Advanced Healthcare Materials
·
2021
·Vol. 10
·期 21
·2101199
·
IF 9.933
Haihui Wang,Yongfei Liu,Xiaohui Zhu,Chengyun Chen,Zhangcheng Fu,Min Wang,Danying Lin,Zhaowei Chen,Chunhua Lu,Huanghao Yang
Combinatorial CpG oligonucleotide (CPG) and chemotherapy drug represent a promising approach to reactivate immune system. However, these two agents possess different physicochemical properties, hindering the application of direct self-assembly of these two cargos into a single nanostructure. Here, a multistage cooperative nanodrug is developed by the direct self-assembly of cis-platinum (CDDP, Pt), l -arginine ( l -Arg, R), and CPG (defined as PtR/CPG) for antitumor chemoimmunotherapy. First, the CDDP can induce cell apoptosis. Meanwhile, CDDP also promotes the production of H 2 O 2 , catalyzing the conversion of l -Arg into nitric oxide (NO). The generated NO decreases the multidrug resistance of cells toward CDDP. Thus, the synergistic effects of CDDP and NO can trigger immunogenic cell death to produce tumor-associated antigens (TAAs). The TAAs and CPG will induce the maturation of dendritic cells (DCs) and enhance antigen presentation ability of DCs. In this way, the PtR/CPG can reverse the immunosuppressive microenvironment, sensitizing tumors to immune checkpoint inhibitors mediated by the programmed death-ligand 1 (PD-L1) antibody. Furthermore, the PtR/CPG combined with the PD-L1 antibody decreases the exhaustion and dysfunction of cytotoxic T lymphocytes to elicit durable systemic immune response. As a result, the prepared PtR/CPG nanodrug in combination with PD-L1 may be highly significant for cancer immunotherapy.
研究领域:
癌症免疫治疗
·
纳米技术
·
药学
·
免疫学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
SENSORS AND ACTUATORS B-CHEMICAL
·
2023
·
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.
研究领域:
材料科学
·
分析化学
·
生物传感器
·
催化
✓ 已验证
产品关联
DOI
高影响因子
International Journal of Nanomedicine
·
2022
·
IF 7.033
Cunqing Kong,Banghao Xu,Guanhua Qiu,Meng Wei,Mengqi Zhang,Shengxian Bao,Jiali Tang,Lequn Li,JunJie Liu
Introduction Photoimmunotherapy is a breakthrough treatment for malignant tumors. Its uniqueness is that it uses antibody mediated targeted delivery to achieve high tumor specificity and uses laser-activated biophysical mechanism to accurately induce the rapid death of cancer cells and avoid damaging the surrounding normal tissues. Methods In this paper, an iron-based micelle was designed to encapsulate the photothermal agent indocyanine green (ICG) and a cyclic tripeptide of arginine-glycine-aspartic acid (cRGD) as targeted multifunctional ICG@SANPs-cRGD nanoparticles for combined photothermal/photodynamic/immune therapy of breast cancer. Results The experimental results show that ICG@SANPs-cRGD nanoparticles have good biocompatibility and photothermal conversion ability. Photothermal therapy (PTT) and photodynamic therapy (PDT) based on ICG@SANPs-cRGD can not only inhibit the proliferation, invasion and migration of tumor cells, but also directly kill tumor cells by inducing apoptosis or necrosis. Dual-mode fluorescence light (FL) and magnetic resonance imaging (MRI) imaging in mice confirmed the selective accumulation at tumor sites and imaging ability of ICG@SANPs-cRGD. PTT/PDT combined with Anti-PD-L1 immunotherapy based on ICG@SANPs-cRGD mediated the immunogenic cell death (ICD) of tumor cells by regulating the expression of immune-related indicators and activated the body's immune response mechanism, which enhanced the immunotherapy effect of immune checkpoint block (ICB). PTT/PDT combined with Anti-PD-L1 therapy not only prevented the progression of the primary tumor but also inhibited the distant metastasis of the tumor. Discussion This study explores the biomedical application of PTT/PDT combined with Anti-PD-L1 based on ICG@SANPs-cRGD nanomaterials for breast cancer treatment and demonstrates the potential of ICG@SANPs-cRGD as a multifunctional therapeutic platform for future cancer therapy.
