Journal of Materials Chemistry B
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2017
·Vol. 5
·期 35
·7307-7318
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IF 4.543
Yu Wang,Guangxing Guo,Yanxian Feng,Hongyan Long,Dik-Lung Ma,Chung-Hang Leung,Lei Dong,Chunming Wang
Tumour-associated macrophages (TAMs) play pivotal roles in promoting cancer progression. Systemic delivery of therapeutic agents to efficiently eliminate these cells remains challenging. Here, we report the development of a bio-responsive polymeric complex (P3AB) that can be systemically administrated to target and eliminate TAMs in tumours. This complex comprises a polymeric ‘shell’ and ‘core’. The shell (PPP) consists of poly(ethylene glycol) (PEG), poly(lactic-co-glycolic acid) (PLGA), and a peptide that can be cleaved by matrix metalloproteases (MMPs) in the tumour microenvironment; and the ‘core’ (AB) is a bisphosphonate–glucomannan conjugate that has affinity for macrophage mannose receptors and selectively eliminates TAMs. Our data show that the P3AB complex can be accumulated in the tumour site thanks to its appropriate size and its PPP shell is sensitively cleaved by MMPs, efficiently releasing the AB core that can potently reduce TAM viability. The systemically delivered P3AB complex demonstrates favourable responses to the physiological features of the tumour microenvironment (e.g. underdeveloped vasculature and high MMP levels), and effectively inhibits tumour growth and restores local immunosurveillance in vivo, without exerting hepatotoxicity. Taken together, our findings suggest that P3AB has the potential to be an effective and safe tool for TAM-targeting cancer immunotherapy.
研究领域:
肿瘤学
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免疫学
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药学
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PubMed
高影响因子
Pharmaceutics
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2023
·Vol. 15
·期 4
·1241
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IF 5.4
Zun Yang,Haijiao Li,Wenrui Zhang,Mingzu Zhang,Jinlin He,Zepeng Yu,Xingwei Sun,Peihong Ni
Tumor-associated macrophages (TAMs)-based immunotherapy is a promising strategy. Since TAMs are mainly composed of M2-type macrophages, they have a promoting effect on tumor growth, invasion, and metastasis. M2-type macrophages contain a specific receptor CD163 on their surface, providing a prerequisite for active targeting to TAMs. In this study, we prepared CD163 monoclonal antibody modified doxorubicin-polymer prodrug nanoparticles (abbreviated as mAb-CD163-PDNPs) with pH responsiveness and targeted delivery. First, DOX was bonded with the aldehyde group of a copolymer by Schiff base reaction to form an amphiphilic polymer prodrug, which could self-assemble into nanoparticles in the aqueous solution. Then, mAb-CD163-PDNPs were generated through a “Click” reaction between the azide group on the surface of the prodrug nanoparticles and dibenzocyclocytyl-coupled CD163 monoclonal antibody (mAb-CD163-DBCO). The structure and assembly morphology of the prodrug and nanoparticles were characterized by1H NMR, MALDI-TOF MS, FT-IR UV-vis spectroscopy, and dynamic light scattering (DLS). In vitro drug release behavior, cytotoxicity, and cell uptake were also investigated. The results show that the prodrug nanoparticles have regular morphology and stable structure, especially mAb-CD163-PDNPs, which can actively target TAMs at tumor sites, respond to the acidic environment in tumor cells, and release drugs. While depleting TAMs, mAb-CD163-PDNPs can actively enrich drugs at the tumor site and have a strong inhibitory effect on TAMs and tumor cells. The result of the in vivo test also shows a good therapeutic effect, with a tumor inhibition rate of 81%. This strategy of delivering anticancer drugs in TAMs provides a new way to develop targeted drugs for immunotherapy of malignant tumors.Keywords:anti-tumor;TAMs;CD163 monoclonal antibody;targeted drug delivery;prodrug;click reaction;doxorubicin;immunotherapy
研究领域:
肿瘤学
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药学
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免疫治疗
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高影响因子
COLLOIDS AND SURFACES B-BIOINTERFACES
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2020
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IF 4.389
Hui Peng,Jia-Hui Wang,Feng Guo,Fang-Fang Zhu,Zu-Jun Wen,Hai-Jun Zhong,De-Sheng Liang
M2 tumor-associated macrophages (TAMs) play a pivotal role in cancer progression and therapy resistance. Inhibition of TAMs is of great significance to reshape the protumor environment to benefit therapeutic outcomes. In this work, we developed a novel TAMs and tumor cells dual-targeting nanoparticle (AT pep -NPs) system for cancer chemotherapy by integrating a docetaxel (DTX)-loaded nanocarrier and a multi-function peptide AT pep , which is composed of a phagocytosis-stimulating peptide-tuftsin (T pep ) fused with a substrate peptide-alanine-alanine-asparagine (AAN) of endoprotease legumain . In vitro protelytic and cellular uptake assays confirmed AT pep -NPs can be responsively activated into T pep -NPs by cleavage of legumain that is overexpressed in both tumor cells and TAMs, which then promoted tumor cells internalization and TAMs phagocytosis through neuropilin-1/Fc receptor pathways. Due to AAN deactivation effect, AT pep -NPs can effectively decrease the T pep -induced non-specific uptake by M1-polarized and normal macrophage during systemic circulation. Our results of in vivo experiments demonstrated AT pep -NPs outperformed T pep -NPs in tumor and TAMs dual-targeting delivery efficiency with markedly enhanced efficacy against both tumor growth inhibition and TAMs depletion. Overall, this study offers a novel approach for development of multitargeted delivery vehicle for improved cancer chemotherapy.
