BIOCONJUGATE CHEMISTRY
·
2018
·
IF 4.485
Jinjin Zhao,Ning Pan,Fang Huang,Mohanad Aldarouish,Zhifa Wen,Rong Gao,Yuye Zhang,Hong-Ming Hu,Yanfei Shen,Li-xin Wang
A simple and effective strategy was developed to enrich ubiquitinated proteins (UPs) from cancer cell lysate using the α-Al2O3 nanoparticles covalently linked with ubiquitin binding protein (Vx3) (denoted as α-Al2O3–Vx3) via a chemical linker. The functionalized α-Al2O3–Vx3 showed long-term stability and high efficiency for the enrichment of UPs from cancer cell lysates. Flow cytometry analysis results indicated dendritic cells (DCs) could more effectively phagocytize the covalently linked α-Al2O3–Vx3-UPs than the physical mixture of α-Al2O3 and Vx3-UPs (α-Al2O3/Vx3-UPs). Laser confocal microscopy images revealed that α-Al2O3–Vx3-UPs localized within the autophagosome of DCs, which then cross-presented α-Al2O3–Vx3-UPs to CD8+ T cells in an autophagosome-related cross-presentation pathway. Furthermore, α-Al2O3–Vx3-UPs enhanced more potent antitumor immune response and antitumor efficacy than α-Al2O3/cell lysate or α-Al2O3/Vx3-UPs. This work highlights the potential of using the Vx3 covalently linked α-Al2O3 as a simple and effective platform to enrich UPs from cancer cells for the development of highly efficient therapeutic cancer vaccines.
研究领域:
纳米技术
·
癌症研究
·
免疫学
·
生物医学工程
✓ 已验证
DOI
PubMed
高影响因子
ACS Applied Materials & Interfaces
·
2018
·
IF 8.097
Dandan Jiang,Weiwei Mu,Xiuping Pang,Yongjun Liu,Na Zhang,Yunmei Song,Sanjay Garg
Enhancing cytosol delivery of exogenous antigens in antigen presenting cells can improve cross-presentation and CD8+ T cell-mediated immune response. The antigen cytosol delivery speed, which has great importance on the rate of MHC class I molecules (MHC I) antigen presentation pathway and cytotoxic T lymphocytes (CTLs) induction, has not been well studied. We hypothesized that micelle-tailored vaccine with multiple cascaded lysosomal responsive capabilities could accelerate lysosomal escape and enhance cancer immunotherapy. To test our hypothesis, we created a novel micellar cancer vaccine (ovalbumin-loaded pH/redox dual-sensitive micellar vaccine, OLM-D) by cleavable conjugation of an antigen with house-made amphiphilic poly(l-histidine)–poly(ethylene glycol) (PLH–PEG) in current study. OLM-D was supposed to achieve cascade cytosol delivery of ovalbumin through three steps in terms of (i) initial redox triggered ovalbumin release, (ii) promoted proton inflow and micelle disassembly, and (iii) speeded proton sponge effect and lysosome bulging/broke. Redox-sensitive antigen release and consequently accelerative OLM-D disassembly were confirmed by sodium dodecylsulphate polyacrylamide gel electrophoresis (SDS–PAGE), transmission electronic microscopy (TEM), particle sizes, zeta potentials, and in vitro Ova release evaluation. The speeded cytosol delivery of ovalbumin was visualized under a confocal laser scanning microscope (CLSM). The ability of OLM-D to increase the MHC I molecule combination rate and antigen cross-presentation efficiency was identified by antigen presentation assay and maturation assay in bone marrow-derived dendritic cells (BMDCs). In vivo, the capability of OLM-D to accumulate in draining lymph nodes (LNs) after injection was visualized by real-time near infrared fluorescence imaging (NIRF) and the distribution order in different LNs was first observed (a, d, c, b). Enhanced cancer immunity of OLM-D was confirmed by increased CD3+CD8+ T cell quantity, CD3+CD8+25D11.6+ T cells quantity, and IFN-γ, IL-2 secretion post subcutaneous or intraperitoneal injection (p < 0.05). Taken together, our results indicated that OLM-D provided a promising cascade cytosol delivery strategy, which held great potential to guide further design of nano-particulate cancer vaccines for efficient cancer immunotherapy.
