ADVANCED FUNCTIONAL MATERIALS
·
2024
·
IF 18.5
Jiahui Yan,Haoyu Chen,Carlos F. Guimarães,Rui L. Reis,Zhihua Zhu,Tianyi Wang,Fenglan Zhang,Yaqian Lv,Qihui Zhou,Xiaoying Kong,Jinsheng Shi
Ion interference including copper (Cu + )/calcium (Ca 2+ ) overload activate cell-specific death channels, damage mitochondria and disrupt cellular homeostasis, showing great potential in anti-tumor therapy. However, the complex metabolic environment and the powerful self-protection of tumors cause clinical failure of ion interference. Thus, metabolic disruption is expected an innovative strategy for the enhancement of ion interference. Herein, CuS-α-CHCA&penthiopyrad@CaCO 3 -RGD nanoparticles (CCPCR NPs) are prepared to provide a Cu + /Ca 2+ dual-overload anti-tumor therapy assisted by metabolic-symbiosis-destruction strategy, realizing the collapse of tumor self-protection. Specifically, precise CuS and CaCO 3 delivery triggered irreversible Cu + /Ca 2+ dual-overload and reactive oxygen species (ROS) attack toward 4T1 cells. Meanwhile, α-CHCA and penthiopyrad disturbed the metabolic symbiotic environment by disrupting the TCA cycle and preventing lactate efflux to aggravate intracellular acidosis and promote Fenton-like reaction of Cu + , enhancing the sensitivity of tumor cells to copper death and Ca 2+ overload. Further, aided by the metabolism of symbiosis, the destroyed tumor cells further activate the polarization of M1 macrophages and the maturation and antigen cross-presentation of dendritic cells (DCs), which further eliminate tumor cells. In summary, an amplified anti-tumor dual-ion interference strategy assisted by metabolic symbiotic destruction is established, which is of great significance in improving the clinical effect of ion therapy for tumors.
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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产品关联
DOI
高影响因子
Theranostics
·
2021
·
IF 11.556
Yuce Li,Yuchen Lou,Yu Chen,Jing Yang,Danqi Li,Biling Jiang,Jiajia Lan,Jingjing Wen,Yangxue Fu,Yamin Zhang,Juan Tao,Jintao Zhu
Immune-mediated inflammatory diseases (IMIDs) are characterized by immune dysregulation and severe inflammation caused by the aberrant and overactive host immunological response. Mycophenolic acid (MPA)-based immunosuppressive drugs are potential treatments for IMIDs because of their mild side-effect profile; however, their therapeutic effects are limited by the high albumin binding rate, unsatisfactory pharmacokinetics, and undefined cellular uptake selectivity. Methods: Polysaccharide mycophenolate was synthesized by conjugating MPA molecules to dextran (a typical polysaccharide widely used in drug delivery) and encapsulated extra free MPA molecules to fabricate MPA@Dex-MPA nanoparticles (NPs). The efficacy of these NPs for mediating immunosuppression and treatment of IMIDs was evaluated in imiquimod-induced psoriasis-like skin inflammation in Balb/c mice, a representative IMID model. Results: The MPA@Dex-MPA NPs exhibited high MPA loading efficiency, low albumin binding rates, and sustained MPA release, resulting in improved pharmacokinetics in vivo . Compared to free MPA, MPA@Dex-MPA NPs induced more robust therapeutic effects on IMIDs. Mechanistic studies indicated that MPA@Dex-MPA NPs were primarily distributed in dendritic cells (DCs) and significantly suppressed the overactivated DCs in vivo and in vitro . Furthermore, the recovered DCs rehabilitated the IL-23/Th17 axis function and significantly ameliorated imiquimod-induced psoriasis-like skin inflammation. Importantly, MPA@Dex-MPA NPs showed favorable safety and biocompatibility in vivo . Conclusion: Our results indicated the polysaccharide mycophenolate-based NPs to be highly promising for IMID treatment.
