Frontiers in Bioengineering and Biotechnology
·
2023
·
IF 5.7
Ruan Yejiao,He Lingyun,Chen Jiamin,Wang Jinfeng,Zhao Shujing,Guo Xiaoling,Xie Yao,Cai Zhenzhai,Shen Xian,Li Chao
Hypoxia is one of the major causes of cancer resistance and metastasis. Currently, it is still lack of convenient ways to simulate the in vivo hypoxic tumor microenvironment (TME) under normoxia in vitro. In this study, based on multi-polymerized alginate, we established a three-dimensional culture system with a core-shell structure (3d-ACS), which prevents oxygen diffusion to a certain extent, thereby simulating the hypoxic TME in vivo. The cell activity, hypoxia inducible factor (HIF) expression, drug resistance, and the related gene and protein changes of the gastric cancer (GC) cells were investigated in vitro and in vivo. The results demonstrated that the GC cells formed organoid-like structures in the 3d-ACS and manifested more aggressive growth and decreased drug responses. Our study provides an accessible hypoxia platform in the laboratory with moderate configuration and it may be applied in studies of the hypoxia-induced drug resistances and other preclinical fields.
研究领域:
癌症研究
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生物医学工程
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药学
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细胞生物学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
MOLECULES
·
2022
·Vol. 27
·期 20
·6929
·
IF 4.927
Lei Yang,Mohammad Javad Afshari,Jianxian Ge,Dandan Kou,Lei Chen,Dandan Zhou,Cang Li,Shuwang Wu,Leshuai Zhang,Jianfeng Zeng,Jian Zhong,Roland H. Stauber,Mingyuan Gao
Hypoxia is a common biological condition in many malignant solid tumors that plays an imperative role in regulating tumor growth and impacting the treatment’s therapeutic effect. Therefore, the hypoxia assessment is of great significance in predicting tumor development and evaluating its prognosis. Among the plenty of existing tumor diagnosis techniques, magnetic resonance imaging (MRI) offers certain distinctive features, such as being free of ionizing radiation and providing images with a high spatial resolution. In this study, we develop a fluorescent traceable and hypoxia-sensitiveT1-weighted MRI probe (Fe3O4-Met-Cy5.5) via conjugating notable hypoxia-sensitive metronidazole moiety and Cy5.5 dye with ultrasmall iron oxide (Fe3O4) nanoparticles. The results of in vitro and in vivo experiments show that Fe3O4-Met-Cy5.5 has excellent performance in relaxivity, biocompatibility, and hypoxia specificity. More importantly, the obvious signal enhancement in hypoxic areas indicates that the probe has great feasibility for sensing tumor hypoxia viaT1-weighted MRI. These promising results may unlock the potential of Fe3O4nanoparticles asT1-weighted contrast agents for the development of clinical hypoxia probes.Keywords:tumor hypoxia;ultrasmall iron oxide nanoparticles;magnetic resonance imaging;metronidazole
研究领域:
医学影像
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纳米技术
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肿瘤学
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生物医学工程
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Clinical and Experimental Otorhinolaryngology
·
2023
·
IF 3
Kunyu Liu,Yu Xu
Objectives. Hypoxia-inducible factor 1α (HIF1α) and Tet methylcytosine dioxygenase 2 (TET2) have been reported to mediate nasal polypogenesis through the epithelial-to-mesenchymal transition (EMT). Additionally, HIF1α can regulate the expression and function of TET2. However, the precise mechanism of how TET2 regulates the EMT through HIF1α mediation in nasal epithelial cells is still poorly understood. Methods. Nasal tissue samples were collected from patients with chronic rhinosinusitis (CRS) with nasal polyps (CRSwNP), CRS without nasal polyps (CRSsNP), and controls. The expression of HIF1α and TET2 was detected using Western blotting and immunohistochemistry. EMT markers (E-cadherin and vimentin) were also evaluated by immunohistochemistry. Primary human nasal epithelial cells (hNECs) were stimulated with CoCl 2 to mimic hypoxia. Vitamin C (VC), a TET2 non-specific activator, and small interfering RNA (siRNA) transfection of TET2 were used to further determine the role of TET2 in hypoxia-induced EMT. Finally, reactive oxygen species (ROS) and Nrf2 were measured to explore the downstream consequences of TET2 in hypoxic hNECs. Results. TET2 levels were lower in the nasal epithelium of CRSwNP patients and were positively correlated with E-cadherin but negatively correlated with vimentin in CRS. However, HIF1α exhibited the opposite pattern and was negatively correlated with TET2 expression. CoCl 2 -simulated hypoxia led to EMT and increased HIF1α in hNECs in vitro , with simultaneous downregulation of TET2 expression. Addition of VC activated TET2 expression in hNECs, but inhibited EMT and HIF1α expression. Furthermore, siRNA knockdown of TET2 contributed to the EMT in CoCl 2 -simulated hNECs despite the addition of VC. Finally, TET2 regulated the EMT in hypoxic hNECs through Nrf2 expression and ROS generation. Conclusion. TET2 was negatively correlated with HIF1α and EMT in vivo . TET2 was downregulated by HIF1α, resulting in the EMT in CoCl 2 -hypoxic hNECs via regulation of oxidative stress in vitro . Hence, TET2 might provide a new therapeutic approach for CRSwNP
