CHEMICAL ENGINEERING JOURNAL
·
2024
·
IF 13.3
Xinmin Zheng,Xiang Li,Guolin Shi,Yidan Zhou,Jinxiao Yan,Hao Zhang,Xiru Liu,Jiangong Zhang,Yu Liu,Liangliang Dai,Hui Yang
The low targeting of immunity regulators & chemotherapy drugs and immune tolerance in the tumor microenvironment significantly hindered the chemo-immunotherapy effect. In this work, an MMP-2/GSH-responsive nanobomb loading Resiquimod (R848) and prodrug Cisplatin (Pt) with hierarchical drug delivery and tumor associated macrophages (TAMs) polarization traits was designed for improved chemo-immunotherapy. The Pt-carrying dendrimers penetrate the depth of tumor tissues under MMP-2 and activate the cytotoxicity of Pt prodrug in response to GSH, causing effective tumor damage and enhancing immunogenicity. Meanwhile, R848 is effectively uptake by TAMs, which were re-educated and then greatly relieved immune resistance. In vitro and in vivo results collectively revealed that the nanosystem could not only overcome the barrier of tumor penetration and the heterogeneity action sites of drugs but also re-educate TAMs and suppress immune evasion via activating extracellular signal-regulated kinase/mitogen-activated protein kinase (ERK/MAPK) signal pathway regulated by heparin binding EGF like growth factor ( Hbegf ) gene. The gene silencing or knockout in vitro and in vivo demonstrated that Hbegf could regulate the re-education of TAMs and the progression of tumors.
研究领域:
肿瘤学
·
免疫学
·
药剂学
✓ 已验证
产品关联
DOI
高影响因子
INTERNATIONAL JOURNAL OF BIOLOGICAL MACROMOLECULES
·
2022
·
IF 8.025
Zhimeng Chen,Tiantian Wen,Xueyuan Wang,Lin Yang,Zhongjie Wang,Yanru Qin,Yixue Hu,Tianyu Zhang,Dongna Wang,Amin Liu,Liefeng Zhang,Meng Lei,Yongqiang Zhu
Herein, a cyclodextrin derivative (R6RGD-CMβCD) with tumor target and a carboxymethyl chitosan derivative (M2pep-CMCS) with tumor-associated macrophages 2 (TAM2) target were successfully synthesized, respectively. DOX-loaded nanoparticles (R6RGD-CMβ [email protected] NPs, RCNP DOX ) and R848-loaded nanoparticles ( [email protected] NPs, MCNP R848 ) were prepared. Furthermore, the RCNP DOX and MCNP R848 exhibited good DOX and R848 absorption. Meanwhile, the synergetic cell toxicity of RCNP DOX and MCNP R848 was found. Additionally, RCNP DOX + MCNP R848 nanoparticles greatly promoted the expression levels of cleaved Caspase3, which indicated that the nanoparticles could induce cell apoptosis. At the same time, the immunohistochemical images exhibited that RCNP DOX + MCNP R848 group could effectively transform the phenotype of tumor-associated macrophages. Importantly, in vivo experiments revealed that RCNP DOX + MCNP R848 NPs exerted excellent anticancer effects in tumor-bearing mice. To summarize, RCNP DOX + MCNP R848 NPs are effective anticancer treatment combining chemotherapy and immunotherapy, M2pep-CMCS and R6RGD-CMβCD are good delivery materials.
