Frontiers in Pharmacology
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2023
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IF 5.6
Chen Zhenzhen,Liu Zhihong,Zhang Qian,Huang Sheng,Zhang Zaizhong,Feng Xianquan,Zeng Lingjun,Lin Ding,Wang Lie,Song Hongtao
Drug resistance is a huge hurdle in tumor therapy. Tumor hypoxia contributes to chemotherapy resistance by inducing the hypoxia-inducible factor-1α (HIF-1α) pathway. To reduce tumor hypoxia, novel approaches have been devised, providing significant importance to reverse therapeutic resistance and improve the effectiveness of antitumor therapies. Herein, the nanosystem of bovine serum albumin (BSA)-templated manganese dioxide (MnO2) nanoparticles (BSA/MnO2 NPs) loaded with doxorubicin (DOX) (DOX-BSA/MnO2 NPs) developed in our previous report was further explored for their physicochemical properties and capacity to reverse DOX resistance because of their excellent photothermal and tumor microenvironment (TME) response effects. The DOX-BSA/MnO2 NPs showed good biocompatibility and hemocompatibility. Meanwhile, DOX-BSA/MnO2 NPs could greatly affect DOX pharmacokinetic properties, with prolonged circulation time and reduced cardiotoxicity, besides enhancing accumulation at tumor sites. DOX-BSA/MnO2 NPs can interact with H2O2 and H+ in TME to form oxygen and exhibit excellent photothermal effect to further alleviate hypoxia due to MnO2, reversing DOX resistance by down-regulating HIF-1α expression and significantly improving the antitumor efficiency in DOX-resistant human breast carcinoma cell line (MCF-7/ADR) tumor model. The hypoxia-ameliorated photothermal MnO2 platform is a promising strategy for revering DOX resistance.
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高影响因子
Scientific Reports
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2015
·Vol. 5
·期 1
·1-6
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IF 5.578
Xue Qiang,Ren He,Xu Chao,Wang Gang,Ren Chunhua,Hao Jihui,Ding Dan
In this study, we synthesized a peptide of Nap-GFFYGRGD, which could self-assemble into supramolecular nanofibers. The peptide itself could only form nanofibers but not hydrogels due to the relative weak inter-fiber interactions. The resulting nanofibers were then utilized as the vehicles for anticancer drug doxorubicin. It was found that the nanofibers of Nap-GFFYGRGD could not encapsulate doxorubicin, whereas the drug formed nanospheres, which were located at the surface of the nanofibers. Due to the electrostatic interactions between the negatively charged nanofibers and the positively charged doxorubicin nanospheres, the doxorubicin nanospheres were able to serve as a cross-linker to increase the inter-fiber interactions, leading to the formation of stable three-dimentional fiber networks and hydrogels. The resulting doxorubicin-peptide hydrogels were capable of releasing the drug in a sustained manner, which also showed comparable cytotoxicity as compared to free doxorubicin against a variety of cancer cell lines including HeLa and MCF-7 cancer cells. Therefore, this successful example using drug as the peptide nanofiber cross-linkers provided a new strategy for fabricating supramolecular hydrogelation for controlled delivery of anticancer drugs.