研究领域:
癌症治疗
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纳米技术
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免疫学
·
生物医学工程
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分子生物学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
ACS Applied Materials & Interfaces
·
2022
·
IF 10.383
Qing Hu,Jiayi Yao,Xiaoqin Wang,Yanfang Wang,Xiaoling Fu,Ju Ma,Han Lin,Jiaqi Xu,Longhua Shen,Xiangbin Yu
Chemoimmunotherapy can synergistically enhance the therapeutic effects and decrease the side effects by a combined method. However, the effective targeted codelivery of various chemotherapeutic agents and siRNAs remains challenging. Although nanomedicine-based chemoimmunotherapy has shown great potential in cancer treatment in recent years, further effort is needed to simplify the nanocarrier designs and maintain their effective functions. Here, we report a simple but robust multifunctional liposomal nanocarrier that contains a pH-sensitive liposome (LP) shell and a dendritic core for tumor-targeted codelivery of programmed cell death ligand 1 (PD-L1) siRNA and doxorubicin (DOX) (siPD-L1@PM/DOX/LPs). siPD-L1@PM/DOX/LPs had a suitable particle size and zeta potential, excellent stability in serum, and pH-sensitive drug release in vitro. They exhibited significant cell proliferation inhibition compared to free DOX and DOX-loaded LPs and could escape endosomes, effectively release siRNA into the cytoplasm of MCF-7 cells, and significantly reduce the PD-L1 expression on tumor cells. In vivo imaging confirmed high accumulation of siPD-L1@PM/DOX/LPs at the tumor site. More importantly, compared with siPD-L1@PM/LPs or DOX alone, siPD-L1@PM/DOX/LPs were more effective in inhibiting tumor growth and activating cytotoxic T cells in vivo. In conclusion, this nanocarrier may hold promise as a codelivery nanoplatform to improve the treatment of various solid tumors.
研究领域:
癌症研究
·
药学
·
纳米技术
·
分子生物学
·
治疗学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Frontiers in Oncology
·
2022
·
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
研究领域:
肿瘤学
·
免疫疗法
·
分子生物学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
BIOCHEMICAL PHARMACOLOGY
·
2020
·
IF 4.96
Xuqian Deng,Jiaqi Zhao,Linlin Qu,Zhiguang Duan,Rongzhan Fu,Chenhui Zhu,Daidi Fan
Ginsenoside Rh4, as a bioactive component obtained from Panax notoginseng , has excellent pharmacological efficacy especially antitumor effects. However, its anticancer effects and target mechanisms in regulating human esophageal cancer are still poorly understood. Here, the results suggested that Rh4 exhibited potent anti-esophageal cancer effects in vivo and in vitro . Flow cytometric analysis and Western Blot showed that Rh4 significantly inhibited the growth by inducing G1 phase arrest. In parallel, Rh4 inhibited aerobic glycolysis in esophageal cancer cells by hindering lactate production, glucose uptake and ATP production; reducing the extracellular acidification rate (ECAR) and oxygen consumption rate (OCR); suppressing aerobic glycolysis-related protein expression. Mechanistic studies demonstrated that AKT is a possible target of Rh4, which suppresses aerobic glycolysis. Rh4 administration resulted in AKT deregulation, whereas treatment with insulin abolished the inhibitory effect of Rh4 on aerobic glycolysis. In contrast, treatment with AKT inhibitors or siRNA that silenced AKT enhanced the inhibitory effect of Rh4 on aerobic glycolysis. Moreover, molecular docking results indicated that Rh4 was able to bind to the interdomain region of AKT. Interestingly, the results revealed that Rh4 also inhibited the expression of PD-L1 via the AKT/mTOR pathway. Taken together, our findings provide important insights into the anti-esophageal cancer effects of Rh4 via suppressing aerobic glycolysis and PD-L1 expression, which indicated Rh4 could be as promising drug for clinical treatment.
研究领域:
肿瘤学
·
药理学
·
分子生物学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
INTERNATIONAL JOURNAL OF BIOLOGICAL MACROMOLECULES
·
2022
·
IF 8.025
Mengya Ma,Xiaobin Liu,Chaoqun Ma,Ruyue Guo,Xueling Zhang,Zhenzhong Zhang,Xueling Ren
Improved curative effects with reduced toxicity has always been the ultimate goal of gene delivery vectors for tumor immunotherapy. Panax notoginseng polysaccharide (PNP), a natural plant-derived macromolecule, not only has antitumor immune activity but also has the typical structural characteristics useful for gene delivery. In this work, positively charged polyethyleneimine (PEI) was directly grafted to the backbone of PNP to induced its charge reversal and generate a functional gene vector (PNP-PEI). Moreover, a short hairpin RNA targeting the programmed death-ligand 1 (PD-L1) was loaded into PNP-PEI to generate a potentially therapeutic nanoparticle (PNP-PEI/shPD-L1). In vitro and in vivo experiments demonstrated that PNP-PEI could efficiently carry the therapeutic shPD-L1 into tumor cells and that PNP-PEI/shPD-L1 could significantly inhibit the expression of PD-L1 and growth of B16-F10 cells. Noteworthily, treatment with PNP-PEI reversed the phenotype of macrophages from M2 to M1 subtype and promoted dendritic cell maturation, which encouraged the host immunity and enhanced the therapeutic antitumor effects. In summary, this study describes a PNP-based gene delivery vector and highlights the beneficial immunopotentiating therapeutic outcomes of PNP-PEI for tumor immunotherapy.