研究领域:
药学
·
纳米技术
·
肿瘤学
·
免疫治疗
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Cancer Cell International
·
2024
·Vol. 24
·期 1
·1-15
·
IF 5.3
Cen Lanqi,Zhang Zhe,Sun Yi,Wu Nandie,Shao Jie,Qian Zhaoye,Tian Manman,Ke Yaohua,Liu Baorui
Background The clinical application of peptide vaccines in tumor immunotherapy holds significant promise. Peptide-based tumor vaccines are currently subject to certain limitations in clinical trials, including the challenge of inducing a sustained response from CD4 + T helper cells and cytotoxic T lymphocytes (CTL), as well as human leukocyte antigen (HLA) restrictions. Methods Through the utilization of biological information methodology, a screening process was conducted to identify three potential long peptides that are specifically targeted by the MAGE-A4 antigen. The candidate long peptides were subjected to in vitro testing using human peripheral blood lymphocytes as samples to evaluate their immunogenicity and immune function. The antitumor properties and preliminary mechanism of the long peptide vaccine were investigated through the use of a mouse model designed for the prevention of triple negative breast cancer (TNBC). Results Three predicted multi-epitope long peptides targeting MAGE-A4 have shown to have a strong immunogenicity, with a total positive rate of 72% across different HLA subtypes in Chinese populations. they can also increase the levels of the costimulatory factor CD137 and tumor necrosis factor-alpha (TNF-α), activate T cells, and boost the cytotoxic activity. Results from an animal study have revealed that the long-peptide vaccine, both on its own and in combination with R848, has displayed impressive anti-tumor and target-specific capabilities. Moreover, it has the ability to increase the expression of effector memory T cells and central memory T cells. Conclusions This study was the first to screen three multi-epitope long peptides targeting MAGE-A4 and assess their immunogenicity, immune function, and potential as adjuvant peptides. The results showed that the MAGE-A4 long peptide vaccine can be used as a novel immunoprophylaxis method to prevent TNBC. Moreover, the proposed development model is capable of screening multiple target antigens, which lead to its clinical application.
研究领域:
肿瘤学
·
免疫学
·
疫苗学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Nano Research
·
2021
·Vol. 15
·期 1
·510-518
·
IF 8.897
Wu Jia-Si,Li Jia-Xian,Shu Na,Duan Qi-Jia,Tong Qi-Song,Zhang Jing-Yang,Huang Yong-Cong,Yang Si-Yu,Zhao Zhi-Bin,Du Jin-Zhi
Tumor associated macrophages (TAMs) tend to exhibit tumor-promoting M2 phenotype and contribute to the development of immunosuppressive microenvironment of solid tumors. Reprograming TAMs from M2 into tumoricidal M1 phenotype is robust for stimulating tumor immunosuppressive microenvironment (TIME). In this study, we developed a poly(amidoamine) (PAMAM) derivative dendrimer (denoted as fourth generation- N,N -diethylaminoethyl (G4-DEEA)) for efficient loading of Toll-like receptor 7 and 8 (TLR7/8) agonist (R848) to remodel the TIME for potent cancer immunotherapy. G4-DEEA exhibited a high loading capacity of R848 up to 35.9 wt% by taking advantage of its dendritic structure. The resulting formulation (designated as G4-DEEA@R848) effectively polarized M2 macrophages into M1 phenotype in vitro , and improved the maturation and activation of antigen-presenting cells. In the 4T1 orthotopic breast cancer model, G4-DEEA@R848 showed a stronger tumor inhibitory effect than free drug. The mechanistic studies suggested that G4-DEEA@R848 could significantly stimulate the TIME by repolarizing TAMs into M1 phenotype, reducing the presence of immunosuppressive myeloid cells and increasing the infiltration of tumor cytotoxic T cells. This study provides a simple but effective dendrimer-based strategy to improve the formulation of R848 for improved cancer immunotherapy.
研究领域:
癌症免疫治疗
·
药学
·
免疫学
✓ 已验证
产品关联
DOI
高影响因子
CARBOHYDRATE POLYMERS
·
2025
·
IF 12.5
Liubing Li,Zenghui Gu,Yanxian Wu,Subin Lin,Xiaju Cheng,Leshuai W. Zhang,Jianzhong Qin,Qirong Dong,Yong Wang,Yangyun Wang
Combining radiotherapy with immunotherapy holds promise for treating solid tumors and metastases, but challenges persist, including hypoxia-induced immunosuppression and immune-related adverse events from off-target toxicity. To address this, we engineered an in-situ formed hydrogel by crosslinking hyaluronic acid and polyvinyl alcohol with a reactive oxygen species (ROS)-responsive linker (3-aminophenylboronic acid). This hydrogel leverages radiotherapy-induced ROS within the tumor microenvironment to trigger localized release of nitric oxide (NO) and the toll-like receptor 7/8 (TLR7/8) agonist R848. NO normalizes hypoxic tumor vasculature, while R848 amplifies radiotherapy-initiated antitumor immunity. In breast cancer and bone metastasis models, this radioimmune-regulated hydrogel significantly enhanced tumor normoxia, promoted dendritic cell maturation, and primed CD8 + T cells, substantially improving the efficacy of combined radioimmunotherapy. Our study highlights a potent hydrogel-based strategy to overcome key limitations in advanced cancer therapy.