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International Journal of Nanomedicine
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2013
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IF 3.463
Sai-Ping Jiang,Sai-Nan He,Yun-Long Li,Da-Lin Feng,Xiao-Yang Lu,Yong-Zhong Du,He-Yong Yu,Fu-Qiang Hu,Hong Yuan
Purpose Safe and effective lipid nanoemulsion (LNE) formulations for the antitumor delivery of doxorubicin is designed.Methods LNEs composed of medium-chain triglyceride, soybean oil, lecithin, and doxorubicin are prepared by a solvent-diffusion method in an aqueous system. The effects of lipid material composition and polyethylene glycol (PEG)ylation on the size, drug encapsulation efficiency, and stability of LNEs are investigated. Based on in-vitro cytotoxicity and cellular uptake tests of A549 (human lung carcinoma) cells, in-vivo biodistribution, antitumor activity, and cardiac toxicity are further examined using nude mouse bearing A549 tumor.Results The LNE size decreases from 126.4 ± 8.7 nm to 44.5 ± 9.3 nm with increased weight ratio of medium-chain triglyceride to soybean oil from 1:4 to 3:2, whereas the encapsulation efficiency of doxorubicin is slightly reduced from 79.2% ± 2.1% to 71.2% ± 2.9%. The PEGylation of LNE by 1,2-distearoyl-sn-glycero-3-phosphoethanolamine-N-[carboxy(PEG)2000] (DSPE-PEG 2000) does not significantly change the size and drug encapsulation efficiency. Three-month storage at room temperature and lyophilization process does not affect the drug encapsulation efficiency, whereas the size slightly increases to almost 100 nm. The in-vitro drug-release profiles of LNEs suggest that the present formulation can prolong drug release for 48 hours. LNEs can be internalized into tumor cells in vitro and efficiently accumulate in tumor tissues in vivo by passive targeting. Analysis results of in-vitro and in-vivo antitumor activities reveal that doxorubicin-loaded LNE exerts a therapeutic effect similar to that of the commercial Adriamycin. Moreover, the toxicity of doxorubicin, particularly its cardiac toxicity, is reduced.Conclusion The present LNE formulation of doxorubicin can effectively suppress tumor growth and improve the safety of Adriamycin.
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RSC Advances
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2016
·Vol. 6
·期 37
·31167-31176
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IF 3.289
Wenlong Wang,Liang Zhang,Yuan Le,Jiexin Wang,Jian-Feng Chen
An intelligentized system that can transport chemotherapeutics to targets in tumors is an attractive strategy to reverse drug resistance in tumor cells. In this work, a doxorubicin (DOX) delivery system composed of PEGylated resveratrol (PEG–GLY–RES) and poly(histidine)–PEG (PEG–PHIS) was prepared, characterized and evaluated for synergistic cancer therapy. RES was chemically linked with PEG as a component and DOX was loaded into the polymeric blends. This system had an average size of 80 nm, and showed the desired pH-dependent drug release properties, with much faster drug release at pH 5.5, mimicking the tumoral microenvironment. The MTT assay showed the drug loaded blends had higher cytotoxicity than free DOX in all doses. Confocal laser scanning microscopy observation and flow cytometry analyses indicated that the blends were efficiently internalized into HeLa cells, released DOX into the cytoplasm, and entered the nuclei. Endocytosis inhibition results proved that the blends entered the HeLa cells mainly through clathrin-mediated endocytosis and macropinocytosis. It has been shown that such co-delivery of RES and DOX is promising for improvement of anti-cancer efficacy.
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Nanoscale Advances
·
2024
·
IF 4.6
Yijun Guo,Yong Chen,Yiqun Wu,Ying Zhu,Shiyao Luo,Juan Shen,Yongjun Luo
Cancer, as a global health threat, is often treated with chemotherapy, but its effect is limited, especially the drugs such as doxorubicin (DOX) are limited by their non-specificity and side effects. This study focuses on developing a new drug delivery system to overcome these challenges. Based on the self-assembling peptide hemopressin (HP), we designed and screened FOK peptide, which serves as a pH-responsive carrier with excellent pH sensitivity and mechanical stability. At a concentration of 20 mg mL−1, FOK can spontaneously form a stable hydrogel, efficiently encapsulating DOX with an encapsulation rate exceeding 95%. This system can gradually release the drug in the tumor-specific mildly acidic environment, achieving precise delivery and sustained release of the drug. Rheological analysis revealed the superior mechanical and self-healing properties of FOK hydrogel, suitable for injection delivery with long-lasting stability. Mouse experiments showed that DOX/FOK hydrogel significantly inhibited tumor growth while greatly reducing toxicity. In conclusion, FOK hydrogel, as a delivery vehicle for DOX, not only optimizes the precise delivery and sustained release mechanism of DOX, but also reduces treatment side effects, opening up new avenues for the application of peptide hydrogels in cancer therapy and providing a scientific basis for designing efficient drug delivery systems.
