MOLECULAR PHARMACEUTICS
·
2018
·
IF 4.556
Jiamin Wu,Zhi Li,Zeping Yang,Ling Guo,Ye Zhang,Huihui Deng,Cuifeng Wang,Min Feng
It is not efficient enough using the current approaches for tumor-selective drug delivery based on the EPR effect and ligand–receptor interactions, and they have largely failed to translate into the clinic. Therefore, it is urgent to explore an enhanced strategy for effective delivery of anticancer agents. Clinically, many cancers require large amounts of glutamine for their continued growth and survival, resulting in circulating glutamine extraction by the tumor being much greater than that for any organs, behaving as a “glutamine trap”. In the present study, we sought to elucidate whether the glutamine-trap effect could be exploited to deliver therapeutic agents to selectively kill cancer cells. Here, a macromolecular glutamine analogue, glutamine-functionalized branched polyethylenimine (GPI), was constructed as the carrier to deliver anti-CD47 siRNA for the blockage of CD47 “don’t eat me” signals on cancer cells. The GPI/siRNA glutamine-rich polyplexes exhibited remarkably high levels of cellular uptake by glutamine-dependent lung cancer cells, wild-type A549 cells (A549WT), and its cisplatin-resistant cells (A549DDP), specifically under glutamine-depleted conditions. It was noted that the glutamine transporter ASCT2 was highly expressed both on A549WT and A549DDP but with almost no expression in normal human lung fibroblasts cells. Inhibition of ASCT2 significantly prevented the internalization of GPI polyplexes. These findings raised the intriguing possibility that the glutamine-rich GPI polyplexes utilize the ASCT2 pathway to selectively facilitate their cellular uptake by cancer cells. GPI further delivered anti-CD47 siRNA efficiently both in vitro and in vivo to downregulate the intratumoral mRNA and protein expression levels of CD47. CD47 functions as a “don’t eat me” signal and binds to the immunoreceptor SIRPα inducing evasion of phagocytic clearance. GPI/anti-CD47 siRNA polyplexes achieved significant antitumor activities both on A549WT and A549DDP tumor-bearing nude mice. Notably, it had no adverse effect on CD47-expressing red blood cells and platelets, likely because of selective delivery. Therefore, the glutamine-rich carrier GPI driven by the glutamine-trap effect provides a promising new strategy for designing anticancer drug delivery systems.
研究领域:
肿瘤学
·
药学
·
分子生物学
·
癌症治疗
✓ 已验证
产品关联
DOI
PubMed
高影响因子
JOURNAL OF CONTROLLED RELEASE
·
2023
·
IF 10.8
Ming Gong,Yufeng Huang,Huixiong Feng,Jiaming Lin,Anfei Huang,Jinxin Hu,Qinglian Tang,Xiaojun Zhu,Shisong Han,Jinchang Lu,Jin Wang
Treatments for osteosarcoma (OS) with pulmonary metastases reach a bottleneck with a survival rate of 10–20%. The suppressive tumor associated macrophages(TAMs) and CD47 over-expression greatly lead to the treatment failure. Sonodynamic therapy (SDT) can generate ROS with deep tumor penetration to induce tumor cell apoptosis , which is reported to further induce M1 macrophage polarization. CD47 inhibition combined with SDT to synergistically modulate TAMs may induce superior effects for OS treatment. In this work, for the first time, a biomimetic nanodrug named MPIRx was deveploped by loading IR780 (a sonosensitizer) and RRx-001 (a CD47 inhibitor) in PEG-PCL nanomicelles and then coating with OS cell membranes . After ultrasound activation, the nanodrug significantly inhibited OS proliferation and migration, induced apoptosis and immunogenic cell death in OS cells. Furthermore, MPIRx could guide macrophage migrating towards tumor cells and promote M1-type polarization while increasing the phagocytosis activity of macrophages on OS cells. Ultimately, MPIRx showed good tumor accumulation in vivo and successfully inhibited subcutaneous OS and orthotopic tumor with deterioration of pulmonary metastasis. Overall, by creating a local oxidative microenvironment and modulating the TAMs/CD47 in tumor tissue, the MPIRx nanodrug presents a novel strategy for macrophage-related immunotherapy to successfully eliminate OS and inhibit the intractable pulmonary metastasis.