研究领域:
肿瘤学
·
生物材料
·
免疫治疗
·
放射治疗
·
纳米医学
·
药学
✓ 已验证
DOI
PubMed
高影响因子
ACS Applied Materials & Interfaces
·
2024
·
IF 8.3
Zhaolong Yu,Ziqi Gan,Wei Wu,Xiaojiang Sun,Xiaofei Cheng,Chen Chen,Bihui Cao,Zhongyi Sun,Jiwei Tian
Osteosarcoma, a predominant malignant tumor among adolescents, exhibits high mortality and suboptimal immunotherapy efficacy due to a collagen-dense extracellular matrix (ECM) that hinders cytotoxic T lymphocyte (CTL) infiltration. Herein, we developed mesoporous polydopamine (MPDA) nanoparticles encapsulating bromelain and the immune adjuvant R848 (M@B/R), aimed at enhancing photothermal immunotherapy. These nanoparticles efficiently accumulate at the tumor site following injection. Upon near-infrared (NIR) light irradiation, photothermal therapy (PTT) induces immunogenic cell death in tumor cells and, with the aid of R848, efficiently promotes dendritic cell maturation, activating antitumor immunity and leading to CTL infiltration into the tumor. Concurrently, NIR-induced heating activates bromelain, resulting in ECM degradation and improved CTL penetration into the tumor. Our in vivo evaluations demonstrate potent antitumor effects in osteosarcoma-bearing mice. This integrated approach offers a promising strategy for overcoming physical barriers in ECM-rich tumors, marking a significant advancement in the treatment of osteosarcoma.
研究领域:
肿瘤学
·
免疫学
·
纳米技术
·
生物医学工程
✓ 已验证
产品关联
DOI
PubMed
高影响因子
BIOMATERIALS
·
2023
·
IF 14
Zhenzhen Feng,Gui Chen,Min Zhong,Ling Lin,Ziyi Mai,Yan Tang,Guimei Chen,Wen Ma,Guang Li,Yuanyuan Yang,Zhiqiang Yu,Meng Yu
Pyroptosis is an inflammatory form of programmed cell death (PCD) that is regulated by the Gasdermin protein family in response to various stimuli, playing a critical role in the development of tumor therapy strategies. However, cancers are generally known to escape from PCD via immunosuppressive pathways or other resistant mechanisms. In this study, an acid-responsive Fe/Mn bimetal-organic framework nanosystem carrying metal ions and immune adjuvant R848 (FeMn@R@H) was designed for combining pyroptosis and augmented immunotherapy. The FeMn@R@H would be triggered to disintegrate and release Fe 3+ and Mn 2+ ions in response to the acidic tumor microenvironment (TME), thereby initiating Fenton-like reactions for ROS-mediated pyroptosis. On the one hand, the pyroptosis-caused cell rupture would induce the release of proinflammatory cytokines and immunogenic constituents from tumor cells, further resulting in immunogenic cell death (ICD) to promote antitumor immune responses. On the other hand, the co-delivered R848 could reverse suppressive tumor immune microenvironment (TIME) and induce inflammatory responses by activating the TLR7/8 pathway. In conclusion, this tumor-specific therapy system can co-deliver metal ions and R848 to tumor tissues to perform pyroptosis-mediated PCD and augmented anti-tumor immunotherapy.
