JOURNAL OF MEDICINAL CHEMISTRY
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2025
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IF 6.8
Qing-Hua Shen,Long-Bo Yu,Shan-Ming Yao,Zhi-Yuan Li,Qi-Qi Zhang,Peng Wang,Cai-Ping Tan
Metalloenzyme mimics based on small molecules are valuable therapeutic candidates, but there are few reports on their mechanism of action. Inspired by natural enzymes, we designed two Cu–Fe bimetallic multienzyme mimetics (CuFc1 and CuFc2). Due to the coordination of the bimetallic centers, CuFc1 exhibits mimetic activities for multiple enzymes, including peroxidase (POD), catalase (CAT), superoxide dismutase (SOD), and glutathione oxidase (GSHOx). CuFc1 can catalyze cascade reactions from •O2– and H2O2 to O2 and •OH, which leads to a storm of reactive oxygen species and causes cuproptosis and ferroptosis in cancer cells simultaneously. As CuFc1 treatment upregulates the expression of PD-L1, it acts synergistically with the PD-L1 inhibitor (BMS-1) to remodel the tumor immune microenvironments and stimulates intense anticancer immune responses in vivo. In summary, through reasonable molecular design, we first demonstrate the enormous potential of metallo small molecule-based multienzyme mimics in cancer immunotherapy.
研究领域:
生物无机化学
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癌症生物学
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免疫治疗
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酶学
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金属药物
✓ 已验证
产品关联
DOI
PubMed
高影响因子
International Journal of Nanomedicine
·
2024
·
IF 6.6
Haishui Sun,Xiao Wang,Zhaoyang Guo,Zhenrong Hu,Yuanchen Yin,Shuhan Duan,Wenwen Jia,Wei Lu,Jingzhou Hu
Introduction Traditional surgical resection, radiotherapy, and chemotherapy have been the treatment options for patients with head and neck squamous cell carcinoma (HNSCC) over the past few decades. Nevertheless, the five-year survival rate for patients has remained essentially unchanged, and research into treatments has been relatively stagnant. The combined application of photothermal therapy (PTT) and immunotherapy for treating HNSCC has considerable potential.Methods Live-dead cell staining and CCK-8 assays proved that Fe3O4 nanoparticles are biocompatible in vitro. In vitro, cellular experiments utilized flow cytometry and immunofluorescence staining to verify the effect of Fe3O4 nanoparticles on the polarisation of tumor-associated macrophages. In vivo, animal experiments were conducted to assess the inhibitory effect of Fe3O4 nanoparticles on tumor proliferation under the photothermal effect in conjunction with BMS-1. Tumour tissue sections were stained to observe the effects of apoptosis and the inhibition of tumor cell proliferation. The histological damage to animal organs was analyzed by hematoxylin and eosin (H&E) staining.Results The stable photothermal properties of Fe3O4 nanoparticles were validated by in vitro cellular and in vivo animal experiments. Fe3O4 photothermal action not only directly triggered immunogenic cell death (ICD) and enhanced the immunogenicity of the tumor microenvironment but also regulated the expression of tumor-associated macrophages (TAMs), up-regulating CD86 and down-regulating CD206 to inhibit tumor growth. The PD-1/PD-L1 inhibitor promoted tumor suppression, and reduced tumor recurrence and metastasis. In vivo studies demonstrated that the photothermal action exhibited a synergistic effect when combined with immunotherapy, resulting in significant suppression of primary tumors and an extension of survival.Conclusion In this study, we applied Fe3O4 photothermolysis in a biomedical context, combining photothermolysis with immunotherapy, exploring a novel pathway for treating HNSCC and providing a new strategy for effectively treating HNSCC.
研究领域:
癌症生物学
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纳米技术
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免疫疗法
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生物医学工程
✓ 已验证
产品关联
DOI
PubMed
高影响因子
ACS Applied Materials & Interfaces
·
2025
·
IF 8.2
Mingxi Ma,Chao Yu,Hanyuan Liu,Xuepeng Lv,Haidong Zhu,Weiwei Tang,Gaojun Teng,Fei Xiong
Hepatocellular carcinoma (HCC) is a highly fatal malignant tumor. The clinical outcomes of vascular interventional therapy for HCC based on existing drug-eluting microspheres remain unsatisfactory. This study adopted a unique fabrication method to synthesize methacrylated carrageenan/gelatin hydrogel embolic microspheres (MCGs). The interpenetrating network formed by these two biocompatible and absorbable natural macromolecules endows MCGs with outstanding mechanical properties and vascular conformity. MCGs could be delivered through microcatheters smoothly, and they are provided in various sizes to accommodate different clinical requirements. Their in vivo degradation behavior is controlled and predictable. Due to the strong anionic nature of carrageenan, MCGs can efficiently load and sustainably release Lenvatinib, achieving the precise delivery of this antiangiogenic targeted drug in the tumor region. Animal models reveal that the microspheres block blood vessels effectively and MCGs allow for high-dose Lenvatinib to have prolonged contact with HCC. We also propose an HCC treatment strategy by combining PD-L1 inhibitors with MCGs carrying Lenvatinib. This combination therapy is safe and effective, and the additive and synergistic effects showed impressive antitumor potency and great clinical application potential.