研究领域:
药学
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免疫学
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纳米技术
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炎症研究
✓ 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
JOURNAL OF NANOBIOTECHNOLOGY
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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
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药物递送系统
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免疫疗法
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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
COLLOIDS AND SURFACES B-BIOINTERFACES
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2020
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IF 4.389
Mengyue Pei,Rong Xu,Chuangnian Zhang,Xiaoli Wang,Chen Li,Yunzhang Hu
Cancer immunotherapy is an important tumor therapy option for prevention and treatment of tumors and has attracted tremendous interests. However, the therapeutic outcomes are limited by insufficient antigen uptake and presentation by antigen-presenting cells such as dendritic cells (DCs). In this study, mannose-functionalized antigen nanoparticles with endosome escape activity were designed for targeted DCs, accelerated endosomal escape and enhanced MHC-I antigen presentation for cancer immunotherapy. Mannose was selected as DCs targeting ligand to enhance antigen uptake. Model antigen ovalbumin (OVA) was directly conjugated with mannose to obtain DCs targeting antigen, which was then complexed with polyethylenimine (PEI) through electrostatic interaction to form mannose-functionalized antigen nanoparticles (MAN-OVA/PEI NPs). Flow cytometry analysis revealed that the MAN-OVA/PEI NPs greatly increased antigen uptake by DCs compared with OVA/PEI NPs. Confocal laser scanning microscopy further demonstrated that MAN-OVA/PEI NPs enhanced cytosolic antigen release. Moreover, MAN-OVA/PEI NPs significantly promoted cytokine production and DCs maturation in vitro . More importantly, MAN-OVA/PEI NPs treated DCs exhibited enhanced cross-presentation to B3Z T cell hybridoma in vitro . This work suggests that mannose-functionalized antigen nanoparticles provide a versatile delivery vehicle for targeted DCs, accelerated endosomal escape and enhanced MHC-I antigen presentation for cancer immunotherapy.
研究领域:
癌症免疫治疗
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纳米技术
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免疫学
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药学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Vaccines
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2021
·Vol. 9
·期 7
·786
·
IF 4.422
Linpei Guo,Hui Xie,Zheng Zhang,Zhun Wang,Shuanghe Peng,Yuanjie Niu,Zhiqun Shang
(1) Background: There are currently limited treatments for castration-resistant prostate cancer. Immunotherapy involving Sipuleucel-T has increasingly drawn attention for prostate cancer management. BCG plays a vital role in treating bladder cancer, mainly by inducing immune activation, but is rarely used for prostate cancer. (2) Methods: The TCGA database, PCR, and Western blotting were used to analyze the expression of STEAP1 in mouse and human tissues. Then, we constructed a fusion protein vaccine withMycobacterium tuberculosisAg85B and three repeated octapeptide epitopes of a six-transmembrane epithelial antigen of the prostate 1 (STEAP1186-193), Ag85B-3×STEAP1186-193. The uptake of the fusion protein vaccine by DCs was evaluated by confocal microscopy, and DC markers were detected using flow cytometry after incubation with the fusion protein. The immune response against prostate cancer was evaluated by the LDH assay and xenografts in vitro and in vivo. Then, the tumor microenvironment was determined using IHC and ELISA. In addition, the epitope was mutated using CRISPR-Cas9 to illustrate that the fusion protein elicited immunization against STEAP1. (3) Results: The TCGA database analysis, PCR, and Western blotting showed that STEAP1 was highly expressed in human and murine prostate cancer. After the uptake of the purified fusion protein vaccine by DCs, CD11c, CD80, CD86, and MHC II were upregulated and triggered a cytotoxic T lymphocyte (CTL) response against TRAMP-C1 and RM1 cells in vitro. Furthermore, the fusion protein vaccine inhibited tumor growth and improved the tumor microenvironment in vivo, with more CD3+cells and fewer FOXP3+cells in the tumor. Serum IFN-γ and IL-2 were significantly higher than in the control group, while IL-4 expression was lower, indicating that the fusion protein vaccine activated Th1 immunity. The immune response against prostate cancer was greatly suppressed when the antigen targets were knocked out using CRISPR-Cas9. (4) Conclusion: In summary, our results provide the first evidence that a vaccine based on a fusion protein consisting of Ag85B and a prostate cancer octapeptide epitope with complete Freund’s adjuvant (CFA), triggers a robust immune response and inhibits tumor growth in murine prostate cancer.Keywords:Ag85B;Mycobacteriumtuberculosis;STEAP1;six-transmembrane epithelial antigen of the prostate 1;immune response;prostate cancer;castration-resistant prostate cancer (CRPC)
研究领域:
肿瘤学
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免疫学
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分子生物学
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癌症免疫疗法
✓ 已验证
DOI
PubMed
高影响因子
CARBOHYDRATE POLYMERS
·
2024
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IF 10.7
Jianxiang Xu,Yanyan Zhang,Yilu Zheng,Tong Wang,Huan Zhang,Kai Wang,Yu Wang,Gareth R. Williams,Li-Min Zhu
In this work we present a near-infrared (NIR)-operated nanoswitch based on chitosan nanoparticles (EpCAM-CS-co-PNVCL@IR780/IMQ NPs) that induces cascade immunogenic tumor ferroptosis via cytokine storm. The formulation was prepared by loading a photosensitiser (IR780) and an immunotherapeutic drug (imiquimod; IMQ) into temperature- and pH-responsive chitosan-based NPs functionalized with tumor-targeting aptamers. The EpCAM aptamer can chaperone the NPs selectively into cancer cells, and allow them to enter the cell nucleus. In vi tr o and in vi v o assays revelaed that the NPs were able to effectively induce the immunogenic ferroptosis of cancer cells. Under NIR irradiation, EpCAM-CS-co-PNVCL@IR780/IMQ cause cell death in tumors via photothermal therapy. Moreover, IMQ promotes the maturation of dendritic cells (DCs), which then activate cytotoxic T-lymphocytes (CTLs); these T-cells go on to provide immunotherapy of metastatic tumor cells. The metastatic tumor cells can be induced to undergo ferroptosis by the addition of arachidonic acid (AA), which interacts with interferon cytokines (IFN- γ ) released from CTLs.
