Biomaterials Science
·
2023
·Vol. 11
·期 14
·4890-4906
·
IF 6.6
Jianhao Liu,Xiaoman Xu,Yanying Li,Jingxia Xu,Ruogang Zhao,Siwei Liu,Jingliang Wu,Li Zhang,Bo Zhang
Comprehensively regulating the TME is now regarded as a promising approach for cancer treatment. Herein, a novel “three-in-one” effect is presented for simultaneously killing tumor cells, inhibiting the EMT of CAFs, and improving immune responses. In this study, bortezomib (BTZ) is selected for the treatment of breast cancer; it has multiple pharmacological mechanisms for killing tumor cells through the NF-κB signaling pathway, inhibiting the activity of CAFs by activating caspase-3, and enhancing the function of CD8+ T cells by regulating the expression of immune-stimulating factors. To improve the druggability of BTZ in solid tumors, BTZ-loaded lipid/glycocholic acid mixed micelles (BTZ-LGs) were prepared to verify the “three-in-one” effect in killing tumor cells, inhibiting CAFs, and improving immune responses. In the present work, BTZ-LGs were verified to show enhanced in vitro cytotoxicity in both 4T1 cells and 4T1/NIH3T3 co-cultured cells, as well as a superior in vivo treatment effect in different tumor-bearing mouse models. Additionally, BTZ-LGs could regulate the expression of α-SMA, caspase-3, E-cadherin, and N-cadherin, indicating their good inhibiting ability on both tumor cells and CAFs. More importantly, immunological analysis revealed that BTZ-LGs promoted the expression of the immunostimulatory factor IL-2 in tumor tissues, activated anti-tumor T cells, and overcame tumor-induced CD8+ T cell dysfunction. All these findings suggest that BTZ-LGs can achieve a “three-in-one” effect in terms of killing tumor cells, suppressing CAFs, and improving immune responses. This simple and multi-effective therapeutic strategy offers a promising approach for cancer therapy.
研究领域:
癌症治疗
·
药学
·
免疫学
·
细胞生物学
·
分子生物学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Cell Reports
·
2023
·
IF 8.8
Yingqi Liu,Xuemei Yao,Youbo Zhao,De Fang,Lei Shi,Li Yang,Guanbin Song,Kaiyong Cai,Liqi Li,Qin Deng,Menghuan Li,Zhong Luo
The tumor microenvironment (TME) plays decisive roles in disabling T cell-mediated antitumor immunity, but the immunoregulatory functions of its biophysical properties remain elusive. Extracellular matrix (ECM) stiffening is a hallmark of solid tumors. Here, we report that the stiffened ECM contributes to the immunosuppression in TME via activating the Rho-associated coiled-coil-containing protein kinase (ROCK)-myosin IIA-filamentous actin (F-actin) mechanosignaling pathway in tumor cells to promote the generation of TRIM14-scavenging nonmuscle myosin heavy chain IIA (NMHC-IIA)-F-actin stress fibers, thus accelerating the autophagic degradation of cyclic guanosine monophosphate (GMP)-AMP synthase (cGAS) to deprive tumor cyclic GMP-AMP (cGAMP) and further attenuating tumor immunogenicity. Pharmacological inhibition of myosin IIA effector molecules with blebbistatin (BLEB) or the RhoA upstream regulator of this pathway with simvastatin (SIM) restored tumor-intrinsic cGAS-mediated cGAMP production and enhanced antitumor immunity. Our work identifies that ECM stiffness is an important biophysical cue to regulate tumor immunogenicity via the ROCK-myosin IIA-F-actin axis and that inhibiting this mechanosignaling pathway could boost immunotherapeutic efficacy for effective solid tumor treatment.