研究领域:
肿瘤学
·
药学
·
免疫治疗
·
纳米技术
·
癌症生物学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Advanced Healthcare Materials
·
2024
·
IF 10
Haipeng Tan,Weiyan Li,Zhiqing Pang,Xueyi Weng,Jinfeng Gao,Jing Chen,Qiaozi Wang,Qiyu Li,Hongbo Yang,Zheng Dong,Zhengmin Wang,Guangrui Zhu,Yiwen Tan,Yuyuan Fu,Chengzhi Han,Shiteng Cai,Juying Qian,Zheyong Huang,Yanan Song,Junbo Ge
Efferocytosis, mediated by the macrophage receptor MerTK (myeloid-epithelial-reproductive tyrosine kinase), is a significant contributor to cardiac repair after myocardial ischemia-reperfusion (MI/R) injury. However, the death of resident cardiac macrophages (main effector cells), inactivation of MerTK (main effector receptor), and overexpression of “do not eat me” signals (brake signals, such as CD47), collectively lead to the impediment of efferocytosis in the post-MI/R heart. To date, therapeutic strategies targeting individual above obstacles are relatively lacking, let alone their effectiveness being limited due to constraints from the other concurrent two. Therefore, we aim to develop a strategy that challenges all three barriers in an integrated manner. Methods : We design a collaborative drug delivery strategy based on genetically modified macrophage therapy. The genetic engineering of exogenous macrophages involves overexpression of C-C chemokine receptor type 2 (CCR2) and cleavage-resistant MerTK (MerTK CR ) by adenovirus. Liposomes loaded with PEP-20 (a CD47 antagonist) are then anchored to the engineered macrophage surface by click chemistry. Results : CCR2 targets exogenous macrophages to the injured heart as a direct supplement to efferocytosis effector cells, while MerTK CR preserves functional intact locally. PEP-20 is responsively released to block the braking effect of CD47 on cardiac efferocytosis. In MI/R mice model, this synergistic strategy can effectively restore cardiac efferocytosis after intravenous injection, thereby alleviating the inflammatory response, ultimately preserving cardiac function. Conclusion : Genetically engineered macrophages co-loaded with CD47 inhibitors synergistically reconstruct efferocytosis and improve cardiac remodeling post MI/R injury. This article is protected by copyright. All rights reserved
研究领域:
心脏病学
·
分子生物学
·
药理学
·
基因工程
✓ 已验证
产品关联
DOI
PubMed
高影响因子
ACS Nano
·
2023
·
IF 17.1
Yurong Wei,Min Zhao,Tianpei He,Na Chen,Li Rao,Long Chen,Yun Zhang,Yanbing Yang,Quan Yuan
Immunotherapy including immune checkpoint inhibition has reinvigorated the current cancer treatment field. The development of efficient cancer immunotherapies depends on a thorough understanding of the status of immune checkpoints and how they interact. However, the distribution and spatial organization changes of immune checkpoints during their interactions at the single-molecule level remain difficult to directly visualize due to the lack of in situ imaging techniques with appropriate spatial and stoichiometric resolution. Herein, we report the direct visualization and quantification of the spatial distribution and organization of CD47 on the bladder tumor cell membrane and SIRPα on the macrophage membrane by using a single-molecule localization imaging technique called quantitative direct stochastic optical reconstruction microscopy (QdSTORM). Results showed that a portion of CD47 and SIRPα was present on cell membranes as heterogeneous clusters of varying sizes and densities prior to activation. Quantitative analyses of the reconstructed super-resolution images and theoretical simulation revealed that CD47 and SIRPα were reorganized into larger clusters upon binding to each other. Furthermore, we found that blocking the immune checkpoint interaction with small-molecule inhibitors or antibodies significantly impacted the spatial clustering behavior of CD47 on bladder tumor cells, demonstrating the promise of our QdSTORM strategy in elucidating the molecular mechanisms underlying immunotherapy. This work offers a promising strategy to advance our understanding of immune checkpoint state and interactions while also contributing to the fields including signal regulation and cancer therapy.
