ACS Applied Materials & Interfaces
·
2023
·
IF 9.5
Lei Xia,Chengxue He,Yanhui Guo,Xiangxi Meng,Teli Liu,Xiaoxia Xu,Xiaoyi Guo,Feng Wang,Nan Li,Hua Zhu,Zhi Yang
Programmed death ligand 1 (PDL1) is a specific molecular target for the diagnosis and immunotherapy of solid tumors. PET imaging can be used for noninvasive assessments of PDL1 expression in tumors to aid in therapy selection. The most frequently reported small-molecule radiotracer of PDL1 is limited by low imaging specificity, short residence time, and singular functionality. Here, we combined a biocompatible melanin nanoprobe with the PDL1-binding peptide WL12 to construct a novel radiotracer, 124I-WPMN, to enhance PDL1 targeting. The radiochemical purity of 124I-WPMN was >95%, and uptake in A549PDL1 cells was 1.49 ± 0.08% at 2 h. The uptake was blocked by WL12 (0.39 ± 0.03%, P < 0.0001). This novel radiotracer showed a higher affinity for PDL1 (Kd = 18.5 nM) than 68Ga-NOTA-WL12 (Kd = 24.0 nM). Micro-PET/CT imaging demonstrated specific uptake and a high signal-to-noise ratio in an A549PDL1 xenograft mouse model with a tumor-to-muscle ratio of 27.31 ± 7.03 at 2 h. The levels increased or remained steady for more than 72 h, and tumor uptake was significantly higher than 68Ga-NOTA-WL12, at 6.08 ± 0.62 at 2 h. Prolonged retention of 124I-WPMN makes it possible to conduct PET/MRI imaging over long periods and to perform various imaging techniques. A clear advantage of 124I-WPMN over 68Ga-NOTA-WL12 was observed for PDL1-targeted PET imaging after nanoparticle modification, supporting the utility of 124I-WPMN PET imaging as an effective diagnostic tool for optimizing PDL1-targeted therapies.
研究领域:
肿瘤学
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医学影像
·
生物化学
✓ 已验证
DOI
PubMed
高影响因子
INTERNATIONAL JOURNAL OF BIOLOGICAL MACROMOLECULES
·
2024
·
IF 7.7
Yanan Chen,Zhonghao Jiang,Zhuo Yan,Jierong Liu,Yilin Lai,Li Li,Xiao Lin,Jiantao Lin
Sorafenib (SF) is a first-line drug for the treatment of hepatocellular carcinoma (HCC) in clinical practice. However, acquired drug resistance tremendously limits the clinical efficacy of sorafenib in treating HCC, which has attracted great attention. PDL1 plays a crucial role in the drug resistance of HCC. Here, a codelivery system based on poly-SS-lysine modified chitosan (TAT-C-SS-P) was established and was applied to deliver sorafenib and PDL1-siRNA for synergetic HCC therapy. The successful synthesis of TAT-C-SS-P was confirmed by 1 H NMR. Additionally, sorafenib and PDL1-siRNA were successfully transported into the cells as the decreased expression of VEGF and PD-L1 by administrated with TAT-C-SS-P@SF@ PDL1-siRNA. Simultaneously, the expression of pro-apoptosis proteins cyt-c and Bax was prominently augmented, whereas the expression of anti-apoptosis protein Bcl-2 was decreased. The reduced expression of PDL1 resulted in the downregulation of P-GP and MRP1, which contributed to more sorafenib aggregation in tumor cells. Moreover, TAT-C-SS-P@PDL1-siRNA@SF efficiently promotes apoptosis of HepG2-SI cells, as the apoptosis rate rised to 73 %. A sorafenib-insensitive model was established to evaluate in vivo antitumor effect of TAT-C-SS-P@PDL1-siRNA@SF. TAT-C-SS-P@PDL1-siRNA@SF showed a tumor inhibition rate of 90.2 ± 3.5 % and no significant decrease in body weight. Taken together, our study provided compelling evidence that TAT-C-SS-P@PDL1-siRNA@SF has great potential application in the treatment of HCC clinically.