研究领域:
癌症生物学
·
免疫学
·
细胞生物学
·
生物物理学
✓ 已验证
DOI
PubMed
高影响因子
CHEMICAL ENGINEERING JOURNAL
·
2021
·
IF 13.273
Xiangyu Meng,Kaiying Jia,Kai Sun,Liming Zhang,Zhifei Wang
Smart responsive nanomedicines serving as carriers can take advantage of the specific tumor microenvironment (TME) to convert non-toxic drugs into effective anticarcinogens and release chemotherapeutic drugs in situ to improve therapeutic efficiency against tumors without inducing off-target toxicity to surrounding normal tissues/cells. Herein, a pH-responsive metal-organic framework nanoparticle is constructed by encapsulating disulfiram (DSF) and doxorubicin (DOX) into the zeolitic imidazolate framework-8 (ZIF-8) and then coating with copper ion (Cu 2+ )-tannic acid (TA) complex (denoted as DSF/ [email protected] @Cu-TA) to achieve enhanced combination chemotherapy. The release of Cu 2+ from the outer shell of DSF/ [email protected] @Cu-TA and the cooperative exposure of DSF and DOX are triggered at multiple stages by mild acidity TME. The accumulation of DSF (non-toxic drugs) and Cu 2+ results in the rapid formation of high cytotoxic bis(N, N-diethyl dithiocarbamato)-Cu 2+ complexes (CuL 2 ) in situ via DSF and Cu 2+ chelating reaction, which accompany the production of ROS via Cu + -based Fenton-like reaction. Besides, the anticancer effect of DOX is augmented by CuL 2 -modulated ROS-MAPK and NF-κB signal pathways. The constructed DSF/ [email protected] @Cu-TA present significantly improved therapeutic efficiency as demonstrated both in vitro and in vivo . The strategy of nontoxicity-to-toxicity transitions with the addictive effect of chemotherapeutics provides a promising paradigm to design novel nanoplatforms for synergistic cancer chemotherapy.
研究领域:
纳米技术
·
癌症研究
·
药学
·
化疗
✓ 已验证
产品关联
DOI
高影响因子
CHINESE JOURNAL OF CHEMISTRY
·
2024
·
IF 5.5
Junfeng Ding,Tianran Wang,Yan Rong,Chaoliang He,Xuesi Chen
Comprehensive Summary Due to the immunosuppressive tumor microenvironment (TME), T cells are usually inactivated and tend to differentiate into regulatory T cells (Tregs) in the tumor tissues, which seriously hinders the anti-tumor efficiency of immunotherapy. In this study, an immune-stimulating polypeptide hydrogel conjugated with an indoleamine-2,3-dioxygenase (IDO) inhibitor, 1-methyl- D -tryptophan (D1MT), through a glutathione (GSH)-responsive spacer was developed as an immunotherapy platform capable of regulating the TME. A combined immunotherapy system was further constructed through encapsulating doxorubicin (Dox) and immune checkpoint blocking antibody targeting programmed cell death protein 1 (aPD-1) in the hydrogel. Dox released from the hydrogel could cause the immunogenic cell death (ICD) of tumor cells and induce the maturation of antigen presenting cells (APCs). After intratumoral injection, the multiple agent-loaded hydrogel elicited effective anti-tumor immunity in mice bearing B16F10 melanoma. Moreover, compared with the control hydrogel without D1MT, the immune-stimulating hydrogel showed better efficiency in improving the immunosuppressive TME with increased number of activated T cells and reduced number of Tregs. Therefore, the immune-stimulating hydrogel has great potential as a stimuli-responsive platform for regulating suppressive TME and enhanced anti-tumor chemo-immunotherapy.
研究领域:
癌症免疫疗法
·
药学
·
生物医学工程
·
免疫学
·
肿瘤学
✓ 已验证
产品关联
DOI
高影响因子
Nano Today
·
2023
·
IF 17.4
Nan Wang,Pin Li,Jing Zhao,Yamin Liu,Xi Hu,Daishun Ling,Fangyuan Li
Photoimmunotherapy, which not only directly kills tumor cells but also elicits antitumor immune responses by inducing immunogenic cell death (ICD), has emerged as a promising approach for cancer treatment. However, the hypoxic immunosuppressive tumor microenvironment (TME) with limited immune response immensely compromises the therapeutic outcomes. Herein, an end-deposited plasmonic catalyst (GCNRs) is developed by selectively depositing semiconducting ceria nanosheets onto the two ends of gold nanorods for plasmonic catalysis-mediated TME modulation. Specially, an efficient low-power near-infrared-triggered electron-hole spatial separation along the longitudinal axis of GCNRs occurs due to the end-deposition morphology. The generated hot electrons and hot holes separately participate in the reactive oxygen species (ROS) generation and oxygen-evolution half-reaction, thereby modulating the immunosuppressive TME via concurrent ROS-mediated ICD-induction and H 2 O 2 -independent hypoxia relief. Unprecedentedly, mere injection of GCNRs can induce significant infiltration of cytotoxic T cells into tumor tissues, significantly inhibiting the growth and metastasis of tumors. Our study represents a promising plasmonic catalysis-mediated TME modulation strategy in phototherapy-based immuno-oncology.
