Acta Pharmaceutica Sinica B
·
2024
·
IF 14.7
Qiuxia Peng,Xiaolong Li,Chao Fang,Chunyan Zhu,Taixia Wang,Binxu Yin,Xiulin Dong,Huaijuan Guo,Yang Liu,Kun Zhang
Homeostasis and energy and substance metabolism reprogramming shape various tumor microenvironment to sustain cancer stemness, self-plasticity and treatment resistance. Aiming at them, a lipid-based pharmaceutical loaded with CaO 2 and glucose oxidase (GOx) (LipoCaO 2 /GOx, LCG) has been obtained to disrupt calcium homeostasis and interfere with glycometabolism. The loaded GOx can decompose glucose into H 2 O 2 and gluconic acid, thus competing with anaerobic glycolysis to hamper lactic acid (LA) secretion. The obtained gluconic acid further deprives CaO 2 to produce H 2 O 2 and release Ca 2+ , disrupting Ca 2+ homeostasis, which synergizes with GOx-mediated glycometabolism interference to deplete glutathione (GSH) and yield reactive oxygen species (ROS). Systematical experiments reveal that these sequential multifaceted events unlocked by Ca 2+ homeostasis disruption and glycometabolism interference, ROS production and LA inhibition, successfully enhance cancer immunogenic deaths of breast cancer cells, hamper regulatory T cells (Tregs) infiltration and promote CD8 + T recruitment, which receives a considerably-inhibited outcome against breast cancer progression. Collectively, this calcium homeostasis disruption glycometabolism interference strategy effectively combines ion interference therapy with starvation therapy to eventually evoke an effective anti-tumor immune environment, which represents in the field of biomedical research.
研究领域:
肿瘤学
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药学
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免疫学
·
生物医学工程
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产品关联
DOI
高影响因子
JOURNAL OF NUTRITIONAL BIOCHEMISTRY
·
2024
·
IF 4.8
Li-Li Zhang,Jia-Ying Xu,Wei Wei,Zhi-Qiang Hu,Yan Zhou,Jia-Yang Zheng,Yu Sha,Lin Zhao,Jing Yang,Qi Sun,Li-Qiang Qin
Background Radiation injury to the intestine is one of the most common complications in patients undergoing abdominal or pelvic cavity radiotherapy, limiting the clinical application of this treatment. Evidence shows the potential benefits of dietary restriction in improving metabolic profiles and age-related diseases. The present study investigated the effects and mechanisms of dietary restriction in radiation-induced intestinal injury. Methods The mice were randomly divided into the control group, 10 Gy total abdominal irradiation (TAI) group, and groups pretreated with 30% caloric restriction (CR) for 7 days or 24h fasting before TAI. After radiation, the mice were returned to ad libitum. The mice were sacrificed 3.5 days after radiation, and tissue samples were collected. Results CR and fasting reduced radiation-induced intestinal damage and promoted intestinal recovery by restoring the shortened colon length, improving the impaired intestinal structure and permeability, and remodeling gut microbial structure. CR and fasting also significantly reduced mitochondrial damage and DNA damage, which in turn reduced activation of the cyclic GMP-AMP synthase/stimulator of interferon gene (cGAS/STING) pathway and the production of type I interferon and other chemokines in the jejunum. Since the cGAS/STING pathway is linked with innate immunity, we further showed that CR and fasting induced polarization to immunosuppressive M2 macrophage, decreased CD8 + cytotoxic T lymphocytes, and downregulated proinflammatory factors in the jejunum. Conclusions Our findings indicated that CR and fasting alleviate radiation-induced intestinal damage by reducing cGAS/STING-mediated harmful immune responses.
