BIOORGANIC CHEMISTRY
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2021
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IF 5.275
Gaochao Lv,Yinxing Miao,Yinfei Chen,Chunmei Lu,Xiuting Wang,Minhao Xie,Ling Qiu,Jianguo Lin
Programmed death ligand 1 (PD-L1) expression level is a reproducible biomarker for guiding stratification of patients to immunotherapy. However, the most widely used immunohistochemistry method is incompetent to fully understand the PD-L1 expression level in the whole body because of the highly complex PD-L1 expression in the tumor microenvironment. In this work, a novel small-molecular radiotracer [ 18 F]LG-1 based on the biphenyl active structure was developed to evaluate PD-L1 expression in tumors. [ 18 F]LG-1 was obtained by conjugating and radiolabeling with [ 18 F]FDG with high radiochemical purity (>98.0%) and high molar activity (37.2 ± 2.9 MBq/nmol). In vitro experimental results showed that [ 18 F]LG-1 could target PD-L1 in tumor cells and the cellular uptake in A375-hPD-L1 cells (PD-L1 + ) was clearly higher than that in A375 cells (PD-L1-). In vivo dynamic PET images of [ 18 F]LG-1 provided clear visualization of A375-hPD-L1 tumor with high tumor-to-background contrast, and the tumor uptake was determined to be 3.98 ± 0.21 %ID/g at 60 min, which was 2.6-fold higher than that of A375 tumor. These results suggested that [ 18 F]LG-1 had great potential as a promising PD-L1 radiotracer.
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JOURNAL OF CONTROLLED RELEASE
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2021
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IF 9.776
Minglu Zhou,Chaohui Luo,Zhou Zhou,Lian Li,Yuan Huang
Triple negative breast cancer (TNBC) with highly metastatic features generally does not respond to anti–programmed cell death 1 ligand 1 (PD-L1) therapy due to multiple immunosuppressive mechanisms to exclude and disable T cells . Here, we develop a polymer-based combinatory approach consisting of both immunogenic cell death (ICD)-inducing and CXCR4-inhibiting function to prime tumor microenvironment and improve anti-PD-L1 therapy in TNBC. Our findings revealed that the combination therapy was able to spur the T cell response in primary tumors by increasing the tumor immunogenicity to recruit T cells, removing the physiological barriers of intratumoral fibrosis and collagen to increase T cell infiltration , and reducing the immunosuppressive cells to revive T cells. Meanwhile, such approach efficiently inhibited the formation of pre-metastatic niche in abscopal lung. Because of the significant promotion of anti-tumor and anti-metastasis immunity, the non-responding TNBC gained robust responsiveness to anti-PD-L1 therapy which resulted in complete eradication of orthotopic tumors, inhibition of pulmonary metastasis , and durable memory effects against tumor recurrence . Our work provided a generalizable approach of simultaneous ICD induction and CXCR4 blockade to apply anti-PD-L1 therapy in TNBC.
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Acta Biomaterialia
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2024
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IF 9.4
Yi-Shu Li,Lu-Yi Ye,Yan-Xi Luo,Wen-Jie Zheng,Jing-Xing Si,Xue Yang,You-Ni Zhang,Shi-Bing Wang,Hai Zou,Ke-Tao Jin,Tong Ge,Yu Cai,Xiao-Zhou Mou
Oncolytic viral therapy (OVT) is a novel anti-tumor immunotherapy approach, specifically replicating within tumor cells. Currently, oncolytic viruses are mainly administered by intratumoral injection. However, achieving good results for distant metastatic tumors is challenging. In this study, a multifunctional oncolytic adenovirus, OA@CuMnCs, was developed using bimetallic ions copper and manganese. These metal cations form a biomineralized coating on the virus's surface, reducing immune clearance. It is known that viruses upregulate the expression of PD-L1. Copper ions in OA@CuMnCs can decrease the PD-L1 expression of tumor cells, thereby promoting immune cell-related factor release. This process involves antigen presentation and the combination of immature dendritic cells, transforming them into mature dendritic cells. It changes "cold" tumors into "hot" tumors, further inducing immunogenic cell death. While oncolytic virus replication requires oxygen, manganese ions in OA@CuMnCs can react with endogenous hydrogen peroxide. This reaction produces oxygen, enhancing the virus's replication ability and the tumor lysis effect. Thus, this multifunctionally coated OA@CuMnCs demonstrates potent amplification in immunotherapy efficacy, and shows great potential for further clinical OVT. Statement of significance : Oncolytic virus therapy (OVs) is a new anti-tumor immunotherapy method that can specifically replicate in tumor cells. Although the oncolytic virus can achieve a therapeutic effect on some non-metastatic tumors through direct intratumoral injection, there are still three major defects in the treatment of metastatic tumors: immune response, Hypoxia effect, and Administration route. Various studies have shown that the immune response in vivo can be overcome by modifying or wrapping the surface protein of the oncolytic virus. In this paper, a multifunctional coating of copper and manganese was prepared by combining the advantages of copper and manganese ions. The coating has a simple preparation method and mild conditions, and can effectively enhance tumor immunotherapy.