研究领域:
癌症治疗
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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
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药学科学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Journal of Advanced Research
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2024
·
IF 11.4
Chunhua Huang,Cheng Lyu,Heung-Lam Mok,Yiqi Xu,Ka-Wing Cheng,Cheng Zhang,Die Hu,Lin Zhu,Chengyuan Lin,Xin Chen,Hor-Yue Tan,Zhaoxiang Bian
Introduction Ulcerative colitis (UC) is a chronic inflammatory disease characterized by loss of immune tolerance to luminal antigens and progressive intestinal tissue injury. Thus, the re-establishment of immune tolerance is crucial for suppressing aberrant immune responses and UC progression. Objectives This study aimed to investigate the mechanisms underlying the action of CDD-2103 and its bioactive compounds in mediating immune regulation in mouse models of colitis. Methods Two experimental colitis models, chronic 2,4,6-trinitrobenzene sulfonic acid (TNBS)- and T-cell transfer-induced Rag1 -/- mice, were used to determine the effects of CDD-2103 on colitis progression. Single-cell transcriptome analysis was used to profile the immune landscape and its interactions after CDD-2103 treatment. Liquid chromatography-mass spectrometry (LC-MS) was used to analyze the major components interacting with lymphoid cells. A primary cell co-culture system was used to confirm the effects of bioactive component. Results CDD-2103 dose-dependently suppresses the progression of colitis induced by chemicals or T cell transplantation in Rag1 -/- mice. The effect of CDD-2103 is primarily attributable to an increase in the de novo generation of regulatory T cells (Tregs) in the lamina propria (LP). Single-cell transcriptomic analysis revealed that CDD-2103 treatment increased the number of tolerogenic dendritic cells (DCs). Mechanistically, CDD-2103 promoted tolerogenic DCs accumulation and function by upregulating several genes in the electron transport chain related to oxidative phosphorylation, leading to increased differentiation of Tregs. Further LC-MS analysis identified several compounds in CDD-2103, particularly those distributed within the mesenteric lymph nodes of mice. Subsequent studies revealed that palmatine and berberine promoted tolerogenic bone marrow-derived dendritic cells (BMDC)-mediated Treg differentiation. Conclusion Overall, our study demonstrated that the clinically beneficial effect of CDD-2103 in the treatment of UC is based on the induction of immune tolerance. In addition, this study supports berberine and palmatine as potential chemical entities in CDD-2103 that modulate immune tolerance.
研究领域:
免疫学
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药理学
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胃肠病学
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分子生物学
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细胞生物学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
ACS Omega
·
2019
·
IF 2.584
Jiang Ni,Ying Sun,Jinfang Song,Yiqing Zhao,Qiufang Gao,Xia Li
Recent studies have identified photodynamic therapy (PDT) as a promising approach for cancer treatment. Here, in this study, we have constructed cancer cell membrane (CCM)-coated silica nanoparticles (SIL) as an artificial cell carrier (CCM/SIL) to effectively deliver chlorin e6 (Ce6), a commonly adopted photodynamic reagent (CCM/SIL/Ce6), to achieve enhanced PDT of cancer. In addition, apart from the generally recognized cytotoxicity induced by reactive oxygen species (ROS), our study also revealed that ROS could further potentiate the loss of intercellular junctions and integrity disruption as a result of down-regulation of VE-cadherin and CD31. Consequently, dendritic cells (DCs) were more readily accumulated to the tumor tissue and became maturated, which secreted tumor necrosis factor-α and interleukin-12 (IL-12) to trigger the following immune responses. Our work not only explored the anticancer feasibility of a new system but also demonstrated the underlining mechanisms responsible for PDT-induced anticancer effects, which offers a new perspective to employ and improve the efficacy of PDT and related systems.