研究领域:
药理学
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肿瘤学
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纳米技术
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免疫疗法
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PubMed
高影响因子
JOURNAL OF DRUG TARGETING
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2021
·
IF 5.121
Chunjing Guo,Yanguo Su,Bingjie Wang,Qiang Chen,Huimin Guo,Ming Kong,Daquan Chen
With the increasing number of oncology patients and the use of chemotherapeutic agents, tumour multidrug resistance is becoming more and more prevalent. The search for new tumour treatment strategies to overcome tumour multidrug resistance is urgent. In this study, we designed GSH and ROS dual-responsive tumour-associated macrophages (TAMs)-targeted nanoparticles (NPs) for the co-delivery of the clinical first-line anti-breast cancer chemotherapy drug paclitaxel (PTX) and baicalin (Bai), which re-educates TAMs to alter their phenotype. We synthesised oligohyaluronic acid-mannose-folic acid (oHA-Man-FA, HMF) and astragalus polysaccharide-dithiodipropionic acid-paeoniflorol (APS-S-Pae, ASP), two hybrid materials that can self-assemble in water to form hybrid nanoparticles (HP-NPs) co-loaded with paclitaxel and baicalin (HP-NPs@PTX/Bai). The experimental results show that our designed hybrid nanoparticles can be specifically released in the tumour microenvironment and deliver the antitumor drug PTX as well as Bai, which reshapes the phenotype of TAMs, to the tumour site. The hybrid nanoparticles not only effectively re-educated TAMs from M2 TAM to M1 TAM, but also ameliorated the cytotoxic side effects caused by free PTX and provided better tumour suppression than free PTX and HP.
研究领域:
肿瘤学
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药学
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纳米技术
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免疫治疗
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DOI
PubMed
高影响因子
ACS Applied Materials & Interfaces
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2024
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IF 8.3
Nian-Yuan Xu,Jun Li,Mei-Ling Wang,Xue-Yu Chen,Ruizhi Tang,Xi-Qiu Liu
The current research models of breast cancer are usually limited in their capacity to recapitulate the tumor microenvironment in vitro. The lack of an extracellular matrix (ECM) oversimplifies cell–cell or cell–ECM cross-talks. Moreover, the lack of tumor-associated macrophages (TAMs), that can comprise up to 50% of some solid neoplasms, poses a major problem for recognizing various hallmarks of cancer. To address these concerns, a type of direct breast cancer cells (BCCs)–TAMs coculture organoid model was well developed by a sequential culture method in this study. Alginate cryogels were fabricated with appropriate physical and mechanical properties to serve as an alternative ECM. Then, our previous experience was leveraged to polarize TAMs inside of the cryogels for creating an in vitro immune microenvironment. The direct coculture significantly enhanced BCCs organoid growth and cancer aggressive phenotypes, including the stemness, migration, ECM remodeling, and cytokine secretion. Furthermore, transcriptomic analysis and protein–protein interaction networks implied certain pathways (PI3K-Akt pathway, MAPK signaling pathway, etc.) and targets (TNF, PPARG, TLR2, etc.) during breast cancer progression in a TAM-leading immune microenvironment. Future studies to advance treatment strategies for BCC patients may benefit from using this facile model to reveal and target the interactions between cancer signaling and the immune microenvironment.