研究领域:
放射生物学
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免疫学
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胃肠病学
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营养学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Acta Pharmaceutica Sinica B
·
2024
·
IF 14.7
Chongzheng Yan,Ying Liu,Guozhi Zhao,Huatian Yang,Huaiyou Lv,Genju Li,Yuhan Li,Yaqing Fu,Fengqin Sun,Yafei Feng,Yizhe Li,Zhongxi Zhao
Cuproptosis shows enormous application prospects in lung metastasis treatment. However, the glycolysis, Cu + efflux mechanisms, and insufficient lung drug accumulation severely restrict cuproptosis efficacy. Herein, an inhalable poly(2-( N -oxide- N , N -diethylamino)ethyl methacrylate) (OPDEA)-coated copper-based metal–organic framework encapsulating pyruvate dehydrogenase kinase 1 siRNA (siPDK) is constructed for mediating cuproptosis and subsequently promoting lung metastasis immunotherapy, namely OMP. After inhalation, OMP shows highly efficient lung accumulation and long-term retention, ascribing to the OPDEA-mediated pulmonary mucosa penetration. Within tumor cells, OMP is degraded to release Cu 2+ under acidic condition, which will be reduced to toxic Cu + to induce cuproptosis under glutathione (GSH) regulation. Meanwhile, siPDK released from OMP inhibits intracellular glycolysis and adenosine-5ʹ-triphosphate (ATP) production, then blocking the Cu + efflux protein ATP7B, thereby rendering tumor cells more sensitive to OMP-mediated cuproptosis. Moreover, OMP-mediated cuproptosis triggers immunogenic cell death (ICD) to promote dendritic cells (DCs) maturation and CD8 + T cells infiltration. Notably, OMP-induced cuproptosis up-regulates membrane-associated programmed cell death-ligand 1 (PD-L1) expression and induces soluble PD-L1 secretion, and thus synergizes with anti-PD-L1 antibodies (aPD-L1) to reprogram immunosuppressive tumor microenvironment, finally yielding improved immunotherapy efficacy. Overall, OMP may serve as an efficient inhalable nanoplatform and afford preferable efficacy against lung metastasis through inducing cuproptosis and combining with aPD-L1.
研究领域:
肿瘤学
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药学
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免疫学
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纳米技术
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分子生物学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Nano Today
·
2024
·
IF 13.2
Yanjie Han,Haifeng Lu,Zikuan Gu,Peixin Guan,Zhen Liu
In situ reprogramming of tumor associated macrophages (TAMs) to resurge their phagocytic ability holds great potential in cancer treatment. However, most of currently existing TAMs-reshaping approaches fail to effectively reprogram TAMs due to low efficiency, poor specificity, and potential immune side effects. Herein, we report a strategy called molecularly imprinted lysosomal nanodegrader (MILND) for resurging the phagocytosis of macrophages and reversing the "don't eat me" CD47-SIRPα signal via degrading SIRPα in lysosomes. The MILND, which was rationally engineered by controllable molecular imprinting using the N-terminal epitope of SIRPα as template, could specifically bind SIPRα on TAMs. Upon being engulfed by TAMs via endocytosis, the MILND-SIRPα complex was transferred to lysosomes for degradation. The degradation of SIRPα induced a cascade reaction of the downstream PI3K signaling pathway to resurging the phagocytic and recognition capability of TAMs towards cancer cells. Ultimately, MILND resulted in a subsequent series of anti-tumor effects. Benefiting from this, MILND effectively sensitized the immune microenvironment and amplified CD8+ T cell responses, leading to substantial tumor growth inhibition in tumor-bearing mouse model. Thus, this work provides an efficient and versatile immunomodulatory strategy for enhanced antitumor immunotherapy.
研究领域:
癌症生物学
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免疫治疗
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纳米技术
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细胞信号传导
✓ 已验证
产品关联
DOI
高影响因子
Small
·
2021
·Vol. 18
·期 9
·2105118
·
IF 13.281
Yu Hei,Yang Chen,Qian Li,Zi Mei,Jijia Pan,Siqi Zhang,Chunyang Xiong,Xiaodong Su,Shicheng Wei
The immunosuppressive tumor microenvironment (TME) can significantly limit the immunotherapeutic effects of the PD-L1 antibody (aPDL1) by inhibiting the infiltration of CD8 + cytotoxic T cells (CTLs) into the tumor tissues. However, how to reprogram the immunosuppressive TME and promote the infiltration of CTLs remains a huge challenge for aPDL1 to achieve the maximum benefits. Herein, the authors design a multifunctional immunoliposome that encapsulates the adrenergic receptor blocker carvedilol (CAR) and connects the “don't eat me” signal antibody (aCD47) and aPDL1 in series via a reactive oxygen species (ROS)-sensitive linker on the surface. In ROS-enriched immunosuppressive TME, the multifunctional immunoliposome (CAR@aCD47/aPDL1-SSL) can first release the outer aCD47 to block the “do not eat me” pathway, promote the phagocytosis of tumor cells by phagocytic cells, and activate CTLs. Then, the aPDL1 on the liposome surface is exposed to block the PD-1/PD-L1 signaling pathway, thereby inducing CTLs to kill tumor cells. CAR encapsulated in CAR@aCD47/aPDL1-SSL can block the adrenergic nerves in the tumor tissues and reduce their densities, thereby inhibiting angiogenesis in the tumor tissues and reprogramming the immunosuppressive TME. According to the results, CAR@aCD47/aPDL1-SSL holds an effective way to reprogram the immunosuppressive TME and significantly enhance immunotherapeutic efficiency of aPDL1 against the primary cancer and metastasis.
