COLLOIDS AND SURFACES B-BIOINTERFACES
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2015
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IF 4.152
Tingxian Liu,Mingfang Wang,Tianqi Wang,Yao Yao,Na Zhang
The greatest challenge in combining chemotherapy and gene therapy is the construction of a suitable platform for the co-delivery of the drug and the therapeutic gene. In this study, a simplified and effective system for the co-loading and intracellular co-delivery of doxorubicin (Dox) and siRNA was developed. Oligodeoxynucleotides with CGA repeating units (CGA-ODNs) were introduced to load Dox. The loading mechanism was based on the ability of Dox to intercalate within double-stranded 5′-GC-3′ or 5′-CG-3′ sequences. Poly(ethyleneimine) (PEI) was used to condense siRNA and Dox loaded CGA-ODNs (CGA-ODNs-Dox) to obtain Dox and siRNA co-loaded nanocomplexes (PEI/CGA-ODNs-Dox&siRNA, PDR). The cellular uptake of PDR in A549 and HepG2 cells was 39.52% and 36.78%, respectively, indicating that the co-loading and co-delivery effect was achieved through the mono-loading method. An in vitro drug release study indicated that CMCS-poly(ethylene glycol) (PEG)-NGR (CPN) modified PDR (CPN-PDR) displayed a pH-triggered drug release property due to the reversed surface charge of CMCS in an acidic environment. Cellular uptake studies also confirmed that the disassembly of CPN-PDR was induced by an acidic pH in the extracellular matrix. Moreover, lysosomal escape of both Dox and siRNA was observed. Successful accumulation of Dox in the cell nucleus and siRNA in the cytoplasm was also demonstrated. Consequently, the novel construction of a simplified loading method and high co-delivery efficiency was proven to be a promising platform for the co-delivery of drug and siRNA.
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MICROCHEMICAL JOURNAL
·
2024
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IF 4.9
Wen-Juan Wang,Kai-Qi Liu,Jia-Lou Chen,Gang Wang,Feng Li,Yu-Qin Wang,Fen-Ying Kong,Wei Wang,Zhong-Xia Wang
Cancer is currently one of the deadliest diseases in the world. As one of the most common anti-cancer drugs, monitoring the amount of doxorubicin (Dox) with high sensitivity in serum can not only guide the dosage of Dox and minimize their toxicity, but also guarantee the effectiveness of treatment and the safety of patient’s life. Here, a green luminescent probe of the sulfur-enrichment, nitrogen-deficiency carbon nanodots (SCDs) was synthesized by melamine and 3-mercaptopropionic acid as nitrogen-sulfur-oxygen sources. The optical properties and surface functional groups of the SCDs have tremendously changed owing to the enrichment of the sulfur atoms. Interestingly, the SCDs luminescence can be suppressed by Dox through effective inner filter effect, which was permitted to construct high sensing platform for Dox determination. With the help of this mechanism, a wide linear range from 0.1 μM to 300 μM with a low limit of detection of 78.4 nM by utilizing SCDs-based constructed sensing platform were obtained. More importantly, this sensing platform has been successfully used to detect Dox in serum samples, and achieved satisfactory results with the recoveries between 97.7 and 104.2 %. This study conduces to the design of surface sulfur-containing carbon dots and broaden the utilization of functional SCDs in anthraquinone drugs detection.
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JOURNAL OF CELLULAR AND MOLECULAR MEDICINE
·
2025
·Vol. 29
·期 2
·e70358
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IF 4.2
Jiangfang Lian,Hui Lin,Zuoquan Zhong,Yongfei Song,Xian Shao,Jiedong Zhou,Lili Xu,Zhenzhu Sun,Yongyi Yang,Jufang Chi,Ping Wang,Liping Meng
The clinical application of doxorubicin (DOX) is limited due to its cardiotoxicity, which is primarily attributed to its interaction with iron in mitochondria, leading to lipid peroxidation and myocardial ferroptosis. This study aimed to investigate the role of the gut microbiota‐derived metabolite, indole‐3‐lactic acid (ILA), in mitigating DOX‐induced cardiotoxicity (DIC). Cardiac function, pathological changes, and myocardial ferroptosis were assessed in vivo. The cardioprotective effects and mechanisms of ILA were explored using multi‐omics approaches, including single‐nucleus RNA sequencing (snRNA‐seq) and bulk RNA‐seq, and were further validated in Nrf2 knockout mice. The findings revealed that DOX treatment disrupted gut microbiota, significantly reducing the levels of the tryptophan metabolite ILA. In DIC models, ILA supplementation markedly improved cardiac function, reduced collagen deposition, and mitigated cardiac atrophy. The bulk and snRNA‐seq analyses indicated that myocardial ferroptosis played a crucial role in the cardioprotective effects of ILA. Experimental data demonstrated that ILA decreased DOX‐induced ferroptosis in both DIC mice and DOX‐treated H9C2 cells, evidenced by restoration of GPX4 and SLC7A11 levels and reduction of ACSL4. Mechanistically, ILA functions as a ligand for the aryl hydrocarbon receptor (AhR), leading to the upregulation of Nrf2 expression. The protective effects of ILA against ferroptosis were abolished by silencing AhR. Moreover, the beneficial effects of ILA on DIC were eliminated in Nrf2‐deficient mice. In conclusion, ILA exerts therapeutic effects against DIC by inhibiting ferroptosis through activation of the AhR/Nrf2 signalling pathway. Identifying the cardioprotective role of the microbial metabolite ILA could offer viable therapeutic strategies for DIC.