研究领域:
生物医学工程
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肿瘤学
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药学
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生物材料
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免疫治疗
✓ 已验证
产品关联
DOI
PubMed
高影响因子
INTERNATIONAL JOURNAL OF PHARMACEUTICS
·
2022
·
IF 6.51
Chan Jin,Jinbo Li,Xiaoguang Yang,Shuang Zhou,Chang Li,Jiang Yu,Zhaomeng Wang,Dun Wang,Zhonggui He,Yiguo Jiang,Yongjun Wang
Immune checkpoint inhibitors (ICIs) represent a new class of immunotherapy drugs, and are used to relieve immune suppression or enhance the immune response through the blockade of checkpoint ligands or receptors. ICIs have achieved great success in clinical cancer treatment. Monoamine oxidase A (MAOA) is a potent immune checkpoint of immunotherapy. Recently, it has been reported that MAOA inhibitors could enhance CD8 + T cell activity by upregulating 5-HT autocrine pathway in T cells. In this study, we synthesized doxorubicin (DOX) and isoniazid (INH, a MAOA inhibitor) conjugates through a pH sensitive hydrazone bond. Results of the in vivo studies showed that DOX-INH could effectively enhance the activity of CD8 + T cells and perform a synergistic anti-tumor effect with PD-L1 small molecular inhibitor (BMS202). In addition, in an orthotopic 4T1 breast cancer model, it was demonstrated that DOX-INH could inhibit the epithelial-mesenchymal transition process by blocking Shh, IL-6, and TGF-β signaling pathways, thereby inhibiting the growth and metastasis of breast cancer. Thus, a simple and effective small molecule conjugate produced by the combination of a chemotherapy drug and a MAOA inhibitor shows broad prospect in cancer therapy.
研究领域:
癌症免疫治疗
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肿瘤学
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药理学
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免疫学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
ACS Materials Letters
·
2023
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IF 11.4
Quan Liu,Zhe Sun,Yanhong Duo,Lei Yin,Kongpeng Lv,Ludan Yue,Qian-Fang Meng,Dingmeng Nie,Jiaojuan Chen,Dixian Luo,Li-Ping Liu,Lang Rao
Immune checkpoint blockade has been regarded as a highly promising cancer immunotherapy approach. However, inefficient immune cell infiltration and the immunosuppressive tumor microenvironment (TME) remain significant causes of low clinical response rates. Here, we identified that trivalent chromium irons (Cr3+) could enhance tumor infiltration of immune cells including M1-type tumor-associated macrophages and CD8+ T cells. Mechanistically, this effect is dependent on the expression of macrophage inflammatory protein-1α (MIP-1α) and the PI3K/Akt/mTOR pathway. Moreover, the Cr-based nanoparticles (Cr NPs) exhibited superior photothermal properties under near-infrared laser irradiation, showing great potential in transforming “cold” tumors into “hot” ones. In combination with the PD-1/PD-L1 pathway inhibitor, we demonstrated that the Cr NPs significantly improved anticancer efficacy in mouse models of hepatoma and melanoma by increasing antitumor immune cell infiltration and relieving immunosuppressive TME. Overall, the Cr NPs offer a new dual-functional platform for local and systemic cancer treatments, paving the way toward cancer photometalloimmunotherapy.