研究领域:
免疫学
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耳鼻喉科学
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分子生物学
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细胞生物学
✓ 已验证
DOI
PubMed
高影响因子
Theranostics
·
2018
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IF 8.537
Zaigang Zhou,Baoli Zhang,Haoran Wang,Ahu Yuan,Yiqiao Hu,Jinhui Wu
Tumors are usually hypoxic, which limits the efficacy of current tumor therapies, especially radiotherapy in which oxygen is essential to promote radiation-induced cell damage. Herein, by taking advantage of the ability of perfluorocarbon (PFC) to promote red blood cell penetration, we developed a simple but effective two-stage oxygen delivery strategy to modulate the hypoxic tumor microenvironment using PFC nanoparticles. Methods: We first examined the two-stage oxygen delivery ability of PFC nanoparticles on relieving tumor hypoxia through platelet inhibition. To evaluate the effect of PFC nanoparticles on radiation sensitization, CT26 tumor and SUM49PT tumor model were used. Results: In this study, PFC was encapsulated into albumin and intravenously injected into tumor-bearing mice without hyperoxic breathing. After accumulation in the tumor, PFC nanoparticles rapidly released the oxygen that was physically dissolved in PFC as the first-stage of oxygen delivery. Then, PFC subsequently promoted red blood cell infiltration, which further released O 2 as the second-stage of oxygen delivery. Conclusion: The hypoxic tumor microenvironment was rapidly relieved via two-stage oxygen delivery, effectively increasing radiotherapy efficacy. The safety of all substances used in this study has been clinically demonstrated, ensuring that this simple strategy could be rapidly and easily translated into clinical applications to solve the clinical problems associated with tumor hypoxia.
研究领域:
肿瘤学
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纳米技术
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放射生物学
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治疗学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Journal of Stroke & Cerebrovascular Diseases
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2021
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IF 2.136
Chaoqun Lin,Shiying Huang,Jianfeng Zhang,Huaitao Yuan,Tuchao Yao,Lukui Chen
Objective To assess the potential effect of dl-3-N-butylphthalide (dl-NBP) for the proliferation and differentiation of neural stem cells (NSCs) against hypoxia and the underlying mechanism. Materials and methods Hippocampal NSCs were obtained from fetal rats. NSCs combined with dl-NBP and single NSCs were cultured. The impact of siRNA-mediated hypoxia-inducible factor-1alpha (HIF-1α) knockdown on NSCs was detected with western blotting (WB) and quantitative real-time reverse transcription polymerase chain reaction (RT-qPCR). Cell-counting kit-8 assay was used for evaluating the viability of NSCs. Levels of HIF-1α protein were measured using WB, and vascular endothelial growth factor (VEGF) expression was quantified using RT-qPCR and enzyme-linked immunosorbent assay. Results Compared with 7 different concentrations of dl-NBP, 0.25 g/L was determined as the optimal concentration to significantly increase the viability of NSCs (p < 0.001). Dl-NBP can significantly increase the viability of hypoxic NSCs ( p < 0.001) and improve the differentiation of hypoxic NSCs into astrocytes ( p = 0.001) and oligodendrocytes ( p < 0.001). Meanwhile, Dl-NBP can significantly elevate levels of HIF-1α protein ( p < 0.001) and VEGF mRNA ( p = 0.001) / protein ( p < 0.001) in NSCs in the hypoxic environment. However, after transfection with HIF-1α siRNA in NSCs, the viability and differentiation of NSCs was not recovered using dl-NBP under the hypoxic condition, as well as levels of HIF-1α and VEGF. Conclusion Dl-NBP can reverse the weaker proliferation and differentiation power of NSCs in the hypoxic environment. The HIF-1α - VEGF pathway may be implicated in this protective effect of dl-NBP.