研究领域:
癌症生物学
·
免疫学
·
显微镜技术
·
细胞生物学
·
分子生物学
✓ 已验证
DOI
PubMed
高影响因子
PHARMACOLOGICAL RESEARCH
·
2024
·
IF 9.1
Xiaozhi Hu,Yanyang Nan,Yuting Zhang,Jiajun Fan,Hanqi Wang,Yu Bai,Yuanzhen Zhang,Xuyao Zhang,Zeguo Zhu,Zhonglian Cao,Xiaomiao Ye,Tao Wu,Shuwen Xu,Zhengyu Wu,Wei Hu,Dianwen Ju
Atherosclerosis (AS) ultimately cause major adverse cardiovascular events (MACEs). While traditional strategies by lipid-reducing have reduced MACEs, many patients continue to face significant risks. It might attribute to the upregulation of CD47 expression in AS lesions, that mediated anti-efferocytosis of macrophages. Therefore, we propose simultaneously blocking ANGPTL3, a vital regulator of lipid metabolism, and CD47 might be a potential approach for AS therapy. Firstly, we investigate the role of a novel anti-ANGPTL3 nanobody-Fc (FD03) in AS. We found that FD03 treatment significantly decreased circulating lipids, plaque size, and lipid deposition in apoE -/- mice compared to control Ab, but there was a twofold increase in plaque formation in comparison to baseline. However, immunofluorescence indicated the upregulation of CD47 expression in the plaques even after FD03 treatment compared to normal vascular tissue. Next, a bifunctional protein containing signal regulatory protein alpha (SIRPα) and FD03 (SIRPαD1-FD03) was constructed to block CD47 and ANGPTL3 concurrently, which had high purity, robust stability, and high affinity to CD47 and ANGPTL3 with biological activity in vitro . Furthermore, SIRPαD1-FD03 fusion protein exhibited the enhanced therapeutic effect on AS compared with SIRPαD1-Fc or FD03, regressing plaque contents and the necrotic core equal to baseline. Mechanistically, SIRPαD1-FD03 reduced serum lipids, augmented the efferocytosis rate and macrophage M2 polarization, and decreased the reactive oxygen species (ROS) and lipid peroxidation level in atherosclerotic plaques. Collectively, our project suggests an effective approach for AS by simultaneously blocking ANGPTL3 and CD47 to regulate lipid metabolism, macrophage activity and lipid peroxidation.
研究领域:
心血管疾病
·
免疫学
·
药理学
·
分子生物学
✓ 已验证
DOI
高影响因子
Advanced Healthcare Materials
·
2024
·
IF 10
Huanhuan Wang,Runze Zhao,Lei Peng,Ao Yu,Yongjian Wang
Atherosclerosis is a primary contributor to cardiovascular disease. Current studies have highlighted the association between the immune system, particularly immune cells, and atherosclerosis, although treatment options and clinical trials remain scarce. Immunotherapy for cardiovascular disease is still in its infancy. Bruton's tyrosine kinase (BTK), widely expressed in various immune cells, represents a promising therapeutic target for atherosclerosis by modulating the anti-inflammatory function of immune cells. This study introduces a polydopamine-based nanocarrier system to deliver the BTK inhibitor, ibrutinib, to atherosclerotic plaques with an active targeting property via an anti-CD47 antibody. Leveraging polydopamine's pH-sensitive reversible disassembly, the system offers responsive, controlled release within the pathologic microenvironment. This allows precise and efficient ibrutinib delivery, concurrently inhibiting the activation of the NF-κB pathway in B cells and the NLRP3 inflammasome in macrophages within the plaques. This treatment also modulates both the immune cell microenvironment and inflammatory conditions in atherosclerotic lesions, thereby conveying promising therapeutic effects for atherosclerosis in vivo. This strategy also provides a novel option for atherosclerosis treatment.