研究领域:
肿瘤学
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免疫学
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纳米技术
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生物医学工程
✓ 已验证
产品关联
DOI
高影响因子
International Journal of Nanomedicine
·
2025
·
IF 6.5
Zhecheng Yu,Zeya Zhou,Yunqi Zhao
Background Cancer immunotherapy has achieved great success in breast cancer treatment in recent years. The Programmed Death-1 (PD-1) /Programmed Death-Ligand 1 (PD-L1) immune checkpoint pathway is among the most studied. BMS-1166, a PD-L1 inhibitor, can interfere with PD-1 and PD-L1 interaction. Transferrin Receptor 1 is a transmembrane glycoprotein overexpressed in various cancer cells, including breast cancer, and can specifically interact with the T7 (HAIYPRH) peptide.Purpose This study hypothesized that BMS-1166-loaded T7-modified poly(ethylene glycol)-poly(ε-caprolactone) (PEG-PCL) polymeric micelles (BMS-T7) could block PD-L1 interaction with PD-1, serving as a targeted immunotherapy for TfR1-positive breast cancer.Methods BMS-1166 was encapsulated in T7-PEG-PCL micelle. Particle size and zeta potential were determined by dynamic light scattering. Particle morphology was studied by transmission electron microscopy. The particles were characterized by Fourier transform infrared, thermogravimetric analysis, and differential scanning calorimetry. Drug encapsulation efficiency, loading degree, and release profile were examined by high-performance liquid chromatography. Human breast cancer MDA-MB-231 was used to test the cytotoxicity. Flow cytometry and immunofluorescence imaging were used to study the PD-L1 inhibition in cell surface and exosomes. MDA-MB-231 and Jurkat co-culture studied T-cell activation and apoptosis.Results The particle size of the empty and drug-loaded micelles showed a size distribution with an average diameter of 54.62 ± 2.28 nm and 60.22 ± 2.56 nm, respectively. The encapsulation efficiency of BMS-T7 was 83.89 ± 5.59%. The release half-life of drug-loaded micelles was 48h. The IC50 of BMS-1166 was 28.77 μM in MDA-MB-231 cells. In addition, the BMS-T7 showed a better inhibitory effect on PD-L1 expression in breast cancer cells and exosomes than the naked drug. The formulation significantly restored T-cell function compared to the BMS-1166 treatment.Conclusion These results provide preliminary evidence indicating that BMS-T7 may have the potential to deliver drugs to breast cancer cells via active targeting and hold great promise in cancer immunotherapy drug delivery applications.
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
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Bioactive Materials
·
2021
·
IF 14.593
Jie Yu,Sha Liu,Yupeng Wang,Xidong He,Qingfei Zhang,Yanxin Qi,Dongfang Zhou,Zhigang Xie,Xiaoyuan Li,Yubin Huang
The combination of tumor ablation and immunotherapy is a promising strategy against tumor relapse and metastasis. Photothermal therapy (PTT) triggers the release of tumor-specific antigens and damage associated molecular patterns (DAMPs) in-situ. However, the immunosuppressive tumor microenvironment restrains the activity of the effector immune cells. Therefore, systematic immunomodulation is critical to stimulate the tumor microenvironment and augment the anti-tumor therapeutic effect. To this end, polyethylene glycol (PEG)-stabilized platinum (Pt) nanoparticles (Pt NPs) conjugated with a PD-L1 inhibitor (BMS-1) through a thermo-sensitive linkage were constructed. Upon near-infrared (NIR) exposure, BMS-1 was released and maleimide (Mal) was exposed on the surface of Pt NPs, which captured the antigens released from the ablated tumor cells, resulting in the enhanced antigen internalization and presentation. In addition, the Pt NPs acted as immune adjuvants by stimulating dendritic cells (DCs) maturation. Furthermore, BMS-1 relieved T cell exhaustion and induced the infiltration of effector T cells into the tumor tissues. Thus, Pt NPs can ablate tumors through PTT, and augment the anti-tumor immune response through enhanced antigen presentation and T cells infiltration, thereby preventing tumor relapse and metastasis.