研究领域:
癌症生物学
·
纳米技术
·
免疫治疗
·
药学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Nature Communications
·
2024
·Vol. 15
·期 1
·1-20
·
IF 14.7
Liu Jinhu,Zhao Huajun,Gao Tong,Huang Xinyan,Liu Shujun,Liu Meichen,Mu Weiwei,Liang Shuang,Fu Shunli,Yuan Shijun,Yang Qinglin,Gu Panpan,Li Nan,Ma Qingping,Liu Jie,Zhang Xinke,Zhang Na,Liu Yongjun
Cytotherapy is a strategy to deliver modified cells to a diseased tissue, but targeting solid tumours remains challenging. Here we design macrophages, harbouring a surface glypican-3-targeting peptide and carrying a cargo to combat solid tumours. The anchored targeting peptide facilitates tumour cell recognition by the engineered macrophages, thus enhancing specific targeting and phagocytosis of tumour cells expressing glypican-3. These macrophages carry a cargo of the TLR7/TLR8 agonist R848 and INCB024360, a selective indoleamine 2,3-dioxygenase 1 (IDO1) inhibitor, wrapped in C16-ceramide-fused outer membrane vesicles (OMV) of Escherichia coli origin (RILO). The OMVs facilitate internalization through caveolin-mediated endocytosis, and to maintain a suitable nanostructure, C16-ceramide induces membrane invagination and exosome generation, leading to the release of cargo-packed RILOs through exosomes. RILO-loaded macrophages exert therapeutic efficacy in mice bearing H22 hepatocellular carcinomas, which express high levels of glypican-3. Overall, we lay down the proof of principle for a cytotherapeutic strategy to target solid tumours and could complement conventional treatment.
研究领域:
肿瘤学
·
免疫治疗
·
药理学
·
细胞生物学
✓ 已验证
DOI
PubMed
高影响因子
ACS Applied Materials & Interfaces
·
2021
·
IF 9.229
Qingle Song,Guofang Zhang,Bo Wang,Guoli Cao,Dongjie Li,Yu Wang,Yuqian Zhang,Jin Geng,Hongchang Li,Yang Li
Although immuno-oncotherapy in clinic has gained great success, the immunosuppressive tumor microenvironment (TME) existing in the “cold” tumor with insufficient and exhausted lymphocytes may result in a lower-than-expected therapeutic efficiency. Therefore, a properly designed synergistic strategy that can effectively turn the “cold” tumor to “hot” should be considered to improve the therapeutic effects of immuno-oncotherapy. Herein, TME-responsive penetrating nanogels (NGs) were developed, which can improve the delivery and penetration of the co-loaded resiquimod (R848) and green tea catechin (EGCG) in tumors by a nano-sized controlled releasing system of the soluble cyclodextrin-drug inclusion complex. Consequently, the NGs effectively promoted the maturation of dendritic cells, stimulated the cytotoxic T lymphocytes (CTLs), and decreased the PD-L1 expression in tumors. The combination of NGs with the OX40 agonist (αOX40) further synergistically enhanced the activation and infiltration of CTLs into the deep tumor and inhibited the suppression effects from the regulatory T cells (Tregs). As a result, an increased ratio of active CTLs to Tregs in tumors (20.66-fold) was achieved with a 91.56% tumor suppression effect, indicating a successful switch of “cold” tumors to “hot” for an immunologically beneficial TME with significantly improved anti-tumor immune therapeutics. This strategy could be tailored to other immuno-oncotherapeutic approaches to solve the urgent efficiency concerns of the checkpoint-based treatment in clinic.