研究领域:
癌症免疫学
·
药学
·
纳米技术
·
生物医学工程
✓ 已验证
产品关联
DOI
PubMed
高影响因子
JOURNAL OF CONTROLLED RELEASE
·
2022
·
IF 11.467
Hong Liu,Zhitao Hu,Haolin Chen,Yanzi Yan,Zhicheng Le,Cong Wei,Wenqiang Cao,Tianfeng Chen,Yongming Chen,Lixin Liu
Vaccination with subunit nanovaccines is a promising strategy to combat virus infection and tumor development. However, immunogenicity of present nanovaccines is still unsatisfied for clinical translation. Here, we developed a nanovaccine loading a STING agonist, 2′3′-cGAMP and, a model subunit antigen, OVA , by using a well-defined self-degradable poly(β-amino ester)s to treat B16F10-OVA melanoma tumors. The polymer underwent slow hydrolysis at pH 5.5 but self-degraded induced by the amino groups along the polyester chain at pH > 6.5. It is shown that the self-degradation products facilitated the release of 2′3′-cGAMP and OVA from early endolysome to the cytosol, where the two components strongly activated CD8 + T lymphocytes (CTLs) and significantly enhanced Ifn1, TNF , Cxcl9, and Cxcl10 expression. In turn, the tumor microenvironment was remolded from cold to hot. Moreover, the nanovaccine could be quickly drained to sentinel lymph nodes after intratumoral injection. The nanovaccine with strong immunogenicity also could reduce the side effects of systemic inflammatory reaction caused by molecular 2′3′-cGAMP. The tumor progression of animals was inhibited, and their survival rates increased significantly. Thus, the multifunctional biodegradable material provided a new delivery system for a cancer vaccine to translate to clinics.
研究领域:
癌症研究
·
免疫学
·
生物医学工程
·
分子生物学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
ADVANCED FUNCTIONAL MATERIALS
·
2023
·
IF 19
Yongjuan Li,Ningjing Lei,Xiaohan Yao,Yu Zhang,Ya Dong,Jinmeng Yi,Xinyan Li,Wenjing Deng,Guangjun Nie,Zhihai Qin
The clinical application of ferroptosis, characterized by iron-dependent lipid peroxidation, is limited because of the serious side effects of using toxic-dose iron. Herein, a polyvalent ferroptosis agonist-a hypoxia responsive polymer bearing 18-crown-6 ring (hPPAA18C6) is developed. In contrast to the natural ferroptosis agonists (erastin, RSL3, and sorafenib), hPPAA18C6 stimulates the ferroptosis by releasing endogenous iron stored in the natural “iron pools” of cellular organelles and depleting glutathione (GSH) via the benzoquinone generated from the cascade decaging reactions in hypoxia. hPPAA18C6 nanoparticle is loaded with photosensitizer-chlorine e6 (Ce6) (hPPAA18C6@Ce6) due to the inhomogeneous hypoxia microenvironment. Moreover, the exposed positively charged primary amine (NH 2 ) from hPPAA18C6 acts as an immune adjuvant, facilitating dendritic cells maturation, antigen presentation, and cytotoxic T lymphocyte activation. hPPAA18C6@Ce6 induces anti-tumor responses that are dependent on ferroptosis, photodynamics therapy (PDT), and CD8 + T-cell activity. In addition, the combination of hPPAA18C6 and Ce6 leads to combined therapeutic outcomes in primary, distant, and metastatic tumors. The activation of the ferroptosis pathway through functional polymer-hijacking endogenous iron and GSH may offer new therapeutic opportunities.