研究领域:
肿瘤学
·
纳米技术
·
免疫治疗
·
光动力疗法
✓ 已验证
产品关联
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
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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
Nano Research
·
2022
·Vol. 15
·期 9
·8326-8335
·
IF 10.269
Li Xiangxia,Chen Guiyuan,Wang Yangyi,Su Lanhong,Chen Bo,Wu Kecheng,Xing Yun,Song Zechenxi,Dai Ruike,Liu Tianxin,Zhao Jiaao,Xie Zhe,Zhou Peijie,Xia Xiaoping,Min Yuanzeng
In the tumor immunosuppressive microenvironment (TIME), antigen presenting cells (APCs) usually exhibit a tumor suppressor phenotype. Toll-like receptors (TLRs) agonists could reprogram M2-type macrophages to M1-type and stimulate dendritic cells (DCs) maturation. The combination of TLR7/8 and TLR9 agonists seems to have synergistic therapeutic efficacy. Here, we designed a lipid-coated mesoporous silica nanoparticle (MSNs@Lipo) for the co-delivery of TLR7/8 agonist resiquimod (R848) and TLR9 agonist CpG oligodeoxynucleotides (ODNs) (CpG@MSNs-R@L-M). R848 was firstly conjugated onto the nanoparticle via silane chemistry, which is acidic responsive drug release. Then, CpG was loaded onto the nanoparticle through the positive charge mainly from TLR7/8 agonist R848. Our in vitro experiments further indicated that both drugs have acid-responsive release properties and could be taken up by DCs and located on the endosomes of APCs. More importantly, CpG@MSNs-R@L-M could significantly improve the antitumor efficacy in B16F10 melanoma model. The mechanistic study demonstrated that CpG@MSNs-R@L-M could remarkably modulate the TIME by promoting the maturation of DCs and repolarizing macrophages from M2 to M1 phenotype and facilitating the infiltration of tumor cytotoxic T cells. It was concluded that in comparison to single agonist, the co-delivery of dual agonists, CpG and R848, can improve anti-tumor immune responses for cancer immunotherapy.
研究领域:
免疫学
·
纳米医学
·
肿瘤学
·
药学
✓ 已验证
产品关联
DOI
高影响因子
Nano Today
·
2024
·
IF 13.2
Jingyi Liu,Qing You,Siyuan Ye,JinJin Wang,Rong Du,Fuming Liang,Zhaohui He,Chen Wang,Ling Zhu,Yanlian Yang
Photothermal therapy (PTT) can mediate the immunogenic cell death (ICD) of tumors through photothermal transformation, thus releasing tumor-associated antigens (TAAs) and damage-associated molecular patterns (DAMPs) to stimulate the maturation of dendritic cells (DCs) and elicit the immune response against tumors. However, PTT-mediated upregulation of the immune checkpoint molecule programmed cell death ligand 1 (PD-L1) will cause the immune evasion of tumor cells and thus increases the immunosuppression of cytotoxic T lymphocytes (CTLs), resulting in restricted photothermal immune activation. Taking advantage of the high expression of programmed cell death protein 1 (PD-1) in T lymphocytes, we develop an immunogenic photothermal hybrid nanovesicle to reverse immunosuppression and enhance PTT-induced ICD. The hybrid vesicle (TMVL-I) is constructed by phospholipid bilayer fusion of T cell-derived membrane vesicle (TMV) with high PD-1 expression and the indocyanine green (ICG)-loaded thermosensitive liposome (L-I). TMVL-Is bind to the tumor cells with PTT-induced upregulation of PD-L1, effectively blocking the PD-1/PD-L1 pathway between CTLs and tumor cells, thus reversing PD-L1-mediated tumor immunosuppression and intensifying photothermal-induced ICD effects. These processes significantly induce the maturation of DCs and enhance the infiltration of CTLs into both primary and distal tumors and the activation of spleen CTLs, strongly inhibiting the growth of B16 xenograft tumors and greatly improving the survival rate of B16 xenograft mice. This work provides a feasible strategy for immunosuppressive microenvironment reprogramming-based combination therapy.
研究领域:
癌症治疗
·
纳米技术
·
免疫学
·
生物医学工程
✓ 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）