研究领域:
神经科学
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药理学
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细胞生物学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
ADVANCED FUNCTIONAL MATERIALS
·
2021
·Vol. 31
·期 42
·2104607
·
IF 18.808
Meng Qiu,Yanhong Duo,Weiyuan Liang,Yunlong Yang,Bin Zhang,Zhongjian Xie,Xiaoli Yang,Guiqing Wang,Ni Xie,Guohui Nie,Omar A. Alhartomy,Ahmed A. ALGhamdi,Swelm Wageh,Yihai Cao,Han Zhang
Most anticancer drugs with broad toxicities are systematically administrated to cancer patients and their distribution in tumors is extremely low owing to hypoxia, which compromises the therapeutic efficacies of these cancer drugs. Consequently, a preponderant proportion of cancer drugs is distributed in off-target-healthy tissues, which often causes severe adverse effects. Precision cancer therapy without overdosing patients with drugs remains one of the most challenging issues in cancer therapy. Here, a novel concept of nanopoxia is presented, which is a tumor-hypoxia-based photodynamic nanoplatform for the release of therapeutic agents to achieve precision cancer therapy. Under tumor hypoxia, exposure of tumors to laser irradiation induces the fracture of polymer outer shell and produces anticancer reactive oxygen species, and switches 2D antimonene (Sb) nanomaterials to cytotoxic trivalent antimony to synergistically kill tumors. In preclinical cancer models, delivery of Sb nanomaterials to mice virtually ablates tumor growth without producing any detectable adverse effects. Mechanistically, the tumor hypoxia-triggered generation of trivalent antimony displays direct damaging effects on cancer cells and suppression of tumor angiogenesis. Together, the study provides a proof-of-concept of hypoxia-based precision cancer therapy by developing a novel nanoplatform that offers multifarious mechanisms of cancer eradication.
研究领域:
肿瘤学
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纳米技术
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药学
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生物医学工程
✓ 已验证
DOI
高影响因子
JOURNAL OF CONTROLLED RELEASE
·
2025
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IF 11.5
Xinxin Xie,Jinxia Zhang,Lihong Sun,Shuyu Xu,Shiti Sha Ma,Haonan Wang,Xiaoda Li,Qiong Xiang,Ligang Cui,Xiaolong Liang
Hypoxia is a common feature of malignant tumors, which can accelerate tumor growth and reduce the sensitivity of chemotherapy and sonodynamic therapy by activating the hypoxia-inducible factor (HIF) signaling pathway. In HER2-positive gastric cancer, HER2 overexpression enhances HIF-1α synthesis, exacerbating hypoxia and impairing sonodynamic therapy. It also reduces trastuzumab-mediated antibody-dependent cytotoxicity, significantly compromising therapeutic outcomes. Herein, pyropheophorbide-conjugated lipid (pyropheophorbide-lipid, PL) and trastuzumab were fabricated into targeted nanoparticles (TP NPs) for loading perfluorobromooctane (PFOB) carrying oxygen (TPPO NPs), thus enabling oxygen self-supplied sonodynamic and antibody therapies. In vitro experiments showed that antibody targeting significantly increased the cellular uptake of sonosensitizers, and the controlled release of oxygen was dependent on ultrasound parameters, greatly enhancing the killing effects of SDT and antibody therapy. In vivo animal experiments showed that TPPO NPs-mediated enhanced permeation and retention (EPR) effects, along with antibody targeting, improved the enrichment of sonosensitizers in tumors. Notably, ultrasound-triggered topical delivery of oxygen significantly alleviated tumor hypoxia and further improved the efficacy of SDT and antibody therapy. Given the good biosafety profile of TPPO NPs, this system holds great promise for future clinical applications in gastric cancer.