研究领域:
心脏病学
·
免疫学
·
纳米医学
·
药理学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
BIOMATERIALS
·
2021
·
IF 12.479
Lili Cheng,Xiaoge Zhang,Junjie Tang,Qijun Lv,Jie Liu
CD47 , overexpressed on kinds of tumor cells, activates a “don't eat me” signal through binding to signal regulatory protein α (SIRPα), leading to immune escape from the mononuclear phagocyte system (MPS). It is also a huge challenge to deliver therapeutic drugs to the tumor sites due to the short retention time in blood, poor targeting of tumor cells and accelerated clearance by MPS. Herein, we designed a hybrid therapeutic nanovesicles, named as hGLV, by fusing gene-engineered exosomes with drug-loaded thermosensitive liposomes . We demonstrated that the CD47-overexpressed hGLV exhibited the long blood circulation and improved the macrophages-mediated the phagocytosis of tumor cells by blocking CD47 signal. Moreover, the resulted hGLV could remarkably target the homologous tumor in mice, achieving the preferential accumulation at the tumor sites. Importantly, hGLV loading the photothermal agent could achieve the excellent photothermal therapy (PTT) under laser irradiation after the intravenous injection, completely eliminating the tumors, leading to immunogenic cell death and generating substantial tumor-associated antigens, which could promote the maturation of immature dendritic cells with the help of the co-encapsulated immune adjuvant to trigger strong immune responses. Generally, the hybrid nanovesicles based on CD47 immune check point blockade can be a promising platform for the drug delivery in cancer treatment.
研究领域:
纳米技术
·
癌症治疗
·
免疫学
·
药物递送系统
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Nature Communications
·
2024
·Vol. 15
·期 1
·1-19
·
IF 14.7
Zhang Weiqi,Zeng Yinghua,Xiao Qiuqun,Wu Yuanyuan,Liu Jiale,Wang Haocheng,Luo Yuting,Zhan Jie,Liao Ning,Cai Yanbin
Targeted immunomodulation for reactivating innate cells, especially macrophages, holds great promise to complement current adaptive immunotherapy. Nevertheless, there is still a lack of high-performance therapeutics for blocking macrophage phagocytosis checkpoint inhibitors in solid tumors. Herein, a peptide-antibody combo-supramolecular in situ assembled CD47 and CD24 bi-target inhibitor (PAC-SABI) is described, which undergoes biomimetic surface propagation on cancer cell membranes through ligand-receptor binding and enzyme-triggered reactions. By simultaneously blocking CD47 and CD24 signaling, PAC-SABI enhances the phagocytic ability of macrophages in vitro and in vivo, promoting anti-tumor responses in breast and pancreatic cancer mouse models. Moreover, building on the foundation of PAC-SABI-induced macrophage repolarization and increased CD8 + T cell tumor infiltration, sequential anti-PD-1 therapy further suppresses 4T1 tumor progression, prolonging survival rate. The in vivo construction of PAC-SABI-based nano-architectonics provides an efficient platform for bridging innate and adaptive immunity to maximize therapeutic potency.