研究领域:
癌症研究
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纳米技术
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免疫治疗
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光热疗法
✓ 已验证
产品关联
DOI
PubMed
高影响因子
INTERNATIONAL IMMUNOPHARMACOLOGY
·
2024
·
IF 4.8
Shengsheng Mei,Shanshan Peng,Eu Gene Vong,Jinbiao Zhan
Background Clinical data indicate that a substantial portion of cancer patients, though eligible for immune checkpoint inhibitor (ICI) therapy, cannot fully benefit from ICI monotherapy due to the poor immunogenicity of tumors and lack of tumor-infiltrating lymphocytes within the ‘cold’ tumor microenvironment (TME). In addition to poor antibody penetrance into the TME, systemic delivery of ICIs is associated with immune-related adverse events (irAEs) among recipients, some of which are life-threatening. Oncolytic virotherapy is a potentially viable approach to improving the efficacy of ICI therapy because of their ability to selectively replicate and lyse tumor cells, release tumor-associated antigens (TAAs), induce inflammatory response and promote lymphocyte infiltration in tumors. Methods A recombinant oncolytic adenoviruses (OAd), denoted ZD55-aPD-L1 scFv, which carried the expression cassette for anti-PD-L1 scFv was constructed by molecular cloning. Western blot and ELISA assay were performed to detect aPD-L1 scFv expression. Flow cytometry were used to analyse PD-L1 expression and count tumor cells. Co-culture assay of human peripheral blood mononuclear cells (PBMCs) with tumor cells in vitro and triple-negative breast cancer (TNBC) MDA-MB-231 tumor-bearing model in vivo were evaluated the antitumor effects of recombinant oncolytic adenoviruses ZD55-aPD-L1 scFv. Results We found that cells infected with recombinant oncolytic adenovirus ZD55-aPD-L1 scFv can effectively express aPD-L1 scFv, which function similarly to its full-length anti-PD-L1 antibody. PBMCs have inherently very limited killing effect on tumor cells even with administration of anti-PD-L1 antibody as observed from our in vitro co-cultures. Treatment consisting of ZD55 alone or ZD55 combined with anti-PD-L1 antibody yielded mediocre antitumor efficacy in subsequent in vitro and in vivo investigations, but were all substantially surpassed by the synergistic antitumor effects observed with ZD55-aPD-L1 scFv treatment. We show that the concomitant direct oncolysis by the recombinant OAd and localized autocrine/paracrine interception of PD-1:PD-L1 checkpoint interaction mediated by ZD55-aPD-L1 scFv-infected cells is exceedingly superior to co-administration of ZD55 and anti-PD-L1 antibody in the human TNBC mice model. Conclusions Our results provided evidence for the development of novel strategies, in this case an anti-PD-L1 scFv-armed OAd, to bolster immune responses to ‘cold’ tumors and to improve therapeutic responsiveness to ICIs.
研究领域:
肿瘤学
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免疫疗法
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分子生物学
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癌症研究
✓ 已验证
产品关联
DOI
PubMed
高影响因子
JOURNAL OF CONTROLLED RELEASE
·
2021
·
IF 9.776
Yingli Wang,Jiang Yu,Dan Li,Liwen Zhao,Bingjun Sun,Jiamei Wang,Zhenjie Wang,Shuang Zhou,Menglin Wang,Yinxian Yang,Hongzhuo Liu,Haotian Zhang,Qingzhi Lv,Qikun Jiang,Zhonggui He,Yongjun Wang
The combination of chemotherapy with the immune checkpoint blockade (ICB) therapy is bringing a tremendous hope in the treatment of malignant tumors. However, the treatment efficacy of the existing chemo-immunotherapy is not satisfactory due to the high cost and immunogenicity of ICB antibodies, low response rate to ICB, off-target toxicity of therapeutic agents, and low drug co-delivery efficacy. Therefore, a high-efficient nanosystem combining the delivery of chemotherapeutics with small molecule ICB inhibitors may be promising for an efficient cancer therapy. Herein, a novel reactive oxygen species (ROS)-activated liposome nanoplatform was constructed by the loading of a ROS-sensitive paclitaxel derivative (PSN) into liposomes to overcome the difficulties on delivering paclitaxel mostly represented by premature drug release and a low amount accumulated into the tumor. The innovative liposomal nanosystem was rationally designed by a remote loading of BMS-202 (a small molecule PD-1/PD-L1 inhibitor) and PSN into the liposomes for a ROS-sensitive paclitaxel release and sustained BMS-202 release. The co-loaded liposomes resulted in a high co-loading ability and improved pharmacokinetic properties. An orthotopic 4 T1 breast cancer model was used to evaluate the efficiency of our nanoplatform in vivo, resulting in a superior antitumor activity . The antitumor immunity was activated by paclitaxel-mediated immunogenic cell death , while BMS-202 continuously blocked PD-L1 which could be up-regulated by paclitaxel in tumors to increase the response to ICB and further recover the host immune surveillance. These results revealed that this dual-delivery liposome might provide a promising strategy for a high-efficient chemo-immunotherapy, exhibiting a great potential for clinical translation.