研究领域:
肿瘤学
·
免疫治疗
·
分子生物学
·
聚合物化学
✓ 已验证
DOI
高影响因子
INTERNATIONAL JOURNAL OF PHARMACEUTICS
·
2024
·
IF 5.3
Gang Wang,Xiao-Na Xu,Zhu Zhi-Min,Kun Wang,Fei Li
This study tried to develop the α-Hederin/Oxaliplatin (OXA) dual-loaded rHDL (α-Hederin-OXA-rHDL) modified liposomes to improve the therapeutic index on colon adenocarcinoma (COAD). The α-Hederin-OXA-rHDL were prepared and evaluated for characterizations, accumulate to tumor tissues, and antitumor activity. A thorough investigation into oxaliplatin resistant and KRAS-mutant related hub keg genes were identified and performed to assess the prognosis role of the genetic signature in COAD. The potential immune signatures and molecular docking for verifing the predicted targets of α-Hederin-OXA-rHDL in tumor-bearing mice. Results suggested that α-Hederin-OXA-rHDL could enhance the sensitivity of oxaliplatin in HCT116/L-OHP cells via the regulation of KEAP1/NRF2 -mediated signaling and HO1 or GPX4 proteins. Furthermore, α-Hederin-OXA-rHDL regulated the predicted targets of PRDM1 interaction with miR-140-5p, efficient activing CD8 T cell to improve therapeutic response in vivo . Collectively, this work provides drug delivery with rHDL dual-loaded α-Hederin and oxaliplatin synergistically targets cancer cells and effectory T cells combating COAD.
研究领域:
药学
·
癌症生物学
·
分子生物学
·
免疫学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
ACS Applied Materials & Interfaces
·
2025
·
IF 8.2
Shiwen Wang,Ying Shen,Binbin Hu,Qiping Wu,Nanzhou Wang,Zichao Wang,Zifeng Zhang,Yujie Li,Jianhui Jiang
Breast cancer therapy confronts dual challenges of metabolic plasticity-driven drug resistance and immunosuppression. To address this, we developed DCP-TPP, a therapeutic nanoplatform that integrates dysregulation of copper homeostasis and lipid metabolism for precise breast cancer therapy. Leveraging the overexpression of cluster of differentiation 36 (CD36) in breast cancer cells, DCP-TPP employs fatty acid camouflage (PCM) to deliver disulfiram (DSF) and photothermal Cu3BiS3 to cancer cells and features triphenylphosphonium (TPP) modification for targeted mitochondrial drug delivery. Near-infrared (NIR) irradiation triggers the phase transition of DCP-TPP’s outer layer, inducing spatiotemporal release of DSF to liberate copper ions from inert Cu3BiS3, thereby generating diethyldithiocarbamate–copper complex (CuET). This disrupts copper homeostasis and induces cuproptosis, which subsequently triggers S-acetyltransferase (DLAT) aggregation, impairing tricarboxylic acid (TCA) cycle flux, acetyl-CoA production, ATP citrate lyase (Acly)-dependent lipogenesis, and ultimately collapses mitochondrial oxidative phosphorylation. Multiomics profiling revealed oleic acid depletion, arachidonic acid oxidation, and glutathione exhaustion, collectively amplifying metabolic collapse. DCP-TPP-induced cell death enhanced dendritic cell (DC) activation and CD8+ T cell infiltration. In breast cancer models, DCP-TPP achieved 90.9% tumor suppression, with 60% of mice resisting rechallenge. By transforming lipid metabolic dependency into a therapeutic vulnerability and coupling it with copper ion toxicity, DCP-TPP offers a promising strategy for breast cancer therapy.
研究领域:
癌症生物学
·
纳米医学
·
免疫治疗
·
代谢工程
·
生物无机化学
·
靶向药物递送
✓ 已验证
产品关联
DOI
PubMed
高影响因子
npj Precision Oncology
·
2025
·Vol. 9
·期 1
·1-15
·
IF 8
Huo Ran,Xu Quan-guo,You Yi-qing,Chen Yan-lin,Su Guang-jian,Yang Kun-rong,Xiao Yan-ping,Xue Zhong,Li Yang-jin,Sun Pei,Cui Zhao-lei,Lin Ying-ying,Guo Jun-ying,Xu Hai-yan,Chen Zhao-shuo,Xie Wen-ting,Xu Shao-hua,Chen Min-yong,Wu Jing,He Shi-jie,Xiao Zhen-zhou,Chen Yan
Hepatocellular carcinoma (HCC) is a prevalent and deadly cancer. Gut microbiota affect tumor immunity and immunotherapy efficacy, but the exact mechanisms are unclear. A study compared gut microbiota in HCC patients and healthy controls (HC) using 16S rDNA analysis and metabolomics. It found higher levels of Bifidobacterium and a positive correlation between Bifidobacterium and isobutyric acid in HC group. Animal models showed that the combination of HC fecal matter and αPD-1 treatment reduced tumor volume more effectively than the combination of HCC fecal matter and αPD-1. The combination of Bifidobacterium or isobutyrate with αPD-1 also decreased tumor size. In vitro, isobutyrate-stimulated CD8 + T cells increased IFN-γ secretion, suppressed liver cancer cells, and downregulated the JAK/STAT3 pathway. Combined treatments increased CD8 + T cells and IFN-γ levels and reduced JAK/STAT3 signaling in the tumor microenvironment. This suggests that Bifidobacterium and isobutyrate can inhibit tumor growth, offering insights into gut microbiota-host interactions and potential strategies to overcome HCC immunotherapy resistance.