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CARBOHYDRATE RESEARCH
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2021
·
IF 2.104
Qin Zhou,Caixia Li,Jiahao Guo,Wenbo Jiang,Yan Zhu,Weixia Mao,Liang Li
An array of self-assembled biocompatible doxorubicin (DOX) loaded heparin--cyclodextrin supramolecular hydrogels (DOX@HGs) with highly encapsulated efficiency was constructed using heparin-β-cyclodextrin derivatives (Hep-β-CD), α-cyclodextrin (α-CD), pluronic F-127 and DOX via the synergy of host-guest and multiple hydrogen bonding interactions. These hydrogels were characterized by GPC measurements (GPC), scanning electron microscopy (SEM), transmission electron microscopy (TEM), Size and zeta potential determinations, X-ray diffraction (XRD), and rheological characteristics; the data confirmed successful formation of the hydrogels. Furthermore, these hydrogels demonstrated distinctive thixotropy, indicating rapid self-repairing after continuously oscillatory shear stress. Variable release of DOX from DOX @HGs was obtained at various pH after 84 h depending on the strength of the hydrogels. At pH 7.4, cumulative DOX release was approximately 49.07% for DOX@HG 1 , 32.15% for DOX@HG 2 , and 27.12% for DOX@HG 3 . While at pH 5.5, release of DOX was increased to 59.08% for DOX@HG 1 and to 43.2% for DOX@HG 3 after 84 h (P < 0.05). This information demonstrated that a higher DOX release rate was observed under a lower pH due to strong charge expansion of CDs and weakening of electrostatic interactions between heparin and DOX. Additionally, cytotoxicity of free DOX and DOX@HGs in ovarian cancer SKOV-3 cells was studied at various exposure durations. The results revealed that cytotoxicity of DOX@HG 1–3 toward ovarian cancer SKOV-3 cells was lower than that of free DOX (P < 0.05), suggesting prolonged DOX release from the hydrogels in SKOV-3 cells.
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Nanomaterials
·
2019
·Vol. 9
·期 4
·547
·
IF 4.034
Meng Li,Jian-Wei Guo,Wei-Qiu Wen,Jem-Kun Chen
A typical amphiphilic star polymer adamantane-[poly(lactic-co-glycolic acid)-bis(2-carboxyethyl) sulfide-poly(ethylene glycol) monomethyl ether)]4with a specific hydrophilic/redox-sensitive/hydrophobic structure was designed and synthesized through ring opening and esterification reactions. The self-assembled nanomicelles were used as doxorubicin (DOX) delivery vehicles with suitable critical micelle concentrations (5.0 mg/L). After the drug being loaded, drug-loaded micelles showed good drug-loading efficiency (10.39%), encapsulation efficiency (58.1%), and drug release (up to 60%) under simulated biological environment conditions. In addition, the backbone structure of the biodegradable polymer was easily hydrolyzed by the action of biological enzymes. As expected, cell-based studies showed that the designed polymer micelles possessed good biocompatibility (a survival rate of 85% for NH-3T3 cells). Moreover, the drug (DOX) still maintained good anti-cancer effects after being loaded, which caused 40% of MCF-7 cells to survive. These redox-sensitive micelles showed anti-tumor therapeutic potential.
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RSC Advances
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2017
·Vol. 7
·期 66
·41675-41685
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IF 3.108
Yu Qin,Changyu Wang,Yun Jiang,Tao Liu,Jianyong Yang,Run Lin,Tao Zhang
A novel phosphorylcholine oligomer-grafted and folate moiety-labeled graphene oxide (GO–PCn–FA) was designed, prepared, and characterized by Fourier transform infrared spectra, nuclear magnetic resonance, Raman spectra, X-ray diffraction, X-ray photoelectron spectroscopy, scanning transmission electron microscopy, transmission electron microscopy, and atomic force microscopy. GO–PCn–FA proved to be an excellent water-soluble and pH-responsive drug carrier for the targeted delivery of doxorubicin (DOX) with a drug loading content of 21%. An in vitro cytotoxicity assay and flow cytometry analysis revealed the superior biocompatibility of GO–PCn–FA compared to normal cells, while DOX-loaded GO–PCn–FA exerted efficient eradication of tumor cells, especially of those with folate receptor expression. An in vivo test showed that GO–PCn–FA was deposited mainly in the pulmonary parenchyma after intravenous administration, and no obvious adverse effect was observed. In summary, phosphorylcholine oligomer-grafted graphene oxide was developed for targeted drug delivery with optimal biocompatibility.