研究领域:
肿瘤学
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免疫学
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生物医学工程
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病毒学
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ACS Applied Materials & Interfaces
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2018
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IF 8.097
Ling Mei,Yayuan Liu,Jingdong Rao,Xian Tang,Man Li,Zhirong Zhang,Qin He
Because of the limited drug concentration in tumor tissues and inappropriate treatment strategies, tumor recurrence and metastasis are critical challenges for effectively treating malignancies. A key challenge for effective delivery of nanoparticles is to reduce uptake by reticuloendothelial system and to enhance the permeability and retention effect. Herein, we demonstrated Cu(I)-catalyzed click chemistry triggered the aggregation of azide/alkyne-modified micelles, enhancing micelles accumulation in tumor tissues. In addition, combined doxorubicin with the adjuvant monophosphoryl lipid A, an agonist of toll-like receptor4, generated immunogenic cell death, which further promoted maturity of dendritic cells, antigen presentation and induced strong effector T cells in vivo. Following combined with anti-PD-L1 therapy, substantial antitumor and metastasis inhibitory effects were achieved because of the reduced PD-L1 expression and regulatory T cells. In addition, effective long-term immunity from memory T cell responses protected mice from tumor recurrence.
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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化学
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Food & Function
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2019
·Vol. 11
·期 1
·456-471
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IF 3.241
Manling Hu,Jing Yang,Linlin Qu,Xuqian Deng,Zhiguang Duan,Rongzhan Fu,Lihua Liang,Daidi Fan
Ginsenoside Rk1 is a substance derived from ginseng and exhibits various activities such as anti-diabetic, anti-inflammatory and anti-cancer effects; however, its anti-tumor effect and target signaling mechanism in lung adenocarcinoma are not well understood. Here, we show that Rk1, a natural drug product, can function as an antitumor modulator that induces apoptosis in lung adenocarcinoma cells by inhibiting NF-κB transcription and triggering cell cycle arrest. Mechanistically, Rk1 suppressed the proliferation and clonal formation of two lung adenocarcinoma cell lines (A549 and PC9) in vitro and caused G1 phase cell arrest. In the A549 xenograft model, Rk1 significantly inhibited tumor growth and had few toxic side effects on normal organs. Western blotting results showed that Rk1 increased the protein expression of Bax, cleaved caspase-3, -8, and -9, and PARP, decreased the expression of Bcl-2 and blocked the NF-κB signaling pathway. Furthermore, ginsenoside Rk1 also reduced the high expression of PD-L1 in lung adenocarcinoma cells by inhibiting NF-κB signaling. These data revealed a previously unreported antitumor mechanism of Rk1, providing new ideas and an experimental basis for further study of the mechanism of action of Rk1 in lung adenocarcinoma.