研究领域:
肿瘤学
·
药理学
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分子生物学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
JOURNAL OF MEDICINAL CHEMISTRY
·
2025
·
IF 6.8
Yunhai Wei,Wenjing Hu,Huancen Guo,Jinyu Zhang,Jingrui Cao,Chu Shen,Zhongxin Wu,Lei Yin,Yuhai Gao
Immune checkpoint inhibitors (ICIs) show effectiveness in gastric cancer (GC) treatment, yet enhancing their efficacy remains challenging. We encapsulated the anticancer compound Heterophyllin B (HB) in mPEG–PLGA-NH2 nanoparticles (NPs), modified with αPDL1, forming mPEG–PLGA-NH2@HB-αPDL1 NPs. These NPs displayed low toxicity to GES-1 cells and good blood compatibility. They effectively inhibited GC cell malignant phenotypes and downregulated PD-L1 expression via the PI3K/AKT pathway. In GC allograft mice, the HB and αPDL1 combination therapy outperformed monotherapy, with the NPs showing better efficacy than free drugs. Additionally, the NPs improved the tumor immune microenvironment. H&E staining confirmed no significant toxicity to major mouse organs. Thus, mPEG–PLGA-NH2@HB-αPDL1 offers a promising strategy for optimizing ICI therapy in GC treatment.
研究领域:
纳米医学
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肿瘤学
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免疫治疗
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药物递送系统
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药理学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
BIOORGANIC CHEMISTRY
·
2024
·
IF 4.5
Yimei Zhang,Shiyi Xiang,Yayi Wu,Can Yang,Dianyong Tang,Zhongzhu Chen,Zheng Huang
Photodynamic therapy (PDT) combined with immunotherapy has become a promising antitumor strategy. However, precise regulation of the activation of antitumor immunity and effective reversion of immunosuppressive tumor microenvironment (TME) remains challenging. In this paper, a novel co-delivery nanomedicine is developed to solve these issues for photodynamic amplified immunotherapy. Specifically, the glycolysis inhibitor (Lon) is coupled with PD1/PDL1 blocker (BMS-1) by thioketal linkage to form smartly responsive prodrug LTB , which could further encapsulate photosensitizer chlorine e6 (Ce6) to construct a co-delivery nanoplatform ( LTB-6 NPs ) by self-assembly. Of note, LTB-6 NPs possess favorable stability, uniform morphology and improved cellular uptake. More importantly, LTB-6 NPs are capable of inhibiting glycolysis and blocking PD1/PDL1, which could greatly improve the immunosuppressive TME to promote immune activation. LTB-6 NPs -mediated PDT not only inhibits tumor proliferation but also induces ICD response to activate immunological cascade. In vivo experiments indicate that intravenously injected LTB-6 NPs remarkably suppresses the tumor growth while leads to a minimized side effect. This research provides a multi-synergized strategy for developing effective photodynamic nanoplatforms in tumor treatment.
研究领域:
肿瘤学
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纳米医学
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免疫学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
JOURNAL OF EXPERIMENTAL & CLINICAL CANCER RESEARCH
·
2024
·Vol. 43
·期 1
·1-19
·
IF 11.4
Liang Mingkang,Wang Yongqiang,Liu Lisha,Deng Dashi,Yan Zeqin,Feng Lida,Kong Chenfan,Li Chenchen,Li Yuqing,Li Guangzhi
Background CRISPR-Cas13a is renowned for its precise and potent RNA editing capabilities in cancer therapy. While various material systems have demonstrated efficacy in supporting CRISPR-Cas13a to execute cellular functions in vitro efficiently and specifically, the development of CRISPR-Cas13a-based therapeutic agents for intravesical instillation in bladder cancer (BCa) remains unexplored.
Methods In this study, we introduce a CRISPR-Cas13a nanoplatform, which effectively inhibits PDL1 expression following intravesical instillation. This system utilizes a fusion protein CAST, created through the genetic fusion of CRISPR-Cas13 and the transmembrane peptide TAT. CAST acts as a potent transmembrane RNA editor and is assembled with the transepithelial delivery carrier fluorinated chitosan (FCS). Upon intravesical administration into the bladder, the CAST-crRNAa/FCS nanoparticles (NPs) exhibit remarkable transepithelial capabilities, significantly suppressing PDL1 expression in tumor tissues.To augment immune activation within the tumor microenvironment, we integrated a fenbendazole (FBZ) intravesical system (FBZ@BSA/FCS NPs). This system is formulated through BSA encapsulation followed by FCS coating, positioning FBZ as a powerful chemo-immunological agent. Results In an orthotropic BCa model, the FBZ@BSA/FCS NPs demonstrated pronounced tumor cell apoptosis, synergistically reduced PDL1 expression, and restructured the immune microenvironment. This culminated in an enhanced synergistic intravesical instillation approach for BCa. Consequently, our study unveils a novel RNA editor nanoagent formulation and proposes a potential synergistic therapeutic strategy. This approach significantly bolsters therapeutic efficacy, holding promise for the clinical translation of CRISPR-Cas13-based cancer perfusion treatments.
