang
Although Ginsenoside Rg1 has been reported to have protective cardiac effects, its effects on cardiac toxicity induced by doxorubicin needs to be studied. The present study investigated the effects of oral administration of Rg1 on the heart in mice treated with doxorubicin and found improved fractional shortening and ejection fraction of the heart and decreased cardiac apoptosis in mice treated with doxorubicin. The underlying mechanisms include increased phosphorylation of Akt and Erk by Rg1, increased ratio of Bcl-2 and Bax, and decreased release of cytochrome c from mitochondria, thereby protecting the heart from doxorubicin-induced apoptosis. This phenotype suggested that the oral administration of Rg1 may be a potential method preventing the cardiac toxicity caused by doxorubicin in clinical practice.
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ACS Applied Nano Materials
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2024
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IF 5.3
Nuo Li,Ludan Zhang,Kaijun Sun,Junheng Liu,Zixuan Wang,Yujing Wang,Huinan Lu,Wenjun Xiang,Hailin Yang,Rupei Tang,Guoqing Yan
5-Fluorouracil (5FU) and its derivatives have been widely used for cancer treatment; however they fail to achieve selective chemotherapy. Herein, this work highlights a successful development of a pH-sensitive aliphatic 5-fluorouracil (5FU) derivative prodrug, which is synthesized via chemically linking 5FU and stearyl alcohol (SA) using ortho ester linkage. It can further self-assemble into a synergistic small molecule nanodrug through a noncovalent interaction with doxorubicin (DOX). The nanodrug displays precise structure and high drug loading (more than 15% of drug loading content (DLC) and 87% of drug loading efficiency (DLE)). SA and ortho ester linkages endow the nanodrug with high lipophilicity on tumor cell membrane and tumoral intracellular pH response, respectively. The nanodrug also exhibits a slightly negatively charged surface (−0.513 mV) at physiological pH (7.4) and a large-to-small size change from 176.2 to 128.9 nm at tumoral intracellular pH (5.0). These superior characteristics endow the nanodrugs with blood circulation stability, selective tumor accumulation, improved cellular uptake, efficient drug release, as well as synergistic effect on tumor cells, thereby significantly inhibiting tumor growth (smaller than initial tumor size), reducing side effects, and prolonging survival time. Thus, such a pH-sensitive small molecule nanodrug self-assembled from the aliphatic 5FU derivative and DOX has a great potential for selective synergistic cancer therapy, greatly advancing their clinical use.
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Photodiagnosis and Photodynamic Therapy
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2024
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IF 3.1
Pinggui Chen,Yaoxuan Li,Yunyan Dai,Zhiming Wang,Yunpeng Zhou,Yi Wang,Gaopeng Li
Photodynamic therapy (PDT) is a non-invasive treatment method that has garnered significant attention in recent years. Nanoparticle-based drug delivery systems can achieve targeted drug release, thereby significantly reducing side effects and enhancing therapeutic efficacy. In this study, a covalent organic framework (COF) with an approximately spherical structure connected by azo bonds was synthesized. The synthesized COF was utilized as a hypoxia-responsive carrier for doxorubicin (DOX) drug delivery and was modified with hyaluronic acid (HA). DOX@COF@HA exhibited a reactive release under hypoxic conditions. Under normal oxygen conditions, the release of DOX was 16.9 %, increasing to 60.2 % with the addition of sodium hydrosulfite. In vitro experiments revealed that the group combining photodynamic therapy with chemotherapy exhibited the lowest survival rates for 4T1 and MHCC97-L cells. In vivo experiments further validated the effectiveness of combination therapy, resulting in a tumor volume of only 33 mm 3 after treatment, with no significant change in mouse weight during the treatment period. DOX@COF@HA nanoplatforms exhibit substantial potential in tumor treatment.
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JOURNAL OF COLLOID AND INTERFACE SCIENCE
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2025
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IF 9.7
Yanzhong Hao,Yaqiao Li,Wenfeng Zang,Yixin Sun,Xin Li,Lin Li,Zhonggui He,Bingjun Sun
Doxorubicin (DOX) is a vital anthracycline chemotherapeutic drug, yet presenting significant challenges due to its severe cardiotoxicity. While Doxil enhances the pharmacokinetics and reduces the cardiotoxicity of DOX solution (DOX sol), it shows limitations of low drug loading capacity and inadequate cellular uptake. To overcome these issues, this study developed a novel disulfide bond-linked DOX-maleimide prodrug (DSSM). DSSM could self-assemble into nanoparticles (NPs) with a high drug loading capacity (58.89 %, w/w). DSSM could rapidly bind to endogenous albumin through the maleimide group. Compared to DOX sol, DSSM had increased area under the curve (AUC) by approximately 60-fold, and similarly, quadrupled tumor accumulation after 4 h of administration, achieving efficient tumor targeting. With only 5 % DSPE-mPEG 2K , the cellular uptake of DSSM NPs was better than Doxil. Furthermore, the high reduction sensitivity of the disulfide bond enabled bio-activation of DSSM at the tumor site, while maintaining stability in normal cells. Compared with DOX sol and Doxil, DSSM NPs significantly improved safety and demonstrated better anti-tumor effect at tolerated doses. Our findings present a promising strategy for achieving effective tumor targeting and bio-activation, addressing key limitations of current DOX nanoformulations.