研究领域:
肿瘤学
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生物医学工程
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细胞生物学
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免疫学
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组织工程
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DOI
PubMed
高影响因子
JOURNAL OF CONTROLLED RELEASE
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2024
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IF 10.5
Yi Chen,Xian Shu,Jia-Yi Guo,Yun Xiang,Shi-Yu Liang,Jin-Mei Lai,Jia-Yi Zhou,Li-Han Liu,Ping Wang
As a potential treatment strategy for low immunogenic triple negative breast cancer (TNBC), photodynamic therapy (PDT) induced antitumor immunotherapy is greatly limited by the immunosuppressive tumor microenvironment (ITM), especially the M2 phenotype tumor-associated macrophages (TAMs). The balance of arginine metabolism plays an important role in TAMs polarization. Herein, a multifunctional nanoplatform (defined as HN-HFPA) was employed to burst the anti-tumor immunity of TNBC post PDT by reeducating TAMs through interfering the TAMs-associated arginine metabolism. The L -arginine ( L -Arg) was loaded in the hollow cavity of HN-HFPA, which could not only generate nitric oxide (NO) for tumor therapy, but also serve as a substrate of arginine metabolism pathway. As an inhibitor of arginases-1 (Arg-1) of M2 TAMs, L -norvaline ( L -Nor) was modified to the hyaluronic acid (HA), and coated in the surface of HFPA. After degradation of HA by hyaluronidase in tumor tissue and GSH-mediated disintegration, HN-HFPA depleted intracellular GSH, produced remarkable reactive oxygen species (ROS) under light irradiation and released L -Arg to generate NO, which induced tumor immunogenic cell death (ICD). Real-time ultrasound imaging of tumor was realized taking advantage of the gas feature of NO. The L -Nor suppressed the Arg-1 overexpressed in M2, which skewed the balance of arginine metabolism and reversed the ITM with increased ratios of M1 and CD8 + T cells , finally resulted in amplified antitumor immune response and apparent tumor metastasis inhibition . This study remodeled ITM to strengthen immune response post PDT, which provided a promising treatment strategy for TNBC.
研究领域:
癌症生物学
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免疫学
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药学
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生物医学工程
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PubMed
高影响因子
IMMUNOPHARMACOLOGY AND IMMUNOTOXICOLOGY
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2022
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IF 3.712
Yunting Zhang,Yuxi Liu,Jianguang Wang,Zongying Jiang,Lin Zhang,Yong Cui,Danyu Zhao,Yanjie Wang
Objective M2-like tumor-associated macrophages (TAMs) play a crucial role in promoting tumor proliferation, angiogenesis, and metastasis. In the current study, we investigated the relationship between macrophage polarization and the antitumor effect of Atractylenolide II (AT-II) in lung cancer cells.Materials and methods Cell viability, migration, and invasion were determined by MTT assay, wound healing assay, and transwell assay, respectively. Flow cytometry analysis showed the percentage of CD206+ cells. Gene expression was determined by real-time PCR, western blotting, and immunofluorescence staining. Lewis lung carcinoma mouse xenograft and metastasis models were used to examine the effects of AT-II on lung cancer in vivo.Results AT-II (2.5 and 5 µM) did not cause significant inhibition of A549 cell viability but markedly inhibited IL-4/IL-13-induced M2-like polarization, evidenced by the decreased expression of the M2 surface marker CD206, down-regulation of specific M2-marker genes (Arg-1, IL-10 and TGF-β) as well as inhibition of M2 macrophages-mediated invasion and migration of A549 cells. In addition, AT-II inhibited IL-4/IL-13-induced activation of the STAT6 signaling pathway that is vital in the M2-like polarization of macrophages. In animal models, administration of AT-II (50 mg kg−1, i.g., QD for 21 days) significantly inhibited tumor growth, reduced pulmonary metastatic nodules, and down-regulated the percentages of M2 macrophages (F4/80+ and CD206+) in total macrophages (F4/80+) in tumor tissues and pulmonary metastatic nodules.Conclusions AT-II effectively inhibits M2-like polarization, thereby inhibiting lung cancer cell metastasis both in vivo and in vitro, revealing a novel potential strategy for the antitumor effect of AT-II.