研究领域:
癌症治疗
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分子生物学
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纳米技术
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免疫学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Acta Biomaterialia
·
2025
·
IF 9.6
Xiaokang Zhu,Li Xie,Qing Liao,Jinming Tian,Jinlin Peng,Zhu Chen,Erqun Song,Yang Song
Ferrotherapy has risen as a promising therapeutic approach for triple-negative breast cancer (TNBC); however, its potency is frequently compromised due to tumor cells’ ability to evade ferroptosis via various resistance pathways and insufficient immunogenicity. To overcome these limitations, we have engineered a calcium phosphate-mineralized ferroptosis inducer nanoplatform, termed Lf-PEG-CaP@iFSP1-Brequinar-Erastin-Fe 3+ -TA (LP-CaP@iBEFT), designed to augment ferroptosis by simultaneously targeting three key pathways: glutathione peroxidase 4 (GPX4), ferroptosis suppressor protein 1 (FSP1), and dihydroorotate dehydrogenase (DHODH). Once internalized and reached the acidic tumor microenvironment (TME), the nanoplatform discharges its therapeutic payloads, comprising inhibitors of FSP1 (iFSP), brequinar, erastin, and iron ions. The first three components were tailored to inhibit key pathways to ferroptosis, while the released iron ions initiate ferroptosis by catalyzing the generation of reactive oxygen species (ROS) via Fenton reactions. The calcium phosphate-mineralized ferroptosis inducer nanoplatform promotes the maturation of DC cells, enhances the infiltration of T cells and releases immunity-related factors, thereby altering the immunosuppressive microenvironment. In conjunction with anti-PD-L1 therapy, LP-CaP@iBEFT boosts T lymphocyte-mediated immune infiltration, thereby amplifying the anti-tumor response and offering a therapeutic approach for TNBC. Statement of significance We developed an acid-responsive nanoplatform that specifically targets tumor cells that overexpress lactoferrin receptors. This nanoplatform degrades within the acidic tumor environment to release the payload components iFSP1, brequinar, erastin, and Fe 3+ , which collectively inhibit three pathways of ferroptosis. This approach effectively dismantles the “triple defense” mechanism that tumor cells employ to resist ferroptosis. In addition, this nanoplatform synergizes with anti-PD-L1 immune checkpoint blockade, enhancing the T cell-mediated destruction of tumor cells.
研究领域:
肿瘤学
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免疫学
·
分子生物学
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生物材料学
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转化医学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
ACS Applied Materials & Interfaces
·
2020
·
IF 8.758
Yimou Gong,Muchao Chen,Yanjun Tan,Jingjing Shen,Qiutong Jin,Wutong Deng,Jian Sun,Chao Wang,Zhuang Liu,Qian Chen
Chemotherapeutic agents have been widely used for cancer treatment in clinics. Aside from their direct cytotoxicity to cancer cells, some of them could activate the immune system of the host, contributing to the enhanced antitumor activity. Here, the reactive oxygen species (ROS)-responsive hydrogel, covalently cross-linked by phenylboronic acid-modified 7-ethyl-10-hydroxycamptothecin (SN38-SA–BA) with poly(vinyl alcohol) (PVA), is fabricated for topical delivery of anti-programmed cell death protein ligand 1 antibodies (aPDL1). In the presence of endogenous ROS, SN38-SA–BA will be oxidized and hydrolyzed, leading to the degradation of hydrogel and the release of initial free SN38 and encapsulated aPDL1. It is demonstrated that SN38 could elicit specific immune responses by triggering immunogenic cell death (ICD) of cancer cells, a distinct cell death pathway featured with the release of immunostimulatory damage-associated molecular patterns (DAMPs). Meanwhile, the released aPDL1 could bind to programmed cell death protein ligand 1 (PDL1) expressed on cancer cells to augment antitumor T cell responses. Thus, the ROS-responsive prodrug hydrogel loaded with aPDL1 could induce effective innate and adaptive antitumor immune responses after local injection, significantly inhibiting or even eliminating those tumors.