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BIOMEDICINE & PHARMACOTHERAPY
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2024
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IF 6.9
Jiajin Xu,Zeyi Zhang,Hongtao Hu,Yaqin Yang,Chenghong Xiao,Luyi Xi,Jiahui Lu,Shasha Tian,Huajun Zhao
Peiminine, the primary biologically active compound from Fritillaria thunbergii Miq., has demonstrated significant pharmacological activities. Doxorubicin is one of the most potent chemotherapeutic agents for breast cancer (BC). This study was designed to investigate the efficacy and underlying mechanisms of Peiminine combined with Doxorubicin in treating BC. Our results demonstrated that the combination of Peiminine and 1 mg/kg Doxorubicin exhibited more significant suppression of tumor growth compared with the monotherapy in MDA-MB-231 xenograft nude mice model, which is comparable to the effect of 3 mg/kg Doxorubicin in vivo. Notably, the 3 mg/kg Doxorubicin monotherapy resulted in organ toxicity, specifically in the liver and heart, whereas no toxicity was observed in the combination group. In vitro , this combined treatment exhibited a synergistic reduction on the viability of BC cells. Peiminine enhanced the cell cycle arrest and DNA damage induced by Doxorubicin. Furthermore, the combination treatment effectively blocked DNA repair by inhibiting the MAPKs signaling pathways. And ZEB1 knockdown attenuated the combined effect of Peiminine and Doxorubicin on cell viability and DNA damage. In conclusion, our study found that the combination of Peiminine and Doxorubicin showed synergistic inhibitory effects on BC both in vivo and in vitro through enhancing Doxorubicin-induced DNA damage. These findings support that their combination is a novel and promising therapeutic strategy for treating BC .
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Micro & Nano Letters
·
2025
·Vol. 20
·期 1
·e70008
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IF 2.4
Xiuping Shen,Aiyong Zhu,Yafeng Xu
Doxorubicin (DOX), an anthracycline antibiotic, is widely used to treat a range of solid tumours and haematological malignancies. However, its clinical application in breast cancer is hindered by toxic side effects and the development of multidrug resistance (MDR). Enhancing the selective targeting of DOX and overcoming MDR are critical to improving treatment efficacy. Here, we present a DNA nanoflower (DNF)-based delivery system, designed via rolling circle amplification and multi-primer amplification (MCA), which co-delivers antisense oligonucleotides (ASOs) and DOX to human breast cancer cells (MCF-7). This system, named DNF-ASO@DOX, effectively promotes gene silencing, enhances drug accumulation and significantly inhibits cell proliferation. Furthermore, in vivo studies using mouse models of breast cancer demonstrated potent therapeutic effects, highlighting DNF-ASO@DOX as a promising strategy for enhanced anti-tumour therapy.
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COLLOIDS AND SURFACES B-BIOINTERFACES
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2018
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IF 3.997
Jinbiao Gao,Baiqing Yu,Chao Li,Ming Xu,Zhong Cao,Xiaoyan Xie,Wei Wang,Jie Liu
Ultrasound-triggered delivery system is among the various multifunctional and stimuli-responsive strategies that hold great potential as a robust solution to the challenges of localized drug delivery and gene therapy. In this work, we developed an ultrasound-triggered delivery system PFP/C 9 F 17 -PAsp(DET)/CAD/PGA- g -mPEG nanodroplet, which combined ultrasound responsive phase-change contrast agent, acid-cleavable doxorubicin prodrug and cationic amphiphilic fluorinated polymer carrier, aiming to achieve both high imaging contrast and preferable ultrasound-triggered anti-cancer therapeutic effect. The optimized nanodroplets were characterized as monodispersed particles with a diameter of about 400 nm, slightly positive surface charge and high drug-loading efficiency. The functional augmenter PGA- g -mPEG provided the nanodroplets good sustainability, low cytotoxicity and good serum compatibility, as confirmed by stability and biocompatibility tests. In ultrasound imaging study, the nanodroplets produced significant contrast with ultrasound irradiation (3.5 MHz, MI = 0.08) at 37 ℃. Cell uptake and cytotoxicity studies in HepG2 and CT-26 cells showed the enhanced drug uptake and therapeutic effect with the combination of nanodroplets and ultrasound irradiation. These results suggest that the PFP/CAD-loaded phase change nano-emulsion can be utilized as an efficient theranostic agent for both ultrasound contrast imaging and drug delivery.
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Advanced Healthcare Materials
·
2025
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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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BIOMEDICAL AND ENVIRONMENTAL SCIENCES
·
2025
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IF 4.1
Hao Wu,Huangshui Ma,Xinghan Wu,Qiang Sun,Lin Feng,Ruifang Jiang,Yanhong Li,Quan Shi
Objective Cancer remains a significant global health challenge, necessitating the development of effective treatment approaches. Developing synergistic therapy can provide a highly promising strategy for anti-cancer treatment through combining the benefits of various mechanisms. Methods In this study, we developed a synergistic strategy for chemo-photothermal therapy by constructing nanocomposites using gold nanorods (GNRs) and tetrahedral framework nucleic acids (tFNA) loaded with the anti-tumor drug doxorubicin (DOX). Results Our in vitro studies have systematically clarified the anti-cancer behaviors of tFNA-DOX@GNR nanocomposites, characterized by their enhanced cellular uptake and proficient lysosomal escape capabilities. It was found that the key role of tFNA-DOX@GNR nanocomposites in tumor ablation is primarily due to their capacity to induce cytotoxicity in tumor cells via a photothermal effect, which generates instantaneous high temperatures. This mechanism introduces various responses in tumor cells, facilitated by the thermal effect and the integrated chemotherapeutic action of DOX. These reactions include the induction of endoplasmic reticulum stress, characterized by elevated reactive oxygen species levels, the promotion of apoptotic cell death, and the suppression of tumor cell proliferation. Conclusion This work exhibits the potential of synergistic therapy utilizing nanocomposites for cancer treatment and offers a promising avenue for future therapeutic strategies.
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