研究领域:
肿瘤学
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药剂学
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生物医学工程
✓ 已验证
产品关联
DOI
PubMed
高影响因子
JOURNAL OF CONTROLLED RELEASE
·
2025
·
IF 11.5
Min Gao,Yue Song,Jing Liang,Tiantian Chen,Jiajia Luo,Panyu Du,Han Wang,Hongyu Leng,Zheng Wang,Xinlong Ma,Kai Wang,Yanjun Zhao
Concurrent induction of apoptosis and ferroptosis is promising in handling heterogenous cancers. We report a tailored polymeric micellar nanoplatform for the combinational anti-tumor therapy. Two stimuli-responsive amphiphlic block copolymers were synthesized, bearing three functional moieties, i.e. azobenzene, nitroimidazole and 3-fluorophenylboronic acid. Azobenzene could enhance the cellular uptake of micelles. Nitroimidazole and 3-fluorophenylboronic acid could deplete the reduced nicotinamide adenine dinucleotide phosphate (NADPH), glucose and adenosine triphosphate (ATP) under hypoxia, sensitizing ferroptotic and apoptotic cell death. The proof-of-concept was demonstrated in a triple-negative breast cancer cell line (MDA-MB-231). Irrespective of the free or encapsulated form, doxorubicin and auranofin showed a synergistic action, evidenced by a low combination index (< 1). The co-delivery micelles showed improved potency than the single drug-loaded micelles in terms of the biomarkers of apoptosis ( e.g. caspase 3/9, cytochrome c and ATP) and ferroptosis ( e.g. thioredoxin reductase, thioredoxin, glutathione, NADPH, malondialdehyde and lipid peroxides). The apoptosis and ferroptosis induction ability of cargo-free micelles was proved. The in vivo efficacy was verified in the MDA-MB 231 tumor-bearing nude mice model. The current work offers a promising strategy of combinational anti-tumor drug delivery for potent induction of ferroptosis and apoptosis via the sensitization effect of vehicle in the hypoxic tumor.
研究领域:
生物医学工程
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肿瘤学
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药剂学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Redox Biology
·
2025
·
IF 11.9
Zhanliang Jiang,Jin Li,Mingpeng Shi,Yunfei Li,Ning Sun,Kai Xi,Xiangyan Li,Daqing Zhao,Xiangyang Leng,Zhenwei Zhou,Haisi Dong
Aberrant changes in the hypoxic microenvironment are implicated in osteoarthritis (OA) development. Cuproptosis, a unique copper-dependent form of regulated cell death that depends on the activity of key enzymes in mitochondrial metabolism, is also linked to oxygen levels. However, the crosstalk among hypoxic environment, cuproptosis, and OA development remains unclear. This study confirmed that oxygen levels in the OA model gradually increased during OA progression, which suppressed the expression of anabolic genes for articular cartilage extracellular matrix, upregulated catabolic genes, and increased the cell death rate of primary chondrocytes. Mechanistically, oxygen elevation upregulated the expression of solute carrier family 31 member 1 (SCL31A1), a transmembrane pump facilitating copper uptake, whereas it downregulated the expression of ATPase copper transporting beta (ATP7B), a copper chaperone facilitating copper efflux, leading to aberrant copper accumulation in the cells. Ultimately, this accumulation efficiently induces oligomerization of dihydrolipoamide S-acetyltransferase (DLAT), triggering cell death, known as cuproptosis. Hypoxia-inducible factor-1α (HIF-1α), induced under hypoxic conditions, is negatively correlated with DLAT and the severity of OA, as confirmed in human and rat cartilage. Furthermore, siRNA-mediated HIF-1α silencing sensitized primary chondrocytes to cuproptosis, whereas HIF-1α stabilization had protective effects. In summary, increased oxygen levels in the cartilage induce cuproptosis, thereby accelerating OA progression, whereas HIF-1α stabilization mitigates this process. These findings may provide novel therapeutic targets for OA treatment in clinical practice.