研究领域:
肿瘤学
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药学
·
免疫学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Nature Communications
·
2024
·Vol. 15
·期 1
·1-16
·
IF 14.7
Ye Qian-Ni,Zhu Long,Liang Jie,Zhao Dong-Kun,Tian Tai-Yu,Fan Ya-Nan,Ye Si-Yi,Liu Hua,Huang Xiao-Yi,Cao Zhi-Ting,Shen Song,Wang Jun
The functions of natural killer (NK) and T cells in innate and adaptive immunity, as well as their functions in tumor eradication, are complementary and intertwined. Here we show that utilization of multi-specific antibodies or nano-antibodies capable of simultaneously targeting both NK and T cells could be a valuable approach in cancer immunotherapy. Here, we introduce a tri-specific Nano-Antibody (Tri-NAb), generated by immobilizing three types of monoclonal antibodies (mAbs), using an optimized albumin/polyester composite nanoparticle conjugated with anti-Fc antibody. This Tri-NAb, targeting PDL1, 4-1BB, and NKG2A (or TIGIT) simultaneously, effectively binds to NK and CD8 + T cells, triggering their activation and proliferation, while facilitating their interaction with tumor cells, thereby inducing efficient tumor killing. Importantly, the antitumor efficacy of Tri-NAb is validated in multiple models, including patient-derived tumor organoids and humanized mice, highlighting the translational potential of NK and T cell co-targeting.
研究领域:
免疫学
·
肿瘤学
·
生物技术
·
分子生物学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
ONCOLOGY REPORTS
·
2023
·Vol. 51
·期 1
·1-13
·
IF 4.2
Gongjie Ye,Linglan Tu,Zhuduo Li,Xiangyu Li,Xiaoliang Zheng,Yongfei Song
Synaptopodin 2 (SYNPO2) plays a pivotal role in regulating tumor growth, development and progression in bladder urothelial Carcinoma (BLCA). However, the precise biological functions and mechanisms of SYNPO2 in BLCA remain unclear. Based on TCGA database‑derived BLCA RNA sequencing data, survival analysis and prognosis analysis indicate that elevated SYNPO2 expression was associated with poor survival outcomes. Notably, exogenous SYNPO2 expression significantly promoted tumor invasion and migration by upregulating vimentin expression in BLCA cell lines. Enrichment analysis revealed the involvement of SYNPO2 in humoral immune responses and the PI3K/AKT signaling pathway. Moreover, increased SYNPO2 levels increased the sensitivity of BLCA to PI3K/AKT pathway‑targeted drugs while being resistant to conventional chemotherapy. In in vivo BLCA mouse models, SYNPO2 overexpression increased pulmonary metastasis of 5637 cells. High SYNPO2 expression led to increased infiltration of innate immune cells, particularly mast cells, in both nude mouse model and clinical BLCA samples. Furthermore, tumor immune dysfunction and exclusion score showed that patients with BLCA patients and high SYNPO2 expression exhibited worse clinical outcomes when treated with immune checkpoint inhibitors. Notably, in the IMvigor 210 cohort, SYNPO2 expression was significantly associated with the population of resting mast cells in BLCA tissue following PD1/PDL1 targeted therapy. In conclusion, SYNPO2 may be a promising prognostic factor in BLCA by modulating mast cell infiltration and exacerbating resistance to immune therapy and conventional chemotherapy.
研究领域:
肿瘤学
·
免疫学
·
分子生物学
·
癌症生物学
✓ 已验证
DOI
PubMed
高影响因子
ACS Nano
·
2025
·
IF 16
Zexin Yang,Kang Liu,Huihui Li,Yunlong Li,Quanwei Sun,Wencui Shang,Mingjing Wang,Ye Yang,Hanmeng Liu,Dengke Yin,Wei Shen
Although traditional immunogenic cell death (ICD) inducers generate in situ vaccines (ISV) to potentiate antiprogrammed cell death ligand 1 (anti-PDL1) antibodies therapy, their efficacy remains limited. This limitation may be attributed to the physical barrier created by extracellular matrix (ECM) and immunosuppressive metabolic barrier mediated by adenosine. Here, we report an oncolytic polymer (OP), a well-designed ε-polylysine derivative with ICD-inducing capacity, which can simultaneously facilitate the release of endogenous ECM-degrading enzyme, Cathepsin B. The OP alone is sufficient to induce ISV within tumors and disrupt physical barriers without the need for any additional ECM-regulatory drugs. Furthermore, an oncolytic hydrogel codelivering OP and CD73 inhibitor (AMPCP) was developed (OP@AMPCP Gel). Intratumoral injection of OP@AMPCP Gel generates ISV, decreases tumor ECM deposition, enhances antigen delivery to lymph nodes, increases immune cell infiltration, and promotes penetration of anti-PDL1 antibodies, while reducing adenosine levels. OP@AMPCP Gel+anti-PDL1 treatment showed better therapeutic efficacy than oxaliplatin + anti-PDL1 group against breast cancer. Moreover, 80% of melanoma-bearing mice showed complete tumor regressions after receiving OP@AMPCP Gel + anti-PDL1 treatment. Impressively, OP@AMPCP Gel + anti-PDL1-treated mice showed resistance to tumor rechallenge and metastasis, suggesting induction of long-lasting systemic antitumor immunity. Overall, this study presents an oncolytic hydrogel capable of inducing ISV and remodeling the tumor physical barrier and immunosuppressive barrier, offering a promising strategy for customizing personalized immunotherapy.
