Acta Biomaterialia
·
2024
·
IF 9.4
Yajing Chi,Chaoqi Song,Qian Jia,Ruili Zhang,Fang Sun,Zheng Li,Yuanyuan Jia,Xian An,Zhongliang Wang,Jianxiong Li
Background: Chemodynamic therapy (CDT) has become increasingly important as a tumor treatment strategy, which relies on intracellular acid and hydrogen peroxide to kill tumor cells by generating hydroxyl radicals (·OH) through Fenton/Fenton-like reactions. However, the weakly alkaline intracellular environment considerably caused by the efflux of lactate and H + from glioblastoma cells is not conducive to CDT performance. Intracellular acidification induced by inhibiting the transmembrane monocarboxylate transporter 4 (MCT4) can enhance the therapeutic efficacy of CDT. Existing approaches suffer from insufficient MCT4 inhibition, involve complex drug synthesis, and have many unsatisfactory side effects. Methods: In this study, we constructed an anti-tumor nanoparticle formed by self-assembly driven by the coordination interaction of Fe 3+ and α-cyano-4-hydroxycinnamate (CHC) to avoid safety issues posed by excessive modification. Fe-CHC nanoparticles were designed to decrease intracellular pH through inhibition of MCT4, which transports lactate/H + to the extracellular space. The resulting intracellular accumulation of lactate and H + led to fatal acidosis and promoted ·OH generated by Fenton/Fenton-like reactions with the presence of the Fe 3+ , thus enhancing CDT-induced tumor cell death. Results: In vitro and in vivo results revealed that Fe-CHC exerted a significant synergistic anti-tumor effect by re-establishing acidosis and enhancing CDT in glioblastoma. Furthermore, the decreased H + outside the cells caused by the inhibition of lactate/H + efflux hindered extracellular matrix degradation, thereby inhibiting tumor metastasis. Conclusion: Fe-CHC is an effective anti-cancer agent against glioblastoma. This study provides valuable insights for developing acid-modulating anti-tumor nanoparticles, as well as enriching and optimizing the application of CDT in tumor therapy. Statement of Significance Our study pioneers the Fe-CHC nanoparticle, a metal-coordination polymer that targets MCT4 in glioblastoma cells to restore intracellular acidity and synergize with Fe 3+ to boost chemodynamic therapy (CDT). Unlike other studies, Fe 3+ and CHC work together to maximize the therapeutic potential and safety of Fe-CHC with minimal complexity. This innovative approach not only increased the production of reactive oxygen species within tumor cells, but also hindered tumor metastasis. Our work has important scientific implications for tumor microenvironment regulation and the application of CDT, and will provide a promising pathway for the treatment of aggressive cancers and attract a wide audience through its scientific implications.
研究领域:
肿瘤学
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纳米医学
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生物化学
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DOI
PubMed
高影响因子
Small
·
2021
·Vol. 17
·期 47
·2102269
·
IF 13.281
Xuan Wang,Yuanyuan Zhao,Yan Hu,Yang Fei,Youbo Zhao,Chencheng Xue,Kaiyong Cai,Menghuan Li,Zhong Luo
Ferroptosis is a new form of regulated cell death with significant therapeutic prospect, but its application against drug-resistant tumor cells is challenging due to their ability to effuse antitumor agents via p-glycoprotein (P-gp) and anti-lipid peroxidation alkaline intracellular environment. Herein, an amorphous calcium phosphate (ACP)-based nanoplatform is reported for the targeted combinational ferroptosis/apoptosis therapy of drug resistant tumor cells by blocking the MCT4-mediated efflux of lactic acid (LA). The nanoplatform is fabricated through the biomineralization of doxorubicin-Fe 2+ (DOX-Fe 2+ ) complex and MCT4-inhibiting siRNAs (siMCT4) and can release them to the tumor cytoplasm after the hydrolysis of ACP and dissociation of DOX-Fe 2+ in the acidic lysosomes. siMCT4 can inhibit MCT4 expression and force the glycolysis-generated lactic acid (LA) to remain in cytoplasm for rapid acidification. The nanoplatform-induced remodeling of the tumor intracellular environment can not only interrupt the ATP supply required for P-gp-dependent DOX effusion to enhance H 2 O 2 production, but also increase the overall catalytic efficiency of Fe 2+ for the initiation and propagation of lipid peroxidation. These features could act in concert to enhance the efficacy of the combinational ferroptosis/chemotherapy and prolong the survival of tumor-bearing mice. This study may provide new avenues for the treatment of multidrug-resistant tumors.