研究领域:
肿瘤学
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药理学
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分子生物学
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Advanced Healthcare Materials
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2026
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IF 11
Peng-Wei Chen,Yu-Meng Zhang,Lin-Song Li,Bang-Bang Liu,Han-Lu Sun,Liping Chen,Xiaojing Yang,Mei-Xia Zhao
The combination of phototherapy with oxaliplatin (OXA) represents a potent strategy for triggering immunogenic cell death (ICD) and elicit robust antitumor immunity. In this study, we construct IROTD nanoparticles (IROTD NPs) through self-assembly of a norcantharidin (NCTD)-OXA-conjugated polymer (P2) and the near-infrared (NIR) photosensitizer DTIR780. Under 808 nm laser irradiation, IROTD NPs generate heat and reactive oxygen species (ROS) while release OXA and NCTD, result in severe DNA damage and potent induction of ICD within tumor cells. Concurrently, NCTD inhibits DNA repair mechanisms and down-regulates PD-L1expression, thereby increase the infiltration of cytotoxic T-cell and amplify systemic antitumor immunity. Leverage the enhanced permeability and retention (EPR) effect, IROTD NPs efficiently accumulate at tumor sites, result in remarkable inhibition of tumor growth and recruitment of CD4 + and CD8 + T lymphocytes, which collectively contribute to the activation of a systemic antitumor immunity. In a bilateral tumor model, IROTD NPs effectively inhibit both primary and distant tumor growth. Overall, this work presents a rationally designed combinatorial nanoplatform that effectively ignites systemic immune response, thus establish a prospective chemo-immunotherapeutic stratagem for cancer treatment.
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Scientific Reports
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2026
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IF 4.9
Zhou Kun,Yuan Wei,Zhang Fan
Radix Bupleuri-Radix Paeoniae Alba (RB-RPA) has the potential to ameliorate the immune microenvironment in hepatocellular carcinoma (HCC). The interactions between various cells influence the immune microenvironment. However, the effects of the active components (saikosaponin D (SSD) and paeoniflorin) of RB-RPA on HCC and the cell interactions within its microenvironment warrant further investigations. We established orthotopic mouse models of HCC using Hepa 1–6 cells (a hepatoma cell line) to investigate the infiltration of cancer-associated fibroblasts (CAFs). Following this, we knocked down CLCF1 in the CAFs to explore their interactions with Hepa 1–6 cells. We subsequently treated CAFs with SSD-paeoniflorin. In T-cell activation assays, we overexpressed PD-L1 in Hepa 1–6 cells and co-cultured these cells with T cells. Additionally, we treated HCC mice with SSD-paeoniflorin and induced the overexpression of CLCF1 in vivo. In mice with HCC, tumors were characterized by substantial infiltration of CAFs, which displayed elevated levels of the protein CLCF1. These CAFs play a role in suppressing the HCC immune microenvironment and elevating PD-L1 levels through the production of CLCF1. At the cellular level, SSD-paeoniflorin inhibited the growth of CAFs and the expression of CLCF1 and also suppressed the PD-L1 level in Hepa 1–6 cells through CAF-derived CLCF1. Mechanistically, CLCF1 may promote PD-L1 expression via the JAK/STAT3 signaling pathway. Furthermore, the overexpression of PD-L1 in Hepa 1–6 cells suppressed T cell proliferation and activation. In animal studies, SSD-paeoniflorin improved the HCC immune microenvironment by enhancing the interaction between CAFs and Hepa 1–6 cells through CLCF1. Collectively, SSD-paeoniflorin inhibits CLCF1 secretion in CAFs to downregulate PD-L1 expression in Hepa 1–6 cells and may reactivate the anti-tumor immune microenvironment in HCC.