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Journal of the American Heart Association
·
2026
·Vol. 15
·期 13
·
IF 6
Xinying Wang,Ge Zhan,Jiatian Li,Xinmiao Yang,Yuhang Wen,Yuqi Tang,Puyu Zhang,Yunlong Xia,Xiaolei Yang
BackgroundThe clinical utility of doxorubicin, a potent chemotherapeutic agent, is severely limited by its dose‐dependent cardiotoxicity. Hypoxia‐inducible factor 1α (HIF1α) is a key regulator of cardiovascular adaptation, but its role and mechanism in doxorubicin‐induced cardiotoxicity (DIC) remain unclear.MethodsUsing in vitro (AC16 cells) and in vivo (mouse) models of DIC, we used genetic (knockout, knockdown) and pharmacological (FG4592) approaches to modulate HIF1α. Cardiac function, apoptosis, endoplasmic reticulum (ER) morphology, and ER‐phagy flux were assessed. Molecular mechanisms were investigated using chromatin immunoprecipitation and promoter activity assays.ResultsHIF1α exhibited a dynamic, biphasic expression pattern during DIC progression. Stabilization of HIF1α by FG4592 alleviated doxorubicin‐induced cardiac dysfunction, atrophy, fibrosis, and apoptosis, whereas HIF1α knockout exacerbated these injuries. The protective effects of FG4592 were strictly dependent on HIF1α. Mechanistically, HIF1α transcriptionally activated the ER‐phagy receptor gene testis‐expressed protein 264 (TEX264) by directly binding to its promoter. This activation enhanced ER‐phagy, and suppressed ER stress–mediated apoptosis. Crucially, ablation of TEX264 abolished the cardioprotective effects of both HIF1α and FG4592.ConclusionsThis study identifies a novel HIF1α/TEX264/ER‐phagy axis that is suppressed in DIC and is central to cardiomyocyte survival. Targeting this pathway, particularly with the clinically available HIF1α stabilizer FG4592, represents a promising therapeutic strategy against DIC.
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INTERNATIONAL JOURNAL OF PHARMACEUTICS
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2012
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IF 3.35
Anning Wang,Hui Gao,Yanfang Sun,Yu-long Sun,Ying-Wei Yang,Guolin Wu,Yinong Wang,Yunge Fan,Jianbiao Ma
A series of temperature- and pH-responsive polyurethanes based on hexamethylene diisocyanate (HDI) and 4,4′-diphenylmethane diisocyanate (MDI) were synthesized by a coupling reaction with bis-1,4-(hydroxyethyl) piperazine (HEP), N -methyldiethanolamine (MDEA) and N -butyldiethanolamine (BDEA), respectively. The chemical structure , molecular weight, thermal property and crystallization properties were characterized by Fourier transform infrared (FT-IR) spectroscopy, nuclear magnetic resonance (NMR) spectroscopy, gel permeation chromatography (GPC), differential scanning calorimetry (DSC) and X-ray diffraction (XRD) spectroscopy. The resulting polyurethanes were then used to prepare nanoparticles either by direct dispersion method or dialysis method. Their pH and temperature responsibilities were evaluated by optical transmittance and size measurement in aqueous media. Interestingly, HDI-based and MDI-based polyurethanes exhibited different pH and temperature responsive properties. Nanoparticles based on HDI-HEP and HDI-MDEA were temperature-responsive, while MDI-based biomaterials were not. All of them showed pH-sensitive behavior. The possible responsive mechanism was investigated by 1 H NMR spectroscopy. The cytotoxicity of the polyurethanes was evaluated using methylthiazoletetrazolium (MTT) assay in vitro . It was shown that the HDI-based polyurethanes were non-toxic, and could be applied to doxorubicin (DOX) encapsulation. The experimental results indicated that DOX could be efficiently encapsulated into polyurethane nanoparticles and uptaken by Huh-7 cells. The loaded DOX molecules could be released from the drug-loaded polyurethane nanoparticles upon pH and temperature changes, responsively.