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高影响因子
INTERNATIONAL IMMUNOPHARMACOLOGY
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2025
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IF 4.7
Liya Feng,Yuanxin Wang,Xiangyue Wang,Baochan Li,Yifan Liu,Wanying Zhang,Jianbo Ji,Lijun Shao,Xiuli Guo
In the tumor microenvironment (TME), tumor associated macrophages (TAMs) often exhibit a preference for M2-like phenotype, which supports tumor progression under hypoxia. The underlying mechanisms driving the behavior of hypoxic TAMs are highly complex. Recently, exosomal long non-coding RNAs (lncRNAs) derived from non-cancerous cells within TME have attracted more attention from researchers. In the present study, we investigated the function of exosomal lncRNA MIR210HG derived from hypoxic TAMs in triple negative breast cancer (TNBC). Results showed that MIR210HG was significantly upregulated in hypoxic TAMs, their exosomes, and exosomes-treated TNBC cells. When MIR210HG was suppressed, the expression of M2-polarization markers and proteins associated with the PI3K/Akt/mTOR pathway in hypoxic TAMs was notably inhibited. Moreover, the suppression of TAM-derived exosomal MIR210HG effectively inhibited the migration, invasion and vasculogenic mimicry (VM) formation of TNBC cells. Notably, dual inhibition of both exosomal and endogenous MIR210HG in tumor cells synergistically restricted TNBC metastasis of in vivo . Mechanistically, we elucidated that MIR210HG promoted the malignant phenotypes of TNBC by upregulating the expression of HIF-1α protein, which in turn initiated RASSF7 transcription, resulting in the promotion of epithelial-mesenchymal transition (EMT) process. Collectively, our results identified MIR210HG as a key molecule mediating exosome-based communication from hypoxic TAMs to TNBC cells and revealed its pro-metastatic role, Consequently, MIR210HG emerges as a highly promising therapeutic target of TNBC.
研究领域:
癌症生物学
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分子生物学
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免疫学
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细胞生物学
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遗传学
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生物信息学
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DOI
PubMed
高影响因子
Cell Death & Disease
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2026
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IF 12.2
Ge Yutong,Yu Tao,Yu Shaokun,Sun Ao,Zhang Shiyu,Zhang Meiling,Wang Qian,Liu Jia,Zhang Xuan,Zeng Lulin,Lu Kaihua
Tumor-associated macrophages (TAMs) enriched in tumor microenvironment (TME) promote immune evasion and poor prognosis. Mitochondrial dysfunction, especially branched-chain amino acid (BCAA) metabolic reprogramming, has been confirmed to be involved in regulating TAMs function. The mitochondria-related protein MTFR2 was significantly upregulated in LUAD and closely associated with reduced survival. We conducted flow cytometry, multiplex immunofluorescence, immunohistochemistry on LUAD tissues, combined with analysis of public single-cell sequencing datasets, to characterize the TME features under MTFR2 dysregulation. Transcriptomics, metabolomics, and proteomics analyses revealed BCAA metabolic reprogramming, which was driven by MTFR2 binding to Leu125 within the β8 strand of VDAC1 and promoting its oligomerization. This interaction triggered mtDNA release into the cytoplasm, activating the TLR9-NF-κB pathway to upregulate BCAT1. Elevated concentrations of BCAA metabolites such as α-ketoisocaproate (KIC) and α-keto-β-methylvalerate (KMV) in the TME promoted M2 polarization and infiltration of TAMs by in vitro co-culture, 3D spheroid, and organoid models, and polarized M2 macrophages reciprocally promoted LUAD progression. Our findings establish a LUAD associated MTFR2-VDAC1-BCAT1 axis regulating the BCKAs-M2 axis in TAMs. Notably, targeting BCAT1 or depleting macrophages blocked this loop, offering a potential combination therapy for LUAD.