研究领域:
癌症免疫疗法
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药学
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生物医学工程
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分子生物学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
JOURNAL OF CELLULAR PHYSIOLOGY
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2019
·Vol. 235
·期 5
·4814-4823
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IF 4.522
Jun Lei,Hongjian Wang,Daoming Zhu,Yibin Wan,Lei Yin
CD8 + T cells play a vital role in cancer immunotherapy and can be shaped by metabolism. Avasimibe is an acyl coenzyme A-cholesterol acyltransferase (ACAT) inhibitor, which has been clinically verified safe in other phase Ⅲ clinical trials. It can potentiate the killing function of CD8 + T cells by modulating cholesterol metabolism. Doxorubicin (DOX) is an anticancer drug widely used in many cancers to induce tumor cell apoptosis. Unfortunately, DOX also can induce toxic and side effects in many organs, compromising its usage and efficacy. Herein, we report the combinational usage of avasimibe and a safe pH sensitive nano-drug delivery system composing of DOX and metal–organic frameworks nanoparticles (MNPs). Our findings demonstrated that DOX–MNPs treatment inhibited tumor growth with good safety profile and avasimibe treatment combined DOX–MNPs treatment exhibited a better efficacy than monotherapies in 4T1 breast cancer therapy.
研究领域:
肿瘤学
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药理学
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纳米技术
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免疫学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Theranostics
·
2019
·
IF 8.063
Zeqian Huang,Gaofei Wei,Zishan Zeng,Yanjuan Huang,Liangfeng Huang,Yifeng Shen,Xiaoqi Sun,Congjun Xu,Chunshun Zhao
Cancer metastases is still a hurdle for good prognosis and live quality of breast cancer patients. Treatment strategies that can inhibit metastatic cancer while treating primary cancer are needed to improve the therapeutic effect of breast cancer. Methods: In this study, a dual functional drug conjugate comprised of protoporphyrin IX and NLG919, a potent indoleamine-2,3-dioxygenase (IDO) inhibitor, is designed to combine photodynamic therapy and immune checkpoint blockade to achieve both primary tumor and distant metastases inhibition. Liposomal delivery is applied to improve the biocompatibility and tumor accumulation of the drug conjugate (PpIX-NLG@Lipo). A series of in vitro and in vivo experiments were carried out to examine the PDT effect and IDO inhibition activity of PpIX-NLG@Lipo, and subsequently evaluate its anti-tumor capability in the bilateral 4T1 tumor-bearing mice. Results: The in vitro and in vivo experiments demonstrated that PpIX-NLG@Lipo possess strong ability of ROS generation to damage cancer cells directly through PDT. Meanwhile, PpIX-NLG@ Lipo can induce immunogenic cell death to elicit the host immune system. Furthermore, PpIX-NLG@Lipo interferes the activity of IDO, which can amplify PDT-induced immune responses, leading to an increasing amount of CD8 + T lymphocytes infiltrated into tumor site, finally achieve both primary and distant tumor inhibition. Conclusion: This work presents a novel conjugate approach to synergize photodynamic therapy and IDO blockade for enhanced cancer therapy through simultaneously inhibiting both primary and distant metastatic tumor.