研究领域:
癌症治疗
·
免疫学
·
纳米技术
·
光催化
·
肿瘤学
✓ 已验证
产品关联
DOI
高影响因子
Biomaterials Science
·
2023
·
IF 6.6
Muse Ji,Hongbing Liu,Hanxun Wang,Xinxin Liang,Mingli Wei,Dongmei Shi,Jingxin Gou,Tian Yin,Haibing He,Xing Tang,Yu Zhang
Chemodynamic therapy (CDT) is an emerging oncological treatment that can kill tumor cells by generating lethal hydroxyl radical (•OH) via Fenton or Fenton-like reaction inside tumors. However, the overexpression of glutathione (GSH) and low reaction efficiency in the tumor microenvironment (TME) limited the therapeutic efficacy of CDTs. Herein, CDT agents (Cu2+) and chemotherapeutic agent (Axitinib, AXB) were employed to fabricate a novel pH-activatable metal ion-drug coordinated nanoparticles (Cu-AXB NPs) for enhancing the treatment of tumors. The obtained nanoparticles exhibited ultrahigh drug loading capacity of 87.55% and had an average size of 180 nm. Moreover, the characteristics of excellent plasma stability and pH-responsive drug release contribute to the long circulation in the blood and targeted therapy at the weakly acidic tumor site. The released AXB could play a chemotherapeutic role in killing tumor cells and Cu2+ ion could be reduced to Cu+ by GSH, further generating toxic •OH with hydrogen peroxide (H2O2) for CDT through Fenton-like reaction. Cu-AXB NPs could also efficiently break copper metabolic balances and increase the intracellular Cu content, thus amplifying CDT. In vitro research results of cytotoxicity and apoptosis confirmed the optimal tumor cell killing efficacy of the Cu-AXB NPs, which was attributed to the synergistic effect of CDT with chemotherapy. What is more, Cu-AXB NPs exhibited good tumor targeting and potent tumor inhibition effect (77.53% inhibition), while exhibiting good biocompatibility in tumor bearing mice. In conclusion, this work provided a promising strategy for safe and efficient cancer therapy through the combination of CDT with chemotherapy.
研究领域:
癌症治疗
·
纳米技术
·
药学
·
生物医学工程
✓ 已验证
产品关联
DOI
PubMed
高影响因子
JOURNAL OF MEDICINAL CHEMISTRY
·
2024
·
IF 6.8
Yan Chen,Ming Zhang,Zhifang Liu,Ning Zhang,Qingpeng Wang
Tumor microenvironment (TME) is a pivotal factor driving the tumor metastasis and leading to the failure of tumor therapy. Here, a series of ursodeoxycholic acid platinum(IV) conjugates with potency in remodeling the TME through suppressing JAK2/STAT3 signaling was developed. A candidate was screened out, which displayed potent antiproliferative and antimetastatic performance both in vitro and in vivo. It displayed superior pharmacokinetic properties compared to cisplatin. Serious DNA injury was induced, and then mitochondria-mediated apoptosis was initiated through the Bcl-2/Bax/Caspase3 pathway. The JAK2/STAT3 and TGF-β1 signaling pathways were remarkably inhibited, and pro-death autophagy was subsequently promoted. The inflammatory and hypoxic TME was suppressed by downregulating COX-2, MMP9, and HIF-1α, which resulted in inhibited angiogenesis in tumors by inhibiting the HIF-1α/VEGFA axis. Additionally, the immunosuppressive TME was reversed by blocking the immune checkpoint PD-L1, further improving the density of CD3+ and CD8+ tumor-infiltrating lymphocytes, and promoting macrophage polarization from M2- to M1-type.