研究领域:
免疫学
·
肿瘤学
·
生物技术
·
药学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
PHYTOTHERAPY RESEARCH
·
2025
·
IF 6.3
Xue He,Yinting Lu,Hao Zhang,Bing Lin,Huijiao Lu,Zhaoan Yu,Yan Li,Qing Xi,Rongxin Zhang
Pancreatic cancer is a common malignant tumor of the digestive tract, with insidious onset and rapid metastasis. Most patients have already developed to an advanced stage at the time of diagnosis, and the fatality rate is very high. In recent years, immunotherapy has emerged as a promising potential treatment for pancreatic cancer. Some studies have shown that piperine has the potential to inhibit pancreatic cancer, but the role of piperine in tumor progression and tumor immunity in vivo remains unclear. The effects and mechanisms of piperine on the immunity of pancreatic cancer were studied. The effects of piperine on the proliferation, migration and apoptosis of pancreatic cancer Panc02 and PANC-1 cells were detected by CCK-8, plate colony formation, CFSE staining, wound healing, transwell and flow cytometry. The effects of piperine on the growth, metastasis and immune microenvironment of pancreatic cancer were studied by constructing subcutaneous and orthotopic pancreatic cancer models in mice and using live animal imaging and flow cytometry. The intersection targets of piperine and pancreatic cancer were analyzed by network pharmacology and RNA-seq, and the key genes of immune cell changes were identified. The specific effects of piperine on CD47 in pancreatic cancer tissues and cells were studied by immunohistochemistry, flow cytometry, qRT-PCR, and Western blot. Tumor cells were cocultured with peritoneal/bone marrow-derived macrophages or CD8 + T cells to explore the cellular mechanism, and the phagocytosis of macrophages and the activation of CD8 + T cells were detected by immunofluorescence, magnetic bead sorting and flow cytometry. In the in vitro experiments, piperine inhibited the proliferation and migration of the pancreatic cancer cell lines Panc02 and PANC-1, and induced its apoptosis. In the in vivo experiments, piperine inhibited the growth and metastasis of subcutaneous and orthotopic pancreatic tumors in mice. In the immune microenvironment, piperine significantly increased the proportion of macrophages, especially M1-type macrophages, as well as the proportion of CD8 + T cells in the tumor and spleen. Moreover, piperine reduced the expression of CD47 at the mRNA and protein levels of pancreatic cancer cells, thus enhancing the phagocytosis of macrophages toward tumor cells, and increasing the activation level of CD8 + T cells. Our results suggest that piperine enhances its antitumor immunity in pancreatic cancer by blocking the immune checkpoint CD47. Therefore, piperine is expected to provide a new approach for the immunotherapy of pancreatic cancer.
研究领域:
肿瘤学
·
免疫学
·
药理学
·
分子生物学
·
癌症免疫治疗
✓ 已验证
产品关联
DOI
PubMed
高影响因子
ADVANCED MATERIALS
·
2025
·
IF 26.8
Hua Huang,Qi-Song Tong,Jing-Yang Zhang,Wei-Min Miao,Hui-Han Yu,Jun Wang,Song Shen,Jin-Zhi Du
The phagocytosis of macrophages to tumor cells represents an alluring strategy for cancer immunotherapy; however, its effectiveness is largely hindered by the detrimental upregulation of anti-phagocytic signals and insufficient expression of pro-phagocytic signals of tumor cells. Here, a pro-phagocytic polymer-based nanocomplex is designed to promote the macrophage engulfment of tumor cells through concurrent modulation of both the “eat me” and “don't eat me” signals. The nanocomplex MNC CD47i-CALRt is formed by complexing a synthetic PAMAM derivative (G4P–C7A) that is capable of intrinsically inducing the exposure of calreticulin (CALR, a crucial pro-phagocytic protein) and a small inference RNA that can inhibit the expression of CD47 (a primary anti-phagocytic protein). MNC CD47i-CALRt can significantly delay tumor growth and prolong the survival of tumor-bearing mice with negligible hematopoietic toxicity in multiple murine colorectal cancer models. Furthermore, the pro-phagocytic capacity of MNC CD47i-CALRt is validated in the patient-derived tumor organoid model. Collectively, the phagocytosis-promoting nanocomplex provides a simple and potent strategy for boosting macrophage-mediated cancer immunotherapy.