研究领域:
肿瘤学
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药学
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免疫疗法
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纳米医学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Acta Biomaterialia
·
2022
·
IF 10.633
Xinyao Feng,Fangshen Li,Liangliang Zhang,Wenmo Liu,Xupu Wang,Rui Zhu,Zhen-An Qiao,Bin Yu,Xianghui Yu
Traditional anticancer treatments directly target tumor cells. In contrast, cancer immunotherapy fortifies host immunity. Nanoparticles that incorporate both immunomodulatory and chemotherapeutic agents regulate the tumor microenvironment by activating immune cells and enhancing antitumor immunity. Nanoparticle-based cancer immunotherapy has received considerable attention and has been extensively studied in recent years. In this study, we developed a targeted drug delivery system to enhance immunotherapeutic efficacy and overcome drug resistance by inducing tumor apoptosis and immunogenic cell death (ICD), and activating immune cells. Periodic mesoporous organosilica nanoparticles (PMOs) bore tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) on their surfaces, and their inner cores were loaded with doxorubicin (DOX). TRAIL enhanced the nanoparticle-targeting capacity and worked synergistically with DOX against breast cancer cells in vitro and in vivo . Furthermore, we revealed for the first time the ability of PMOs to activate dendritic cells (DCs) and elevate ICD levels of DOX in vitro , and TRAIL further enhances the immunomodulatory function of PMOs. Systemic exposure to [email protected] induced an immune response, activated DCs and CD4 + and CD8 + T cells , and significantly suppressed tumor growth in a 4T1-bearing immunocompetent mouse model. Overall, our study demonstrates that TRAIL-modified, DOX-embedded PMO nanoparticles represent a good candidate for tumor-targeted immunotherapy, which has relatively superior therapeutic efficacy and highly promising future application prospects. Statement of significance This study revealed for the first time the ability of PMOs to elevate ICD levels and activate DCs in vitro . The results explained the immunomodulatory function of PMOs and demonstrated the synergistic effects of TRAIL and DOX in triple-negative breast cancer. In addition, immunomodulatory effects of the drug delivery vectors constructed in this study were verified in vivo .
研究领域:
癌症研究
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纳米技术
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免疫疗法
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药学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Biomaterials Advances
·
2022
·
IF 0
Zhiwei Li,Jiaqi Bu,Xinyu Zhu,Hao Zhou,Kaiqun Ren,Paul K. Chu,Limin Li,Xiang Hu,Xiaofeng Ding
Programmed cell death receptor ligand 1 (PD-L1)/PD-1 signaling has been exploited to design inhibitors that deliver promising clinical outcome albeit with limited efficacy. Herein, we prepare graphene oxide (GO)-PEI-PEG with low cytotoxicity and long stability and GO-PEI-PEG delivers PD-L1 siRNAs to hepatocellular carcinoma (HCC) cells by the endocytosis-lysosome pathway. The functional GO-PEI-PEG/PD-L1 siRNAs decrease PD-L1 and PD-1 abundance, increase pro-inflammation cytokine IFN-γ and TNF-α release, and improve the proliferation activity of Jurkat T cells. Since GO-PEI-PEG targets the mouse liver effectively, the intrahepatic tumors in C57BL/6 mice are treated with GO-PEI-PEG/Pd-l1 siRNAs via the tail vein, resulting in shrinkage of the HCC tumors and boosting the anti-tumor efficacy in combination with oral sorafenib. A single treatment improves the total CD3 + and cytotoxic CD8 + T cell infiltration in the HCC tumor tissues and even spleen and upregulates the expression of Perforin, Gzmb, Ifng, Il-1b and Tnfa in the tumors after the combined treatment. Both the single and combined treatments enhance reactive oxygen species (ROS) accumulation, and improved HCC ferroptosis. The results suggest that GO-PEI-PEG delivered PD-L1 siRNAs combined with oral sorafenib can activate the adaptive immunity and tumor ferroptosis and reveal an effective therapy to treat advanced HCC patients.