研究领域:
癌症治疗
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纳米技术
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药学
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免疫学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
ACS Applied Materials & Interfaces
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2022
·
IF 10.383
Meng Zhang,Yingzhi Chen,Dongdong Li,Zhidi He,Hairui Wang,Aihua Wu,Weidong Fei,Caihong Zheng,Ergang Liu,Yongzhuo Huang
Cancer immunotherapy represents a medical breakthrough, but there are still many patients unable to benefit from it because of the low response rate. The immunosuppressive tumor microenvironment (TME) is the main barrier to immunotherapy. Alleviating intratumoral immunosuppression is critical for improving the immune therapeutic efficacy. This work developed an in situ vaccination strategy by using gold nanocage (AuNC)-based photothermal effect in combination with an adjuvant and PD-L1 suppressor. In specific, this therapeutic strategy included three components: AuNCs as an inducer for tumor antigen production via photothermal ablation, CpG oligodeoxynucleotides as an adjuvant to amplify immune responses, and JQ1 as a PD-L1 suppressor to inhibit an immune checkpoint. The results showed that the in situ vaccination efficiently activated dendritic cells and primed T cells and exhibited a high therapeutic efficacy in the melanoma-bearing mice. This therapeutic strategy can increase the infiltration of cytotoxic T lymphocytes, suppress the PD-L1 expression in the tumor, and repolarize tumor-associated macrophages from pro-tumor M2 to the anti-tumor M1 phenotype, thereby remodeling the TME via regulating the innate immune and adaptive immune responses.
研究领域:
癌症免疫疗法
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纳米技术
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生物医学工程
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免疫学
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肿瘤学
✓ 已验证
DOI
PubMed
高影响因子
JOURNAL OF COLLOID AND INTERFACE SCIENCE
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2022
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IF 9.965
Bo Ning,Yao Liu,Boshu Ouyang,Xiaomin Su,Huishu Guo,Zhiqing Pang,Shun Shen
Although low-temperature photothermal therapy (PTT) can sensitize tumors to immune checkpoint inhibition, its efficacy is still restricted in the deep and internal tumors without enough oxygen and lymphocytic infiltration . Non-oxygen-dependent alkyl radicals have been demonstrated to synergistically enhance PTT through up-regulating lipid peroxidation and reactive oxygen species (ROS). Herein, an innovative strategy based on alkyl radicals to augment immunogenetic cell death (ICD) caused by mild PTT was proposed to improve poor efficacy of immunotherapy, which composed of a photothermal material of Chinse ink, an azo-initiator of 2,2-azobis[2-(2- imidazoline -2- acyl ) propane ]dihydrochloride (AIPH) and a PD-L1 inhibitor of HY19991 (HY). Upon near-infrared-II laser irradiation, low-temperature (<45℃) stimulation induced a high expression of immune checkpoint receptor (PD-L1) in tumors and triggered a large amount alkyl radicals generated by AIPH. Significantly, the alkyl radicals augmented the ICD and increased the recruitment of tumor-infiltrating lymphocytes against tumors after transformation of the immunologically cold tumor microenvironment into hot by mild PTT. The released HY further enhanced the immunotherapy effect by blocking the binding of activated T lymphocytes and PD-L1. In vivo studies exhibited that the all-in-one hydrogel with synergistic mechanisms had an extraordinary ability to reverse the immunosuppressive microenvironment, stimulate innate and adaptive immune responses to eliminate tumors and prevent metastasis.
研究领域:
癌症研究
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生物医学工程
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免疫学
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诊疗学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Nanoscale
·
2021
·Vol. 13
·期 30
·12966-12978
·
IF 7.79
Jie Yu,Xidong He,Zigui Wang,Yupeng Wang,Sha Liu,Xiaoyuan Li,Yubin Huang
Immune checkpoint blockade (ICB) therapy in combination with immunogenic death (ICD) triggered by photothermal therapy (PTT) and oxaliplatin (OXA) treatment was expected to elicit both innate and adaptive immune responses for tumor control and metastasis prevention. In this study, a photothermal agent (IR780), a folic acid (FA) linked oxaliplatin (OXA) prodrug, and PD-L1 inhibitors (BMS-1) were integrated into a liposomal system. The FA tumor-targeting and enhanced permeability and retention (EPR) effect of the liposomal system prolonged circulating times and increased accumulation in tumors, resulting in an enhanced photothermal effect and less systemic toxicity. In addition, PTT and OXA had a considerable synergistic effect in the induction of a combined ICD. The PD-1/PD-L1 checkpoint, which is a negative immune regulatory mechanism, could be blocked by the thermosensitive released BMS-1. Finally, ICD was harnessed to synergize with a small molecule PD-L1 inhibitor for activation of the immune system in the treatment of tumor relapse and metastasis.
研究领域:
癌症治疗
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免疫学
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纳米技术
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药学
✓ 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）