研究领域:
生物材料学
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药剂学
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肿瘤学
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高分子科学
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纳米医学
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高影响因子
PHYTOMEDICINE
·
2022
·
IF 6.656
Qianqian Jiang,Xu Chen,Xue Tian,Jingmei Zhang,Siming Xue,Yanyan Jiang,Tiantian Liu,Xiaoping Wang,Qianbin Sun,Yiqin Hong,Chun Li,Dongqing Guo,Yong Wang,Qiyan Wang
Background Doxorubicin (DOX) is a powerful anti-tumor anthracycline drug . However, its clinical use is limited due to the side effect of cardiotoxicity . Tanshinone I (Tan I) is one of the major tanshinones isolated from Salvia miltiorrhiza . Studies have shown that Tan I is effective in the treatment of cardiovascular diseases. However, the potential effects of Tan I against DOX-induced cardiotoxicity (DIC) have yet to be explored. Purpose This study aimed to explore whether Tan I can protect against DIC and to reveal whether Tan I can exert anti-oxidative effect by regulating nuclear erythroid factor 2-related factor 2 (Nrf2) pathway. Methods DIC models were established in vivo by intravenous injection of DOX. Echocardiography was used to monitor the cardiac function of mice. Transmission electron microscopy was used to assess mitochondrial damage. Oxidative stress was measured by dihydroethidium (DHE) staining and western blotting . The accumulation and nuclear translocation of Nrf2 was detected by immunofluorescence. H9C2 cellular DIC model was established in vitro to explore the pharmacological mechanism. Nrf2 small interfering (si)-RNA was applied to H9C2 cells to explore whether Tan I exerted protective effect against DIC through Nrf2 signaling pathway . The protective effects of Tan I on mitochondrial function and mitochondrial membrane permeability were measured by MitoSOX™ Red and JC-1 staining assays, respectively. Results In vivo experiments revealed that Tan I could improve cardiac function and protect against DOX-induced myocardial structural damages in mice models. The oxidative stress induced by DOX was suppressed and apoptosis was mitigated by Tan I treatment. Tan I protected against DOX-induced mitochondrial structural damage. Meanwhile, key proteins in Nrf2 pathways were upregulated by Tan I treatment. In vitro studies showed that Tan I attenuated DOX-induced generation of reactive oxygen species (ROS) in cultured H9C2 cells, reduced apoptotic rates , protected mitochondrial functions and up-regulated Nrf2 signaling pathway. Tan I promoted accumulation and nuclear translocation of Nrf2 protein. In addition, interference of Nrf2 abrogated the anti-oxidative effects of Tan I and reversed the expressions of key proteins in Nrf2 pathway. The protective effects of Tan I on mitochondrial integrity was also mitigated by Nrf2 interference. Conclusion Tan I could reduce oxidative stress and protect against DIC through regulating Nrf2 signaling pathway. Nrf2 is a potential target and Tan I is a novel candidate agent for the treatment of DIC.
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ACS Biomaterials Science & Engineering
·
2022
·
IF 5.395
Yuxin Wang,Daliang Zhong,Fan Xie,Siying Chen,Zaiqiang Ma,Xinyan Yang,M. Zubair Iqbal,Quan Zhang,Jiaju Lu,Shibo Wang,Ruibo Zhao,Xiangdong Kong
Inorganic nanomaterials showed great potential as drug carriers for chemotherapeutics molecules due to their biocompatible physical and chemical properties. A manganese-based inorganic nanomaterial manganese phosphate (MnP) had become a new drug carrier in cancer therapy. However, the approach for manganese phosphate preparation and drug integration is still confined in complex methods. Inspired by mimetic mineralization, we proposed a “one-step” method for the preparation of manganese phosphate-doxorubicin (DOX) nanomedicines (MnP-DOX) by manganese ion and DOX complexation. The structural characterization results revealed that the prepared MnP-DOX nanocomplexes were homogeneous with controlled sizes and shapes. More importantly, the MnP-DOX nanocomposites could significantly induce cancer inhibition in vitro and in vivo. The results indicated that the drug molecules were integrated into MnP nanocarriers by mimetic mineralization, which not only prevented the premature release of the drug but also reduced excessive modification. Moreover, the designed MnP-DOX complex showed high loading efficacy and pH-dependent degradation leading to drug release, achieving high efficiency for cancer chemotherapy in vitro and in vivo via a facile process. These achievements presented an approach to construct the manganese phosphate-based chemotherapy nanomedicines by mimetic mineralization for cancer therapy.
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