研究领域:
生物医学工程
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肿瘤学
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纳米医学
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产品关联
DOI
PubMed
高影响因子
Small
·
2021
·Vol. 17
·期 20
·2100130
·
IF 13.281
Xuan Wang,Youbo Zhao,Lei Shi,Yan Hu,Guanbin Song,Kaiyong Cai,Menghuan Li,Zhong Luo
Nanocatalytic tumor therapy is an emerging antitumor option that employs catalytically-active inorganic nanostructures to produce tumor-damaging reactive oxygen species. However, initiation of nanocatalytic reactions in the tumor intracellular environment is a challenge due to the reliance on acidic pH. By exploiting the pH-selective multifaceted catalytic activities of Prussian blue-based nanomaterials (PBNM) as well as the hyperglycolysis characteristics of tumors, it is demonstrated that blocking the monocarboxylate transporter 4 (MCT4)-mediated lactate effusion in tumor cells can reverse the pH gradient across the tumor cell membrane and cause rapid intracellular acidification as well as neutralization of the extracellular compartment, thus creating vulnerabilities for PBNM-based nanocatalytic therapies in situ while suppressing tumor stemness/metastasis in vivo. For this purpose, MCT4-inhibiting siRNAs are incorporated into reactivity-switchable PBNM-based nanocatalysts to initiate hydroxyl radical production. Meanwhile, β-lapachone, a clinically-approved drug with H 2 O 2 -generating capabilities, is also integrated to sustain the nanocatalytic process. In contrast, the nanocatalyst shows no apparent toxicity to normal cells due to its catalase-like activities under neutral pH. This treatment strategy can inhibit tumor growth in mice at optimal safety as well as to suppress the cancer cell stemness and lung metastasis, suggesting the clinical translational potential of the findings.
研究领域:
肿瘤学
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纳米医学
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催化
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生物化学
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产品关联
DOI
PubMed
高影响因子
Small
·
2024
·
IF 13
Yang Liu,Hui Li,Yan-Yun Hao,Ling-Ling Huang,Xia Li,Jing Zou,Shi-Ying Zhang,Xiao-Yue Yang,Hong-Fei Chen,Yi-Xuan Guo,Yun-Yan Guan,Zhi-Yue Zhang
The development of tumors relies on lactate metabolic reprogramming to facilitate their unchecked growth and evade immune surveillance. This poses a significant challenge to the efficacy of antitumor immunity. To address this, a tumor-selective nano-dispatcher, PIMDQ/Syro-RNP, to enforce the immunotherapeutic effect through regulation of lactate metabolism and activation of toll-like receptors is developed. By using the tumor-targeting properties of c-RGD, the system can effectively deliver monocarboxylate transporters 4 (MCT4) inhibitor (Syro) to inhibit lactate efflux in tumor cells, leading to decreased lactate levels in the tumor microenvironment (TME) and increased accumulation within tumor cells. The reduction of lactate in TME will reduce the nutritional support for regulatory T cells (Tregs) and promote the effector function of T cells. The accumulation of lactate in tumor cells will lead to tumor death due to cellular acidosis. In addition, it will also reduce the uptake of glucose by tumor cells, reduce nutrient plunder, and further weaken the inhibition of T cell function. Furthermore, the pH-responsive release of Toll-like receptors (TLR) 7/8 agonist IMDQ within the TME activates dendritic cells (DCs) and promotes the infiltration of T cells. These findings offer a promising approach for enhancing tumor immune response through targeted metabolic interventions.
研究领域:
癌症生物学
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免疫学
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纳米技术
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代谢工程
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产品关联
DOI
PubMed
高影响因子
BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS
·
2024
·
IF 2.5
Jie Shen,Zhongkai Wu,Yu Zhou,Dashuai Yang,Xin Wang,Bin Yu,Kailiang Zhao,Youming Ding
SLC16A3/monocarboxylate transporter 4 (MCT4) regulates intracellular lactate transport and is highly expressed in many tumors, indicating poor prognosis. It may be related to inducing hypoxia, apoptosis and other mechanisms, but the study of MCT4 in HCC is far from complete. In this study, we first analyzed the expression of SLC16A3 in HCC tumor and non-tumor tissue samples based on TCGA data and immunohistochemistry. Subsequently, the effects of SLC16A3 expression on cell proliferation and invasion were analyzed using hepatocellular carcinoma (HCC) lines, and Western blot (WB) analysis was performed to explore the changes in pathway proteins and ferroptosis proteins. Finally, the drug sensitivity was tested by CCK8 kit. We found that SLC16A3 was significantly upregulated in tumor tissues, and was significantly correlated with TNM stage, histological grade, and macrovascular invasion. TCGA data and WB analysis showed that the high expression of SLC16A3 induced hypoxia, and knockdown could reverse hypoxia and inhibit ERK phosphorylation, thus limiting the malignant behavior of HCC cells. Moreover, knockdown of SLC16A3 significantly increased the level of lipid peroxidation and reactive oxygen species (ROS), while the expressions of GPX4, DHODH and SLC7A11 were inhibited. The expression of SLC16A3 affected the sensitivity of HCC cells to chemotherapy and targeted drugs, and RNA sequencing data suggested that the expression level influenced tumor microenvironment and response to immunotherapy. So, we draw a conclude that SLC16A3 is associated with poor prognosis of HCC. Inhibition of SLC16A3 expression is a potential therapeutic target for HCC.