研究领域:
癌症研究
·
免疫学
·
微生物学
·
分子生物学
·
胃肠病学
·
生物信息学
·
药理学
·
细胞生物学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
CELL
·
2020
·
IF 38.637
Adrienne M. Luoma,Shengbao Suo,Hannah L. Williams,Tatyana Sharova,Keri Sullivan,Michael Manos,Peter Bowling,F. Stephen Hodi,Osama Rahma,Ryan J. Sullivan,Genevieve M. Boland,Jonathan A. Nowak,Stephanie K. Dougan,Michael Dougan,Guo-Cheng Yuan,Kai W. Wucherpfennig
Summary Checkpoint blockade with antibodies specific for the PD-1 and CTLA-4 inhibitory receptors can induce durable responses in a wide range of human cancers. However, the immunological mechanisms responsible for severe inflammatory side effects remain poorly understood. Here we report a comprehensive single-cell analysis of immune cell populations in colitis, a common and severe side effect of checkpoint blockade. We observed a striking accumulation of CD8 T cells with highly cytotoxic and proliferative states and no evidence of regulatory T cell depletion. T cell receptor (TCR) sequence analysis demonstrated that a substantial fraction of colitis-associated CD8 T cells originated from tissue-resident populations, explaining the frequently early onset of colitis symptoms following treatment initiation. Our analysis also identified cytokines, chemokines, and surface receptors that could serve as therapeutic targets for colitis and potentially other inflammatory side effects of checkpoint blockade.
研究领域:
免疫学
·
肿瘤学
·
胃肠病学
✓ 已验证
DOI
PubMed
高影响因子
CHEMICAL ENGINEERING JOURNAL
·
2024
·
IF 13.3
Xianya Qin,Hongbo Xu,Siyu Zhao,Li Kong,Conglian Yang,Zhiping Zhang
Inspired by the application of organisms as bioreactors in developing drug delivery systems, the living organisms that have undergone biosynthesis are expected to further expand their application scenarios in biomedical domain. Herein, a whole tumor cell vaccine, named as Au@Cell, was developed by harnessing tumor cells as bioreactors to achieve the reduction of chloroauric acid in a mild aqueous phase system within 24 h. The biogeneration process in tumor cells enabled the retention of plenary tumor antigens, enhancement of MHC-I molecules, and generation of innate immune agonist (dsRNA), demonstrating potential for application as a therapeutic cancer vaccine. The resulting cancer vaccine was proved to be non-tumorigenic, revealing favorable in vivo safety. When administrated via intraperitoneal injection, Au@Cell achieved dual-targeting effects on both spleen and peritoneal tumors. Moreover, the combination therapy of Au@Cell and an immune checkpoint inhibitor (αPD-L1) could reprogram the tumor microenvironment by activating CD8 + T cells and effector B lymphocytes, exhibiting favorable anti-tumor effect in MC38 peritoneal carcinomatosis. This study suggested an alternative vaccine manufacturing strategy enabled by the biogeneration process in tumor cells to augment the efficacy against colon cancer-related peritoneal carcinomatosis.