研究领域:
分子生物学
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病理学
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细胞生物学
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生物医学
✓ 已验证
DOI
PubMed
高影响因子
Small
·
2024
·
IF 13
Quanliang Mao,Mengyin Gu,Chengyuan Hong,Huiying Wang,Xinzhong Ruan,Zhusheng Liu,Bo Yuan,Mengting Xu,Chen Dong,Lei Mou,Xiang Gao,Guangyu Tang,Tianxiang Chen,Aiguo Wu,Yuning Pan
Personalized radiotherapy strategies enabled by the construction of hypoxia-guided biological target volumes (BTVs) can overcome hypoxia-induced radioresistance by delivering high-dose radiotherapy to targeted hypoxic areas of the tumor. However, the construction of hypoxia-guided BTVs is difficult owing to lack of precise visualization of hypoxic areas. This study synthesizes a hypoxia-responsive T 1 , T 2 , T 2 mapping tri-modal MRI molecular nanoprobe (SPION@ND) and provides precise imaging of hypoxic tumor areas by utilizing the advantageous features of tri-modal magnetic resonance imaging (MRI). SPION@ND exhibits hypoxia-triggered dispersion-aggregation structural transformation. Dispersed SPION@ND can be used for routine clinical BTV construction using T 1 -contrast MRI. Conversely, aggregated SPION@ND can be used for tumor hypoxia imaging assessment using T 2 -contrast MRI. Moreover, by introducing T 2 mapping, this work designs a novel method (adjustable threshold-based hypoxia assessment) for the precise assessment of tumor hypoxia confidence area and hypoxia level. Eventually this work successfully obtains hypoxia tumor target and accurates hypoxia tumor target, and achieves a one-stop hypoxia-guided BTV construction. Compared to the positron emission tomography-based hypoxia assessment, SPION@ND provides a new method that allows safe and convenient imaging of hypoxic tumor areas in clinical settings.
研究领域:
医学影像
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放射学
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肿瘤学
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分子成像
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纳米技术
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Nature Communications
·
2023
·Vol. 14
·期 1
·1-13
·
IF 16.6
Guo Jian-Shuang,Li Juan-Juan,Wang Ze-Han,Liu Yang,Yue Yu-Xin,Li Hua-Bin,Zhao Xiu-He,Sun Yuan-Jun,Ding Ya-Hui,Ding Fei,Guo Dong-Sheng,Wang Liang,Chen Yue
The prognosis with pancreatic cancer is among the poorest of any human cancer. One of the important factors is the tumor hypoxia. Targeting tumor hypoxia is considered a desirable therapeutic option. However, it has not been translated into clinical success in the treatment of pancreatic cancer. With enhanced cytotoxicities against hypoxic pancreatic cancer cells, BE-43547A2 (BE) may serve as a promising template for hypoxia target strategy. Here, based on rational modification, a BE prodrug (NMP-BE) is encapsulated into sulfonated azocalix[5]arene (SAC5A) to generate a supramolecular dual hypoxia-responsive complex NMP-BE@SAC5A. Benefited from the selective load release within cancer cells, NMP-BE@SAC5A markedly suppresses tumor growth at low dose in pancreatic cancer cells xenograft murine model without developing systemic toxicity. This research presents a strategy for the modification of covalent compounds to achieve efficient delivery within tumors, a horizon for the realization of safe and reinforced hypoxia target therapy using a simple approach.
研究领域:
肿瘤学
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药学
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分子生物学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Nanomaterials
·
2020
·Vol. 10
·期 10
·2058
·
IF 4.324
Liang Hong,Artem M. Pliss,Ye Zhan,Wenhan Zheng,Jun Xia,Liwei Liu,Junle Qu,Paras N. Prasad
Sonodynamic therapy (SDT) has emerged as an important modality for cancer treatment. SDT utilizes ultrasound excitation, which overcomes the limitations of light penetration in deep tumors, as encountered by photodynamic therapy (PDT) which uses optical excitations. A comparative study of these modalities using the same sensitizer drug can provide an assessment of their effects. However, the efficiency of SDT and PDT is low in a hypoxic tumor environment, which limits their applications. In this study, we report a hierarchical nanoformulation which contains a Food and Drug Administration (FDA) approved sensitizer chlorin, e6, and a uniquely stable high loading capacity oxygen carrier, perfluoropolyether. This oxygen carrier possesses no measurable cytotoxicity. It delivers oxygen to overcome hypoxia, and at the same time, boosts the efficiency of both SDT and PDT. Moreover, we comparatively analyzed the efficiency of SDT and PDT for tumor treatment throughout the depth of the tissue. Our study demonstrates that the strengths of PDT and SDT could be combined into a single multifunctional nanoplatform, which works well in the hypoxia environment and overcomes the limitations of each modality. The combination of deep tissue penetration by ultrasound and high spatial activation by light for selective treatment of single cells will significantly enhance the scope for therapeutic applications.Keywords:photodynamic;sonodynamic;hypoxia;nanoemulsion;delivery;tumor
研究领域:
肿瘤学
·
药剂学
·
生物医学工程
✓ 已验证
DOI
PubMed
高影响因子
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