研究领域:
肿瘤学
·
免疫学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
CHEMICAL ENGINEERING JOURNAL
·
2025
·
IF 13.2
Yaru Zhang,Wenyu Xie,Jiamin Luo,Rui Gao,Zhimin Gao,Xinyi Wang,Yongxin Huang,Chen Lin,Meiling Tan,Zhiyao Hou
Effectively activating macrophages to engulf tumor cells has attracted intensive attention in cancer immunotherapy. However, tumor cells can upregulate anti-phagocytic signals (such as CD47 molecules) to bind with signal regulatory protein-α (SIRPα), ultimately providing a “don’t eat me” signal to evade phagocytosis. Blockading CD47 alone is insufficient to stimulate macrophages phagocytosis due to the absence of endogenous activating signals (“eat me” signal). Herein, a mesoporous silica (MSN) modified by Cu 9 S 5 nanoparticle with mimicking enzyme activities were synthesized and utilized to electrostatically load the anti-CD47 antibodies (aCD47), generating MCC nanozymes, to improve macrophage-mediated cancer immunotherapy. MCC nanozymes can target tumor cells by specifically binding to the cell-surface CD47, disabling the “don’t eat me” signal. Meanwhile, under near infrared light (1064 nm) stimulation, MCC nanozymes exhibit the enhanced glutathione oxidase-like and peroxidase-like enzymatic activities by the photothermal effect, which lead the reactive oxygen species (ROS) generation to induce endoplasmic reticulum (ER) stress amplification, resulting the exposure of calreticulin (CALR) for providing the endogenous “eat-me” signals to macrophages. In a 4T1 breast cancer model, even under mild photothermal condition, MCC nanozymes effectively inhibit tumor growth and metastasis. Collectively, this dual-regulatory strategy presents a promising approach for macrophage-mediated cancer immunotherapy.
研究领域:
肿瘤学
·
免疫学
✓ 已验证
产品关联
DOI
高影响因子
ADVANCED FUNCTIONAL MATERIALS
·
2025
·
IF 19
Haoting Chen,Ding Yang,Dongyue He,Zechuan Li,Gengyou Li,Jing Ma,Jiaqing Wan,Meifen Luo,Qi Chen,Yansong Liu,Qihan Zhang,Yanwen Liang,Ying-Shi Sun,Weisheng Guo,Lu Liu
Immune checkpoint blockade (ICB) therapies have transformed the management of metastatic and advanced malignancies. A novel therapeutic paradigm targeting CD47 has emerged as a promising approach to enhance macrophage-mediated tumor phagocytosis; however, systemic toxicity stemming from nonspecific antibody distribution remains a critical clinical challenge. To address this limitation, a modular nanoparticle system, termed Differentiation Responsive Architected Macrophage (DREAM), was engineered to exploit intrinsic macrophage homing for tumor-specific co-delivery of anti-CD47 antibodies (aCD47) and Resiquimod (R848). This platform circumvents reliance on tumor microenvironment-derived matrix metalloproteinase-9 (MMP-9) by utilizing autocrine MMP-9 secretion to initiate spatially controlled drug release, while simultaneously amplifying protease production via dynamic macrophage differentiation. In vitro analyses demonstrated stimulus-responsive payload dissociation kinetics. In vivo evaluation in murine tumor models revealed that systemic DREAM administration induced robust tumor regression following three treatment cycles, concomitant with a shift in immune microenvironment polarization from an immunosuppressive to pro-inflammatory phenotype. By integrating autonomous activation mechanisms with cell-specific targeting, this strategy establishes a macrophage-centric delivery platform that enhances therapeutic precision, mitigates off-tissue toxicity, and augments antitumor efficacy, thereby advancing the translational potential of next-generation ICB modalities.
研究领域:
肿瘤学
·
免疫学
·
纳米医学
✓ 已验证
产品关联
DOI
高影响因子
危险品化学品经营许可证（带存储）