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PubMed
高影响因子
Materials Today Bio
·
2026
·
IF 11
Liang Feng,Huan Wang,Zuodi Liang,Ying Tian,Yang Guo,Zhuo Li
This study focused on developing a novel nanodelivery system, BP-PEG-S2P@H, with hesperetin-loaded black phosphorus nanosheets to target tumor-associated macrophages (TAMs) in triple-negative breast cancer (TNBC). Through RNA sequencing and proteomic analyses, CEBPG upregulation was observed in TAMs, potentially controlling the SLC7A11-mediated ferroptosis pathway. In vitro and in vivo experiments, including FerroOrange and malondialdehyde assays, demonstrated the induction of ferroptosis by BP-PEG-S2P@H. The nanoplatform facilitated the transition of TAMs from the M2 to the M1 subtype, enhancing IL-12 secretion while reducing IL-10 levels. Functional analyses confirmed the reversal of the pro-migratory TAM phenotype and inhibition of tumor cell invasion. In vivo imaging validated efficient tumor targeting, with immunohistochemical staining revealing decreased CEBPG/SLC7A11 expression in tumors, reduced macrophage infiltration, and enhanced CD8 + T cell activation, promoting the efficacy of PD-L1 immunotherapy. Biosafety assessments indicated no apparent toxicity, supporting the potential of the BP-PEG-S2P@H nanoplatform for TAM-targeted nano-immunotherapy in TNBC.
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PubMed
高影响因子
INTERNATIONAL JOURNAL OF BIOLOGICAL MACROMOLECULES
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2023
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IF 8.2
Tingting Liu,Tao Han,Congyan Liu,Chang Ge,Xi Jiang,Yuping Liu,Fei Kong,Xiangyu Su,Jiachen Shi,Wenting Su,Xiaoqi Li,Yan Chen,Huangqin Zhang,Qiuling Ma,Ding Qu
M1 polarization of tumor-associated macrophages (TAMs) is a promising approach to breaking through therapeutic barriers imposed by the immunosuppressive tumor microenvironment (TME). As a clinically-used immunopotentiator for cancer patients after chemotherapies; however, the immunomodulatory mechanism and potential of polyporus polysaccharide (PPS) remains unclear. Here, we present mannose-decorated PPS-loaded superparamagnetic iron-based nanocomposites (Man/PPS-SPIONs) for synergistic M1 polarization of TAMs and consequent combinational anti-breast cancer therapy. Once internalized by M2-like TAMs, PPS released from Man/PPS-SPIONs induces the M1 polarization via IFN-γ secretion and downstream NF-κB pathway activating. The SPIONs within the nanocomposites mediate a Fenton reaction, producing OH· and activating the subsequent NF-κB/MAPK pathway, further facilitating the M1 polarization. The Man/PPS-SPIONs thereby establish a positive feedback loop of M1 polarization driven by the “IFN-γ-Fenton-NF-κB/MAPK” multi-pathway, leading to a series of anti-tumoral immunologic responses in the TME and holding promising potential in combinational anticancer therapies. Our study offers a new strategy to amplify TME engineering by combinational natural carbohydrate polymers and iron-based materials.
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PubMed
高影响因子
Acta Pharmaceutica Sinica B
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2025
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IF 14.6
Xinping Luo,Yingmeng Jiang,Qing Zhang,Jie Yu,Chenxi Zhou,Zhanwei Zhou,Minjie Sun
Tailoring tumor-associated macrophages (TAMs) into the tumoricidal phenotype represents a high-profile strategy for tumor immunotherapy. However, the existing TAMs repolarization strategies are restricted by hostile microenvironmental stress and metabolic compensation, leading to limited anti-tumor phenotype sustainability. Herein, a “Spark-Relay” nanoinitiator (SRN) with flexible S/R reactant ratio was meticulously designed for rewiring TAMs as tumoricidal bioreactor and precisely overcome metabolic compensation. Briefly, SRN reshaped TAMs in situ relying on tissue tropism of macrophage membrane, firstly upregulating their ROS production via burst release of Spark element and initially shifting the TAMs into the anti-tumoral phenotype, subsequently elevating NO production by releasing Relay element, which is converted to NO via reaction with reactive oxygen species and iNOS, leading to the generation of additional ROS and creating a positive feedback loop, thereby strengthening the metabolic rewiring of TAMs from passively defensive oxidative phosphorylation to positively offensive glycolysis, which significantly enhanced the antitumoral activity of TAMs and shrunk tumor immunosuppressive microenvironment, emerging as 5.5-fold increase of tumor-suppressive/supportive ratio (TSSR) of TAMs, 4.0-fold elevation of CD8 + T cell infiltration, contributing to a satisfactory tumoricidal efficacy and providing a cascade amplification mode for TAMs-based cancer therapeutics.
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高影响因子
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