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JOURNAL OF NANOBIOTECHNOLOGY
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2023
·Vol. 21
·期 1
·1-22
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IF 10.2
Zhang Shushan,Huang Yongquan,Pi Songying,Chen Hui,Ye Feile,Wu Chaoqun,Li Liujun,Ye Qing,Lin Yuhong,Su Zhongzhen
Incomplete radiofrequency ablation (IRFA) triggers mild protective autophagy in residual tumor cells and results in an immunosuppressive microenvironment. This accelerates the recurrence of residual tumors and causes resistance to anti-PD-1/PDL1 therapy, which bringing a great clinical challenge in residual tumors immunotherapy. Mild autophagy activation can promote cancer cell survival while further amplification of autophagy contributes to immunogenic cell death (ICD). To this regard, we constructed active targeting zeolitic imidazolate framework-8 (ZIF-8) nanoparticles (NPs) loaded with STF62247 or both STF62247 and BMS202, namely STF62247@ZIF-8/PEG-FA (SZP) or STF62247-BMS202@ZIF-8/PEG-FA (SBZP) NPs. We found that SZP NPs inhibited proliferation and stimulated apoptosis of residual tumor cells exposed to sublethal heat stress in an autophagy-dependent manner. Further results discovered that SZP NPs could amplify autophagy in residual tumor cells and evoke their ICD, which dramatically boosted the maturation of dendritic cells (DCs). Through vaccination experiments, we found for the first time that vaccination with heat + SZP treatment could efficiently suppress the growth of new tumors and establish long-term immunological memory. Furthermore, SBZP NPs could remarkably promote the ICD of residual tumor cells, obviously activate the anti-tumor immune microenvironment, and significantly inhibit the growth of residual tumors. Thus, amplified autophagy coupled with anti-PD-1/PDL1 therapy is potentially a novel strategy for treating residual tumors after IRFA.Graphical Abstract
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SENSORS AND ACTUATORS B-CHEMICAL
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2023
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IF 8.4
Ruhui Hu,Suyun Zhong,Hezhen Liu,Yawen Liu,Hongxia Chen,Xiaojun Hu
A dual-ligand Cu-MOFs (Cu-F/Hs) based on phenylalanine (Phe) and histidine (His) was innovatively constructed with enhanced catalytic property. Among them, Phe can interact with the dopamine (DA) to enhance the substrate affinity. Meanwhile, the coordination of His with copper ions was inspired by the active site structure of natural laccase to improve the catalytic activity. The K m value of Cu-F/Hs was 0.14 times of laccase, indicating a high affinity for the catalytic substrate DA. Accordingly, a sensitive sensor for PD-L1 detection was designed by using Cu-F/Hs, which can catalyze DA to form redox-active polymeric conjugates deposited on the electrode surface with good electrical conductivity, thereby contributing a “signal-down” electrochemical response with a double signal enhancement. The detection limit was 0.12 ng/mL in the detection range of 0.5 – 200 ng/mL. This work provided a new and simple way to synthesize MOFs with high substrate affinity and efficient activity, and a general signal amplification strategy induced by the catalytic deposition.
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Frontiers in Oncology
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2022
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IF 5.738
Da-Lai Xu,Yuan-Qing He,Bin Xiao,Yuan Si,Jian Shi,Xue-Ang Liu,Lei Tian,Qian Ren,Ya-Song Wu,Yi Zhu
Pancreatic ductal adenocarcinoma (PDAC) is a highly aggressive and lethal malignancy with a limited response to current therapies. Novel and effective treatment is urgently needed. Herein, a chimeric antigen receptor (CAR)-NK92 cell line, with an interleukin (IL)-15Rα-sushi/IL-15 complex and a Programmed cell death-1(PD1) signal inverter was constructed and named SP (
S
ushi-IL15-
P
D1). We showed that CAR expression enabled SP cells to proliferate independently of IL-2 and became more resistant to nutrition starvation-induced apoptosis. Meanwhile, SP cells were more effective than NK92 in PDAC cell killing assays in vitro and in vivo, and there was a positive correlation between the killing capability of SP cells and PD-L1 expression in pancreatic cancer cells. Based on the synergistic and comprehensive effects of the special CAR structure, the adhesion, responsiveness, degranulation efficiency, targeted delivery of cytotoxic granule content, and cytotoxicity of SP cells were significantly stronger than those of NK92. In conclusion, the SP cell line is a promising adoptive immunotherapy cell line and has potential value as an adjuvant treatment for pancreatic cancer, especially in patients with high PD-L1 expression.Keywords: pancreatic ductal adenocarcinoma, Chimeric antigen receptor (CAR), IL-15, IL-15Rα-sushi, programmed cell death ligand 1 (PD-L1), adoptive immunotherapy