研究领域:
肿瘤学
·
分子生物学
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免疫学
·
药理学
✓ 已验证
DOI
PubMed
JOURNAL OF NANOBIOTECHNOLOGY
·
2022
·Vol. 20
·期 1
·1-14
·
IF 9.429
Deng Bo,Ma Bing,Ma Yingying,Cao Pei,Leng Xigang,Huang Pengyu,Zhao Yuanyuan,Ji Tianjiao,Lu Xueguang,Liu Lanxia
Chemotherapeutics that can trigger immunogenic cell death (ICD) and release tumor-specific antigens are effective on treating a variety of cancers. The codelivery of chemotherapeutics with adjuvants is a promising strategy to achieve synergistic therapeutic effect. However, low drug loading and complicated preparation of current delivery systems lead to carrier-associated toxicity and immunogenicity. Herein, we developed a facile approach to construct liposomal spherical nucleic acids (SNA) by the self-assembly of 1,2-dioleoyl-sn-glycero-3-phosphoethanolamine (DOPE)-doxorubicin conjugate and DOPE-matrix metalloproteinases-9 (MMP-9) responsive peptide-CpG conjugate (DOPE-MMP-CpG). Liposomal SNAs efficiently co-delivered DOX and CpG into tumors and released the two drugs upon biological stimuli of MMP-9 enzyme in tumor microenvironment (TME) and high concentration of endogenous glutathione in tumor cells. We demonstrated that liposomal SNA enhanced activation of dendritic cells (DCs), promoted expansion of CD8 + and CD4 + T cells in both tumors and spleen, inhibited tumor growth, and extended animal survival. This work provided a simple strategy of delivering chemotherapeutics and adjuvants to tumors with synergistic therapeutic effect and reduced side effect. Graphical Abstract
研究领域:
癌症治疗
·
药物递送系统
·
免疫疗法
·
纳米医学
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生物化学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Small
·
2022
·Vol. 18
·期 44
·2203114
·
IF 15.153
Junjie Deng,Weide Xu,Siyun Lei,Wanyu Li,Qinghua Li,Kaiqiang Li,Jianxin Lyu,Jilong Wang,Zhen Wang
Although enormous success has been obtained for dendritic cells (DCs)-mediated antigen-specific T cells anticancer immunotherapy in the clinic, it still faces major challenging problems: insufficient DCs in tumor tissue and low response rate for tumor cells lacking antigen expression, especially in low immunogenic tumors such as pancreatic cancer. Here, these challenges are tackled through tumor microenvironment responsive nanogels with prominent tumor-targeting capability by Panc02 cell membranes coating and inhibition of tumor-derived prostaglandin E2 (PGE2), aimed at improving natural killer (NK) cells activation and inducing activated NK cells-dependent DCs recruitment. The engineered nanogels can on-demand release acetaminophen to inhibit PGE2 secretion, thus promoting the activity of NK cells for non-antigen-specific tumor elimination. Furthermore, activated NK cells can secrete chemokines as C C motif chemokine ligand 5 and X-C motif chemokine ligand 1 to recruit immature DCs, and then promote DCs maturation and induce antigen-dependent CD8 + T cells proliferation for enhancing antigen-specific immunotherapy. Notably, these responsive nanogels show excellent therapeutic effect on Panc02 pancreatic tumor growth and postsurgical recurrence, especially combination of the programmed cell death-ligand 1 checkpoint-blockade immunotherapy. Therefore, this study provides a simple strategy for enhancing low immunogenic tumors immunotherapy through an antigen-independent way and antigen-dependent way synergetically.
研究领域:
肿瘤学
·
免疫学
·
纳米技术
·
药学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
ACS Nano
·
2023
·
IF 17.1
Yun Yu,Bo-Ru Xie,Xin-Hua Liu,Jing-Jie Ye,Zhenlin Zhong,Xian-Zheng Zhang
Calcium ion therapy is a potential anticancer treatment. However, the cellular calcium-buffering mechanism limited the effectiveness of calcium ion therapy. Here, we constructed a mineralized porphyrin metal–organic framework (PCa) to produce calcium ions and reactive oxygen species (ROS), which destroyed cell calcium buffering capacity and amplified the cell damage caused by calcium overload. In addition, PCa could induce cell immunogenic death to release tumor-associated antigen (TAA) and be used as an adjuvant. Thus, PCa could increase DC maturation and promote the antitumor activity of CD8+ T cells. For mice experiment, PCa not only showed excellent tumor elimination on the subcutaneous breast tumor but also achieved obvious antimetastasis effect in the metastatic tumor model. This nanosystem could eliminate the primary tumor and boost effective antitumor immunotherapy for comprehensive anticancer treatment.
研究领域:
癌症治疗
·
纳米技术
·
免疫疗法
·
生物化学
·
分子生物学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
危险品化学品经营许可证（带存储）