研究领域:
肿瘤学
·
药理学
·
分子生物学
·
癌症治疗
✓ 已验证
DOI
PubMed
高影响因子
Journal of Materials Chemistry B
·
2024
·
IF 6.1
Dengyue Chen,Jieli Yin,Chen Liu,Jiaqi Guo,Mao Li,Baoyin Chen,Xuewen Zhang,Bing Wang,Xuan Zhu
Both chemodynamic therapy and photodynamic therapy, based on the production of reactive oxygen (ROS), have excellent potential in cancer therapy. However, the abnormal redox homeostasis in tumor cells, especially the overexpressed glutathione (GSH) could scavenge ROS and reduce the anti-tumor efficiency. Therefore, it is essential to develop a simple and effective tumor-specific drug delivery system for modulating the tumor microenvironment (TME) and achieving synergistic therapy at the tumor site. In this study, self-assembled nanoparticles (named CDZP NPs) were developed by copper ion (Cu2+), Doxorubicin (Dox), Zinc phthalocyanine (ZnPc) and a trace amount of poly (2-(di-methylamino) ethylmethacrylate)-poly [(R)-3-hydroxybutyrate]-poly (2-(dimethylamino) ethylmethacrylate (PDMAEMA-PHB-PDMAEMA) through chelation, π-π stacking and hydrophobic interaction. This triple factors-responsive (pH, laser and GSH) nanoparticles demonstrated unique advantages through the synergistic effect. Highly controllable drug release ensured its effectiveness at the tumor site, Dox-induced chemotherapy and ZnPc-mediated fluorescence (FL) imaging exhibited the distribution of nanoparticles. Meanwhile, Cu2+-mediated GSH-consumption not only reduced the intracellular ROS elimination but also produced Cu+ to catalyze hydrogen peroxide (H2O2) and generated hydroxyl radical (∙OH), thereby enhancing chemodynamic and photodynamic therapy. Herein, this study provided a green and relatively simple method for preparing multifunctional nanoparticles that can effectively modulate the TME and improve synergetic cancer therapy.
研究领域:
纳米技术
·
癌症治疗
·
药物递送系统
·
肿瘤微环境
·
活性氧
·
协同治疗
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Asian Journal of Pharmaceutical Sciences
·
2024
·
IF 10.7
Xiaoju Guo,Xiaoxiao Chen,Jiayi Ding,Feng Zhang,Shunyang Chen,Xin Hu,Shiji Fang,Lin Shen,Chenying Lu,Zhongwei Zhao,Jianfei Tu,Gaofeng Shu,Minjiang Chen,Jiansong Ji
Chemotherapy plays a crucial role in triple-negative breast cancer (TNBC) treatment as it not only directly kills cancer cells but also induces immunogenic cell death. However, the chemotherapeutic efficacy was strongly restricted by the acidic and hypoxic tumor environment. Herein, we have successfully formulated PLGA-based nanoparticles concurrently loaded with doxorubicin (DOX), hemoglobin (Hb) and CaCO 3 by a CaCO 3 -assisted emulsion method, aiming at the effective treatment of TNBC. We found that the obtained nanomedicine (DHCaNPs) exhibited effective drug encapsulation and pH-responsive drug release behavior. Moreover, DHCaNPs demonstrated robust capabilities in neutralizing protons and oxygen transport. Consequently, DHCaNPs could not only serve as oxygen nanoshuttles to attenuate tumor hypoxia but also neutralize the acidic tumor microenvironment (TME) by depleting lactic acid, thereby effectively overcoming the resistance to chemotherapy. Furthermore, DHCaNPs demonstrated a notable ability to enhance antitumor immune responses by increasing the frequency of tumor-infiltrating effector lymphocytes and reducing the frequency of various immune-suppressive cells, therefore exhibiting a superior efficacy in suppressing tumor growth and metastasis when combined with anti-PD-L1 (αPD-L1) immunotherapy. In summary, this study highlights that DHCaNPs could effectively attenuate the acidic and hypoxic TME, offering a promising strategy to figure out an enhanced chemo-immunotherapy to benefit TNBC patients.
研究领域:
肿瘤学
·
药理学
·
纳米技术
·
免疫疗法
✓ 已验证
产品关联
DOI
PubMed
高影响因子
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