研究领域:
癌症免疫疗法
·
基因治疗
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药学
·
分子生物学
·
免疫学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
ADVANCED MATERIALS
·
2025
·
IF 26.8
Xiejun Zhao,Xiangchuan Qin,Ruizhe Wang,Yawen Wang,Yinli He,Yuchen Wang,Kefeng Li,Peipei Zhang,Chen Yang,Menghan Wang,Yingtong Dong,Xue Shi,Jia Ma,Jiye Zhang,Xiaojiao Li
Inefficient priming, poor recruitment, and inadequate reinvigoration of T cells challenges the therapy of PD-L1-resistant tumors. Herein, a pH-responsive charge-reversal nanoplatform integrating coactivator-associated arginine methyltransferase 1 (CARM1) inhibitor (iCARM1) and poliovirus receptor siRNA (siPVR) is developed. Upon tumor penetration, iCARM1 released in tumor cells facilitates T cell priming by epigenetically activating cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) signaling-mediated dendritic cell maturation. Meanwhile, in T cells, iCARM1 facilitates their recruitment by upregulating CXC-chemokine receptor 3 (CXCR3) expression. The released siPVR silences pvr to reinvigorate T cells. This epigenetic nanoagonist induces a robust immune response, dramatically suppresses tumor growth, metastasis, and relapse, and confers durable protection against secondary tumor challenge. Multiple PD-L1-resistant models demonstrate the broad applicability of this strategy. This study thus represents an innovative approach for facilitating multilevel T cell responses to combat PD-L1-resistant tumors.
研究领域:
癌症免疫治疗
·
纳米医学
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表观遗传学
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分子生物学
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免疫学
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信号转导
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RNA干扰
✓ 已验证
产品关联
DOI
PubMed
高影响因子
ACS Nano
·
2024
·
IF 15.8
Shizhen Geng,Pengke Guo,Xinling Li,Yaru Shi,Jing Wang,Mengnian Cao,Yunya Zhang,Kaixiang Zhang,Airong Li,Haiwei Song,Zhenzhong Zhang,Jinjin Shi,Junjie Liu,Yiling Yang
Immune checkpoint blockade (ICB) therapy has been approved for breast cancer (BC), but clinical response rates are limited. Recent studies have shown that commensal microbes colonize a variety of tumors and are closely related to the host immune system response. Here, we demonstrated that Fusobacterium nucleatum (F.n), which is prevalent in BC, creates an immunosuppressive tumor microenvironment (ITME) characterized by a high-influx of myeloid cells that hinders ICB therapy. Administering the antibiotic metronidazole in BC can deplete F.n and remodel the ITME. To prevent an imbalance in the systemic microbiota caused by antibiotic administration, we designed a biomimetic nanovehicle for on-site antibiotic delivery inspired by F.n homing to BC. Additionally, ferritin-nanocaged doxorubicin was coloaded into this nanovehicle, as immunogenic chemotherapy has shown potential for synergy with ICB. It has been demonstrated that this biomimetic nanovehicle can be precisely homed to BC and efficiently eliminate intratumoral F.n without disrupting the diversity and abundance of systemic microbiota. This ultimately remodels the ITME, improving the therapeutic efficacy of the PD-L1 blocker with a tumor inhibition rate of over 90% and significantly extending the median survival of 4T1 tumor-bearing mice.