研究领域:
肿瘤学
·
免疫疗法
·
生物技术
·
癌症疫苗
✓ 已验证
产品关联
DOI
高影响因子
JOURNAL OF LIPOSOME RESEARCH
·
2021
·
IF 3.648
Gang Wang,Yu Yang,Du Yi,Lu Yuan,Pei-Hao Yin,Xu Ke,Wang Jun-Jie,Min-Fang Tao
This study aimed to develop polymer Eudragit S100 for preparing pH-responsive liposomes-loaded betulinic acid (pH-BA-LP) to improve the therapeutic index of chemotherapy for colorectal cancer. BA-loaded liposomes were coated with Eudragit S100 by a thin film dispersion and easily scalable pH-driven method. The prepared liposomes were evaluated for size, surface morphology, entrapment efficiency, stability, in vitro drug release, and antitumor activity. In particular, pH-BA-LP showed advantages such as lower size (<100 nm), encapsulation efficiency of 90%, high stability, and stably cumulative release. By detecting the antitumor effects of pH-BA-LP in vivo, it showed that the tumor proliferation and cell migration were significantly inhibited in colorectal cancer. The pH-BA-LP also inhibited tumor growth via the regulation of Akt/TLR-mediated signalling and significantly down-regulated the expression of NFAT1 and NFAT4 proteins. It was found that pH-BA-LP can increase NK cells and CD3+ cells in tumor tissues, and the proportion of CD8+ cells in CD3+ cells was also increased, which proved that pH-BA-LP can play an antitumor effect by enhancing the autoimmunity level in tumor-bearing mice. The positive infiltration rates of CD8 and CD68 were increased and CD163 was relatively decreased by using pH-BA-LP, which proved that pH-BA-LP can regulate the immune infiltration levels in tumor-bearing mice. Therefore, the present work provides an effective method to prepare pH-responsive polymer-coated liposomes for colonic delivery with biologically active compounds.
研究领域:
药学
·
肿瘤学
·
药理学
·
免疫学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Biomaterials Science
·
2022
·Vol. 10
·期 15
·4140-4155
·
IF 7.59
Yingping Zeng,Tong Yu,Shufen Zhang,Guangtao Song,Tingting Meng,Hong Yuan,Fuqiang Hu
Tumor vessel normalization can alleviate hypoxia, reduce the intratumoral infiltration of immunosuppressive cells and increase the intratumoral infiltration of immune effector cells (CD8+ T cells), further reversing the immunosuppressive microenvironment. Here, nanocomplexes (lipo/St@FA–COSA/BMS-202) which can accurately deliver drugs to tumor tissues and release different drugs at different sites with different rates were prepared to combine tumor vessel normalization with immune checkpoint blockade. The results of drug release in vitro showed that in a pH 6.5 release medium, lipo/St@FA–COSA/BMS-202 rapidly released the vascular normalizing drug (sunitinib, St) and slowly released the PD-1/PD-L1-blocking drug (BMS-202). The results of in vivo experiments showed that the rapidly released St normalized tumor vessels and formed an immunosupportive microenvironment which improved the anti-tumor efficacy of BMS-202. In conclusion, the drug delivery strategy significantly inhibited tumor growth and had excellent anti-tumor efficacy, which can provide a potential approach for effective tumor treatment.
研究领域:
肿瘤学
·
药学
·
纳米技术
·
免疫疗法
✓ 已验证
产品关联
DOI
PubMed
高影响因子
MICROBIOLOGICAL RESEARCH
·
2024
·
IF 6.1
Li-Li Zhang,Jia-Ying Xu,Yifei Xing,Pengcheng Wu,Yi-Wen Jin,Wei Wei,Lin Zhao,Jing Yang,Guo-Chong Chen,Li-Qiang Qin
Radiation injury to the intestine is one of the most common complications in patients undergoing abdominal or pelvic cavity radiotherapy. In this study, we investigated the potential protective effect of Lactobacillus rhamnosus GG (LGG) on radiation-induced intestinal injury and its underlying mechanisms. Mice were assigned to a control group, a 10 Gy total abdominal irradiation (TAI) group, or a group pretreated with 10 8 CFU LGG for three days before TAI. Small intestine and gut microbiota were analyzed 3.5 days post-exposure. LGG intervention improved intestinal structure, reduced jejunal DNA damage, and inhibited the inflammatory cGAS/STING pathway. Furthermore, LGG reduced M1 proinflammatory macrophage and CD8+ T cell infiltration, restoring the balance between Th17 and Treg cells in the inflamed jejunum. LGG also partially restored the gut microbiota. These findings suggest the possible therapeutic radioprotective effect of probiotics LGG in alleviating radiation-induced intestinal injury by maintaining immune homeostasis and reshaping gut microbiota.
研究领域:
放射生物学
·
免疫学
·
微生物学
·
胃肠病学
✓ 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）