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JOURNAL OF NANOBIOTECHNOLOGY
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2022
·Vol. 20
·期 1
·1-17
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IF 9.429
Lu Yuan-Fei,Zhou Jia-Ping,Zhou Qiao-Mei,Yang Xiao-Yan,Wang Xiao-Jie,Yu Jie-Ni,Zhang Jin-Guo,Du Yong-Zhong,Yu Ri-Sheng
Background The efficacy of immune checkpoint blockade (ICB), in the treatment of hepatocellular carcinoma (HCC), is limited due to low levels of tumor-infiltrating T lymphocytes and deficient checkpoint blockade in this immunologically "cool" tumor. Thus, combination approaches are needed to increase the response rates of ICB and induce synergistic antitumor immunity.Methods Herein, we designed a pH-sensitive multifunctional nanoplatform based on layered double hydroxides (LDHs) loaded with siRNA to block the intracellular immune checkpoint NR2F6, together with the asynchronous blockade surface receptor PD-L1 to induce strong synergistic antitumor immunity. Moreover, photothermal therapy (PTT) generated by LDHs after laser irradiation modified an immunologically “cold” microenvironment to potentiate Nr2f6-siRNA and anti-PD-L1 immunotherapy. Flow cytometry was performed to assess the immune responses initiated by the multifunctional nanoplatform.Results Under the slightly acidic tumor extracellular environment, PEG detached and the re-exposed positively charged LDHs enhanced tumor accumulation and cell uptake. The accumulated siRNA suppressed the signal of dual protumor activity in both immune and H22 tumor cells by silencing the NR2F6 gene, which further reduced the tumor burden and enhanced systemic antitumor immunity. The responses include enhanced tumor infiltration by CD4+ helper T cells, CD8+ cytotoxic T cells, and mature dendritic cells; the significantly decreased level of immune suppressed regulator T cells. The therapeutic responses were also attributed to the production of IL-2, IFN-γ, and TNF-α. The prepared nanoparticles also exhibited potential magnetic resonance imaging (MRI) ability, which could serve to guide synergistic immunotherapy treatment.Conclusion sIn summary, the three combinations of PTT, NR2F6 gene ablation and anti-PD-L1 can promote a synergistic immune response to inhibit the progression of primary HCC tumors and prevent metastasis. This study can be considered a proof-of-concept for the targeting of surface and intracellular immune checkpoints to supplement the existing HCC immunotherapy treatments.
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Journal of Pharmaceutical Analysis
·
2022
·
IF 14.026
Yinfei Chen,Shiyu Zhu,Jiayu Fu,Jianguo Lin,Yan Sun,Gaochao Lv,Minhao Xie,Tao Xu,Ling Qiu
Despite advances in immunotherapy for the treatment of cancers, not all patients can benefit from programmed cell death ligand 1 (PD-L1) immune checkpoint blockade therapy. Anti-PD-L1 therapeutic effects reportedly correlate with the PD-L1 expression level; hence, accurate detection of PD-L1 expression can guide immunotherapy to achieve better therapeutic effects. Therefore, based on the high affinity antibody Nb109, a new site-specifically radiolabeled tracer, 68 Ga-NODA-cysteine, aspartic acid, and valine (CDV)-Nb109, was designed and synthesized to accurately monitor PD-L1 expression. The tracer 68 Ga-NODA-CDV-Nb109 was obtained using a site-specific conjugation strategy with a radiochemical yield of about 95% and radiochemical purity of 97%. It showed high affinity for PD-L1 with a dissociation constant of 12.34 ± 1.65 nM. Both the cell uptake assay and positron emission tomography (PET) imaging revealed higher tracer uptake in PD-L1-positive A375-hPD-L1 and U87 tumor cells than in PD-L1-negative A375 tumor cells. Meanwhile, dynamic PET imaging of a NCI-H1299 xenograft indicated that doxorubicin could upregulate PD-L1 expression, allowing timely interventional immunotherapy. In conclusion, this tracer could sensitively and dynamically monitor changes in PD-L1 expression levels in different cancers and help screen patients who can benefit from anti-PD-L1 immunotherapy.
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