研究领域:
肿瘤学
·
免疫学
·
纳米医学
·
药学
✓ 已验证
DOI
PubMed
高影响因子
CHEMICAL ENGINEERING JOURNAL
·
2023
·
IF 15.1
Qingxu Song,Gongde Lan,Qian Li,Yang Lin,Xin Chen,Hong Liu,Yufeng Cheng,Yuxia Luan
Hypofractionated radiotherapy (HRT) is a promising approach for tumor treatment, owing to its straightforward elimination of tumor cells and stimulation of immunogenic cell death. However, clinical application of HRT is hindered by the inherent radio-resistance and inadequate immune activation. Herein, an injectable hydrogel platform was reported, enabling a cascade amplification of radiosensitization and immune activation to potentiate HRT. The hydrogel with encapsulated TLR7/8 agonist R848 is in situ constructed in tumor via L-norvaline-based polymer (LNP, a gelator). During HRT, the released L-norvaline from LNP suppresses L-arginine consumption through arginase 1 (ARG1) pathway, sparing adequate L-arginine that was used for radiosensitizer nitric oxide (NO) production by inducible NO synthase (iNOS). Meanwhile, R848 repolarizes tumor-associated macrophages (TAMs) from M2 type with rich ARG1 to M1 type with rich iNOS, reinforcing NO production and disrupting M2-type TAMs-induced radio-resistance and immunosuppression. Therefore, the hydrogel demonstrates a cascade regulation of radio-sensitization and immune activation, achieving powerful inhibition of tumor growth and tumor metastasis. This hydrogel provides a novel approach to potentiate HRT, holding great promise in clinical application.
研究领域:
肿瘤学
·
放射肿瘤学
·
免疫疗法
✓ 已验证
产品关联
DOI
高影响因子
Nano Research
·
2020
·Vol. 13
·期 12
·3403-3415
·
IF 8.183
Zeng Fanchu,Qin Huan,Liu Liming,Chang Haocai,Chen Qun,Wu Linghua,Zhang Le,Wu Zhujun,Xing Da
Effective therapeutic strategies to precisely eradicate primary tumors with minimal side effects on normal tissue, inhibit metastases, and prevent tumor relapses, are the ultimate goals in the battle against cancer. We report a novel therapeutic strategy that combines adjuvant black phosphorus nanoparticle-based photoacoustic (PA) therapy with checkpoint-blockade immunotherapy. With the mitochondria targeting nanoparticle, PA therapy can achieve localized mechanical damage of mitochondria via PA cavitation and thus achieve precise eradication of the primary tumor. More importantly, PA therapy can generate tumor-associated antigens via the presence of the R848-containing nanoparticles as an adjuvant to promote strong antitumor immune responses. When combined with the checkpoint-blockade using anti-cytotoxic T-lymphocyte antigen-4, the generated immunological responses will further promote the infiltrating CD8 and CD4 T-cells to increase the CD8/Foxp3 T-cell ratio to inhibit the growth of distant tumors beyond the direct impact range of the PA therapy. Furthermore, the number of memory T cells detected in the spleen is increased, and these cells inhibit tumor recurrence. This proposed strategy offers precise eradication of the primary tumor and can induce long-term tumor-specific immunity.
研究领域:
肿瘤学
·
纳米技术
·
免疫治疗
·
生物医学工程
✓ 已验证
DOI
PubMed
高影响因子
BIOMATERIALS
·
2024
·
IF 12.8
Qi-Song Tong,Hua Huang,Hui-Han Yu,Rong Liu,Song Shen,Jin-Zhi Du
Remodeling the immunosuppressive tumor microenvironment (TME) by immunomodulators has been well studied in the past years. However, strategies that enable concurrent modulation of both the immunosuppressive TME and tumor-draining lymph nodes (TDLNs) are still in the infancy. Here, we report a pH-sensitive size-switchable nanocluster, SPN-R848, to achieve simultaneous accumulation in tumor and TDLNs for immune activation. SPN-R848 with original size around 150 nm was formed by self-assembly of resiquimod (R848)-conjugated polyamidoamine (PAMAM) derivative, which could disintegrate into its small constituents (～ 8 nm) upon exposure to tumor acidity. The size reduction not only enhanced their accumulation and perfusion in the primary tumor, but promoted their transport and distribution in TDLNs. Accordingly, SPN-R848 remarkably remodeled the immunosuppressive TME by polarizing M2 to M1 macrophages and activated dendritic cells (DCs) in TDLNs, which synergistically facilitated the production and stimulation of cytotoxic T cells, and inhibited tumor growth in breast cancer and melanoma mouse models. Our study suggests that co-activation of immune microenvironments in both tumor and TDLNs may represent a promising direction to elicit strong antitumor immunity.
研究领域:
癌症生物学
·
免疫学
·
纳米技术
·
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）