研究领域:
癌症免疫治疗
·
生物材料
·
肿瘤生物学
·
药物递送
·
免疫学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
JOURNAL OF CONTROLLED RELEASE
·
2024
·
IF 10.5
Mengqi Jia,Xiaodong Zhou,Pengfei Li,Shiyong Zhang
Adapting the mechanical strength between the implant materials and the brain tissue is crucial for the postoperative treatment of glioblastoma. However, no related study has been reported. Herein, we report an injectable lipoic acid‑iron (LA-Fe) hydrogel (LFH) that can adapt to the mechanical strength of various brain tissues, including human brain tissue, by coordinating Fe 3+ into a hybrid hydrogel of LA and its sodium salt (LANa). When LFH, which matches the mechanical properties of mouse brain tissue (337 ± 8.06 Pa), was injected into the brain resection cavity, the water content of the brain tissue was maintained at a normal level (77%). Similarly, LFH did not induce the activation or hypertrophy of glial astrocytes, effectively preventing brain edema and scar hyperplasia. Notably, LFH spontaneously degrades in the interstitial fluid, releasing LA and Fe 3+ into tumor cells. The redox couples LA/DHLA (dihydrolipoic acid, reduction form of LA in cells) and Fe 3+ /Fe 2+ would regenerate each other to continuously provide ROS to induce ferroptosis and activate immunogenic cell death. As loaded the anti-PDL1, anti-PDL1@LFH further enhanced the efficacy of tumor-immunotherapy and promoted tumor ferroptosis. The injectable hydrogel that adapted the mechanical strength of tissues shed a new light for the tumor postoperative treatment.
研究领域:
生物医学工程
·
神经科学
·
癌症研究
·
材料科学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
CELL
·
2024
·
IF 45.5
Feng Lin,Shenyi Yin,Zijian Zhang,Ying Yu,Haoming Fang,Zhen Liang,Rujie Zhu,Haitao Zhou,Jianjie Li,Kunxia Cao,Weiming Guo,Shan Qin,Yuxuan Zhang,Chenghao Lu,Han Li,Shibo Liu,Heng Zhang,Buqing Ye,Jian Lin,Yan Li,Xiaozheng Kang,Jianzhong Jeff Xi,Peng R. Chen
Although immunotherapy has revolutionized cancer treatment, its efficacy is affected by multiple factors, particularly those derived from the complexity and heterogeneity of the tumor-immune microenvironment (TIME). Strategies that simultaneously and synergistically engage multiple immune cells in TIME remain highly desirable but challenging. Herein, we report a multimodal and programmable platform that enables the integration of multiple therapeutic modules into single agents for tumor-targeted co-engagement of multiple immune cells within TIME. We developed the triple orthogonal linker (T-Linker) technology to integrate various therapeutic small molecules and biomolecules as multimodal targeting chimeras (Multi-TACs). The EGFR-CD3-PDL1 Multi-TAC facilitated T-dendritic cell co-engagement to target solid tumors with excellent efficacy, as demonstrated in vitro , in several humanized mouse models and in patient-derived tumor models. Furthermore, Multi-TACs were constructed to coordinate T cells with other immune cell types. The highly modular and programmable feature of our Multi-TACs may find broad applications in immunotherapy and beyond.
研究领域:
免疫学
·
肿瘤学
·
生物技术
·
分子生物学
✓ 已验证
DOI
PubMed
高影响因子
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