研究领域:
肿瘤学
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分子生物学
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细胞生物学
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癌症生物学
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DOI
PubMed
高影响因子
Nano Today
·
2023
·
IF 17.4
Hong Chen,Pingyu Wu,Zhenzhen Xiao,Ting Li,Minjuan Zhong,Yuqi Xie,Yanlan Liu
Chemodynamic therapy (CDT) has sparked increasing interest in selective cancer treatment. However, it remains a challenge to achieve an efficient and sustained therapeutic effect due to the restricted Fenton chemistry and deficient catalytic substrates within the tumor microenvironment (TME). Meanwhile, the lack of strategies to timely monitor the delivery and execution of CDT agents increases the risks of unwanted side effects. Here, we present that integration of TME-triggered cascade catalysis with tumor metabolism reprogramming to engineer activatable theranostic nanocatalysts is an effective way to tackle these challenges. A self-fueling and self-reported theranostic nanocatalyst is reported in this study by modifying multi-enzyme mimic MnO 2 nanosturctures with antisense oligonucleotides (ASO). This catalyst can produce free radicals through logic multi-enzymatic catalysis to induce oxidative damage to cancer cells, yet keeping inert in normal cells. Furthermore, the loaded ASO can silence MCT4 that overexpresses in tumor cells, resulting in efflux blockage of intracellular lactate and decrease of intracellular pH , which remarkably facilitates the cascade catalysis for amplified CDT. Meanwhile, such acidification triggers an MRI enhancement for reporting gene silencing. Results from in vivo testing further support the potential of our design for more effective CDT. This study offers different insights into the design and construction of advanced platforms for noninvasive imaging-guided treatment of a wide range of cancers.
研究领域:
癌症治疗
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纳米技术
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生物医学工程
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分子生物学
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医学成像
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产品关联
DOI
高影响因子
CHEMICAL ENGINEERING JOURNAL
·
2023
·
IF 15.1
Qing Yao,Jinyao Ye,Yahui Chen,Lihui Huang,Lining Sun,Zhinan He,Jianing Wu,Yingyi Zhao,Xinyu Zhao,Aimin Cai,Xiandan Chen,Hailun Zheng,Aliaksei Sysa,Congying Xie,Ruijie Chen,Longfa Kou
The clinical presentation of triple-negative breast cancer signifies a pathophysiological trajectory characterized by an aggressive nature. To satisfy the rapid tumor cell proliferation, glycolysis emerges as the primary modality for energy production, consequently engendering the copious generation of lactic acid. This, in turn, fosters an acidic microenvironment within the tumor milieu, which facilitates angiogenesis, tumor metastasis, extracellular matrix remodeling, and immune evasion. If the glycolytic flux was attenuated, a heightened influx of glucose-6-phosphate (G6P) towards the pentose phosphate pathway (PPP) ensues, promoting the synthesis of nicotinamide adenine dinucleotide phosphate (NADPH) and reduced glutathione (GSH). This orchestrated metabolic cascade gives rise to reductive equivalents and biosynthetic substrates, emblematic of a salient hallmark in the landscape of cancer cell metabolism. To surmount the quandary presented by aberrant tumor metabolism, we developed macrophage-membrane-coated metal–organic framework nanoparticles (AP@ZIF-Mem) to deliver atorvastatin (an inhibitor of MCT4, a lactic acid transporter within glycolysis) and polydatin (an inhibitor of G6PD, the rate-limiting enzyme of PPP) to interfere the glucose metabolism for sensitizing triple-negative breast cancer treatment. After i.v. injection, AP@ZIF-Mem could be accumulated into the tumor site via macrophage-biomimetic behavior. Through orchestrated intervention, these nanoparticles could provoke the accumulation of lactic acid within tumor cells, thereby precipitating a pronounced intratumoral acidosis; In parallel, the abrogation of G6PD function occasioned a surge in intracellular reactive oxygen species (ROS), consequentially culminating in diminished ribulose-5-phosphate and NADPH production. This dual-pronged intervention not only disrupted the tumor's energy provisioning framework but also perturbed the aberrant redox state of the tumor milieu, thereby sensitizing tumor treatment and impeding the metastatic trajectory. This study provided a paradigm of treatment/adjuvant treatment via the manipulation of glucose metabolism for triple-negative breast cancer.
研究领域:
肿瘤学
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药学
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纳米技术
·
癌症代谢
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药物递送系统
✓ 已验证
产品关联
DOI
高影响因子
危险品化学品经营许可证（带存储）