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COLLOIDS AND SURFACES B-BIOINTERFACES
·
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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INTERNATIONAL JOURNAL OF PHARMACEUTICS
·
2017
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IF 3.649
Tingting Meng,Binbin Lu,Shihong Shao,Ming Yuan,Xuan Liu,Hong Yuan,Xuan Huang,Fuqiang Hu
P-glycoprotein (P-gp) is a major efflux transporter overexpressed on multidrug resistant tumor cells and responsible for pumping drugs out. If anti-tumor drugs are given when P-gp level is low, satisfactory treatment efficiency may be achieved. Thus, a P-gp down-regulating siRNA (siMDR1) and doxorubicin (DOX) were applied to eliminate multidrug resistant breast cancer cells (MCF-7/ADR). A redox-responsive glucolipid conjugate (CSO-ss-SA) was used to condense siRNA (CSO-ss-SA/siRNA) and encapsulate DOX (CSO-ss-SA/DOX) separately. They responded to the high reducing environment of tumor cells and fast released the payload. CSO-ss-SA/siMDR1 silenced MDR1 gene and resulted in a transient decrease of P-gp. Sequentially, DOX formulation (CSO-ss-SA/DOX or DOX·HCl) was delivered when P-gp was reduced to the lowest level. After pretreatment by CSO-ss-SA/siMDR1, cytotoxicity of CSO-ss-SA/DOX and DOX·HCl against MCF-7/ADR cells were 6.4 or 3.4-fold respectively of that treated by DOX·HCl alone, which exhibited increased cytotoxin sensitivity of drug resistant cells and maximized therapeutic outcomes. These results revealed that the sequential treatment strategy of CSO-ss-SA/siRNA and CSO-ss-SA/DOX hold potential in achieving an optimal overcoming multidrug resistance efficiency.
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TOXICOLOGY
·
2024
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IF 4.8
Mingyang Chen,Yaodong Yi,Binxin Chen,Hengbin Zhang,Minlei Dong,Luexiang Yuan,Hui Zhou,Huidi Jiang,Zhiyuan Ma
Doxorubicin (DOX) is a widely used antitumor agent; however, its clinical application is limited by dose-related organ damage. Because organic cation/carnitine transporters (OCTN1 and OCTN2), which are critical for DOX uptake, are highly expressed in hepatocytes, we aimed to elucidate the role of these transporters in hepatic DOX uptake. The results indicated that inhibitors and RNA interference both significantly reduced DOX accumulation in HepG2 and HepaRG cells, suggesting that OCTN1/2 contribute substantially to DOX uptake by hepatocytes. To determine whether metformin (MET, an inhibitor of OCTN1 and OCTN2) ameliorates DOX-induced hepatotoxicity, we conducted in vitro and in vivo studies. MET (1–100 μM) inhibited DOX (500 nM) accumulation and cytotoxicity in vitro in a concentration-dependent manner. Furthermore, intravenous MET administration at 250 or 500 mg/kg or by gavage at 50, 100, or 200 mg/kg reduced DOX (8 mg/kg) accumulation in a dose-dependent manner in the mouse liver and attenuated the release of alanine aminotransferase, aspartate aminotransferase, and carboxylesterase 1. Additionally, MET reduced the distribution of DOX in the heart, liver, and kidney and enhanced the urinary elimination of DOX; however, it did not increase the nephric toxicity of DOX. In conclusion, our study demonstrated that MET alleviates DOX hepatotoxicity by inhibiting OCTN1- and OCTN2-mediated DOX uptake in vitro (mouse hepatocytes and HepaRG or HepG2 cells) and in mice.
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JOURNAL OF COLLOID AND INTERFACE SCIENCE
·
2025
·
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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ACS Applied Nano Materials
·
2024
·
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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BIOMEDICINE & PHARMACOTHERAPY
·
2024
·
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
·
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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TALANTA
·
2025
·
IF 6.1
Luke Wei,Yuxin Hu,Jiamin Wu,Jing Mao,Tianqin Yin,Jieqiong Qiu
Doxorubicin (DOX), a widely utilized chemotherapeutic antibiotic, increasingly threatens environmental and public health due to its persistence in marine ecosystems, bioaccumulation in organisms, and contamination of agricultural systems. In response to the urgent demand for effective DOX detection, we have developed a label-free fluorescent aptamer biosensor (FAB) that employs SYBR Green I (SG I)-mediated signal amplification. A key innovation in this design is the strategic fragmentation of the 41-mer complementary strand (CP) of the DOX aptamer into three 11-mer fragments. It significantly mitigates nonspecific SG I binding interference caused by the longer ssDNA CP, enhancing the fluorescence signal ratio (F dsDNA /F ssDNA ) from 4.6-fold to 12.6-fold. Upon DOX introduction, competitive binding between DOX, SG I, and DNA further suppresses background noise, yielding an exceptional fluorescence quenching ratio (F 0 /F) of 52.8. The optimized FAB demonstrates ultra-sensitive DOX detection, with a detection limit of 1.41 nM and a linear response between 1.41 nM and 300 nM. The recoveries of DOX spiked into pond water and drinking water samples ranged from 95.1% to 101.8%, with relative standard deviations (RSDs) below 3.46%, demonstrating negligible matrix effects and confirming the FAB method’s robustness for environmental monitoring applications. This strategy synergistically enhances signal transduction efficiency, and strengthens detection reliability, all while maintaining operational simplicity. As a result, this FAB for DOX detection holds transformative potential, poised to revolutionize biosensor technology in the fields of food safety, environmental monitoring, and biosecurity.
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Photodiagnosis and Photodynamic Therapy
·
2024
·
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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