研究领域:
肿瘤学
·
免疫学
·
纳米技术
·
微生物学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Acta Pharmaceutica Sinica B
·
2024
·
IF 14.7
Chongzheng Yan,Ying Liu,Guozhi Zhao,Huatian Yang,Huaiyou Lv,Genju Li,Yuhan Li,Yaqing Fu,Fengqin Sun,Yafei Feng,Yizhe Li,Zhongxi Zhao
Cuproptosis shows enormous application prospects in lung metastasis treatment. However, the glycolysis, Cu + efflux mechanisms, and insufficient lung drug accumulation severely restrict cuproptosis efficacy. Herein, an inhalable poly(2-( N -oxide- N , N -diethylamino)ethyl methacrylate) (OPDEA)-coated copper-based metal–organic framework encapsulating pyruvate dehydrogenase kinase 1 siRNA (siPDK) is constructed for mediating cuproptosis and subsequently promoting lung metastasis immunotherapy, namely OMP. After inhalation, OMP shows highly efficient lung accumulation and long-term retention, ascribing to the OPDEA-mediated pulmonary mucosa penetration. Within tumor cells, OMP is degraded to release Cu 2+ under acidic condition, which will be reduced to toxic Cu + to induce cuproptosis under glutathione (GSH) regulation. Meanwhile, siPDK released from OMP inhibits intracellular glycolysis and adenosine-5ʹ-triphosphate (ATP) production, then blocking the Cu + efflux protein ATP7B, thereby rendering tumor cells more sensitive to OMP-mediated cuproptosis. Moreover, OMP-mediated cuproptosis triggers immunogenic cell death (ICD) to promote dendritic cells (DCs) maturation and CD8 + T cells infiltration. Notably, OMP-induced cuproptosis up-regulates membrane-associated programmed cell death-ligand 1 (PD-L1) expression and induces soluble PD-L1 secretion, and thus synergizes with anti-PD-L1 antibodies (aPD-L1) to reprogram immunosuppressive tumor microenvironment, finally yielding improved immunotherapy efficacy. Overall, OMP may serve as an efficient inhalable nanoplatform and afford preferable efficacy against lung metastasis through inducing cuproptosis and combining with aPD-L1.
研究领域:
肿瘤学
·
药学
·
免疫学
·
纳米技术
·
分子生物学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Small
·
2021
·Vol. 18
·期 9
·2105118
·
IF 13.281
Yu Hei,Yang Chen,Qian Li,Zi Mei,Jijia Pan,Siqi Zhang,Chunyang Xiong,Xiaodong Su,Shicheng Wei
The immunosuppressive tumor microenvironment (TME) can significantly limit the immunotherapeutic effects of the PD-L1 antibody (aPDL1) by inhibiting the infiltration of CD8 + cytotoxic T cells (CTLs) into the tumor tissues. However, how to reprogram the immunosuppressive TME and promote the infiltration of CTLs remains a huge challenge for aPDL1 to achieve the maximum benefits. Herein, the authors design a multifunctional immunoliposome that encapsulates the adrenergic receptor blocker carvedilol (CAR) and connects the “don't eat me” signal antibody (aCD47) and aPDL1 in series via a reactive oxygen species (ROS)-sensitive linker on the surface. In ROS-enriched immunosuppressive TME, the multifunctional immunoliposome (CAR@aCD47/aPDL1-SSL) can first release the outer aCD47 to block the “do not eat me” pathway, promote the phagocytosis of tumor cells by phagocytic cells, and activate CTLs. Then, the aPDL1 on the liposome surface is exposed to block the PD-1/PD-L1 signaling pathway, thereby inducing CTLs to kill tumor cells. CAR encapsulated in CAR@aCD47/aPDL1-SSL can block the adrenergic nerves in the tumor tissues and reduce their densities, thereby inhibiting angiogenesis in the tumor tissues and reprogramming the immunosuppressive TME. According to the results, CAR@aCD47/aPDL1-SSL holds an effective way to reprogram the immunosuppressive TME and significantly enhance immunotherapeutic efficiency of aPDL1 against the primary cancer and metastasis.
研究领域:
癌症免疫疗法
·
药学
·
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
ACS Applied Materials & Interfaces
·
2025
·
IF 8.2
Mingxi Ma,Chao Yu,Hanyuan Liu,Xuepeng Lv,Haidong Zhu,Weiwei Tang,Gaojun Teng,Fei Xiong
Hepatocellular carcinoma (HCC) is a highly fatal malignant tumor. The clinical outcomes of vascular interventional therapy for HCC based on existing drug-eluting microspheres remain unsatisfactory. This study adopted a unique fabrication method to synthesize methacrylated carrageenan/gelatin hydrogel embolic microspheres (MCGs). The interpenetrating network formed by these two biocompatible and absorbable natural macromolecules endows MCGs with outstanding mechanical properties and vascular conformity. MCGs could be delivered through microcatheters smoothly, and they are provided in various sizes to accommodate different clinical requirements. Their in vivo degradation behavior is controlled and predictable. Due to the strong anionic nature of carrageenan, MCGs can efficiently load and sustainably release Lenvatinib, achieving the precise delivery of this antiangiogenic targeted drug in the tumor region. Animal models reveal that the microspheres block blood vessels effectively and MCGs allow for high-dose Lenvatinib to have prolonged contact with HCC. We also propose an HCC treatment strategy by combining PD-L1 inhibitors with MCGs carrying Lenvatinib. This combination therapy is safe and effective, and the additive and synergistic effects showed impressive antitumor potency and great clinical application potential.
研究领域:
生物医学工程
·
肿瘤学
·
药学
·
生物材料
·
免疫治疗
✓ 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）