Cell Reports
·
2023
·Vol. 42
·期 9
·113090-113090
·
IF 8.8
Wang D,Zhu Z,Fu Y,Zhang Q,Zhang Y,Wang T,Weng Y,Wen Y,Cao W,Tao G,Wang Y
Polycystic ovary syndrome (PCOS) is an endocrine disorder and the main cause of anovulatory infertility, in which persistent activation of androgen receptor (AR) due to aberrant acetylation modifications of transcription is a potential trigger; however, the precise mechanisms of AR activation are poorly understood. In this study, AR activation in dehydroepiandrosterone- and letrozole-induced rat PCOS ovaries coincided with a marked increase of a chromatin acetylation "reader" BRD4. Further bioinformatic analysis showed that the AR promoter contained highly conserved binding motifs of BRD4 and HIF-1α. BRD4 and HIF-1α inducibly bound to the histone 3/4 acetylation-modified AR promoter, while administration of a BRD4-selective inhibitor JQ1 reduced the binding and AR transcription and improved the adverse expression of the core fibrotic mediators in PCOS ovaries and DHT-treated granulosa cells. Our data indicate that BRD4 upregulation and the resultant AR transcriptional activation constitute an important regulatory pathway that promotes ovarian fibrosis in PCOS.
研究领域:
内分泌学
·
生殖医学
·
分子生物学
✓ 已验证
DOI
PubMed
高影响因子
Acta Biomaterialia
·
2021
·
IF 8.947
Xuan Zhang,Yan Zhang,Haiping Zheng,Yufeng He,Honglin Jia,Liyuan Zhang,Chunjie Lin,Shuang Chen,Junfeng Zheng,Qunfang Yang,Tao Liu,Xichun Pan,Haigang Zhang,Chenhui Wang,Lei Ren,Wenjun Shan
Metastasis is the leading cause of death in cancer patients. Eliciting anti-tumor immune responses against lung metastasis is hindered by the immunosuppressive microenvironment. This study explored a biomimetic nanoformulation, comprising a nanovaccine (OP) that delivers tumor antigens and adjuvants spatially and temporally in a virus-like manner, and a pulmonary surfactant-biomimetic liposome with an immunomodulator, JQ1 (PS-JQ1). The findings of this study showed that intratracheal administration of OP+PS-JQ1 activated lung immune cells without concomitant excess inflammation, enhanced tumor antigen cross-presentation, generated a significantly high antigen-specific CD8 + T cell response, and reshaped the immunocellular composition in B16 melanoma tumor-bearing lung. OP+PS-JQ1 nanoformulation exhibited a striking immunotherapeutic efficacy, induced local and systemic tumor suppression, improved survival of mice, initiated immune memory that prevents recurrence of secondary tumors. This stable and nontoxic nanoformulation provides a simple, flexible, and robust strategy for augmenting anti-tumor immunity for metastatic cancer. Statement of significance Egg glue proteins are produced by female insects, which can make the eggs firmly attached to the oviposition sites, not affected by wind and rain. However, genes encoding insect egg glue proteins have not yet been reported, and the molecular mechanism underpinning their adhesion is still unknown. Our study makes a significant contribution to the literature as it identifies the sequence, structure, adhesive property , and mechanism of silkworm egg glue protein. Furthermore, it outlines key insights into the structure-function relationships associated with egg glue proteins. We believe that this paper will be of interest to the readership of your journal as it identifies the first complete sequence of insect egg glue proteins, thereby highlighting their potentials future applications in both the biomedical and technical fields.
研究领域:
肿瘤学
·
免疫学
·
纳米医学
·
生物材料
✓ 已验证
产品关联
DOI
PubMed
高影响因子
BIOMATERIALS
·
2025
·
IF 12.9
Shiman Lu,Zhaoqing Shi,Chendi Ding,Wenyan Wang,Weilang Zhang,Li Huang,Jiachan Lin,Xinpei Wang,Ran Luo,Xiaowei Zeng,Wenhu Zhou,Hongzhong Chen,Qiangsong Wang,Lin Mei
The targeted protein degradation (TPD) strategy modulates tumor growth pathways by degrading proteins of interest (POIs) and has reshaped anti-tumor drug research and development. Recently, the emergence of photodegradation-targeting chimeras (PDTACs) and laser irradiation at specific sites enables precise spatiotemporal controllability of TPD. Capitalizing on the advances of PDTACs, herein, we report a nanoplatform for efficiently delivering PDTAC molecule for photodegradation of bromodomain-containing protein 4 (BRD4) proteins, the key activators of oncogenic transcription. The PDTAC molecule, named as PPa-JQ1, is synthesized through the covalent attachment of the BRD4-targeting ligand JQ1-acid, to the photosensitizer pyropheophorbide-a (PPa), utilizing a 1,6-hexanediamine linker. The PPa-JQ1 is further encapsulated by human serum albumin (HSA) to obtain the HSA@PPa-JQ1 nanoplatform, which facilitates targeted and efficacious delivery to melanoma lesions. Both in vitro and in vivo therapeutic outcomes demonstrate that HSA@PPa-JQ1 can efficiently generate reactive oxygen species (ROS) to degrade BRD4 upon light irradiation, which eventually induces tumor death. Our study represents the first case to validate the anti-tumor therapeutic efficacy of PDTACs by systemic administration, providing the foundation for further application of PDTACs.
研究领域:
肿瘤学
·
药学
·
纳米技术
·
光化学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
BIOMATERIALS
·
2021
·
IF 12.479
Xueqing Zhou,Xuan Liu,Xiqin Yang,Li Wang,Yiling Hong,Keke Lian,Guoxi Qiu,Xuwei Shang,Zhongjun Ma,Hong Yuan,Fuqiang Hu
Tumor-associated macrophages (TAMs) in the tumor microenvironment (TME) play an important role in the development of tumors by secreting a variety of cytokines or directly communicating with tumor cells, making TAMs-targeted therapeutic strategies very attractive. It has been reported that oncogene c-Myc is related to every aspect of the oncogenic process of tumor cells and the alternative activation of macrophages. Hence, we constructed a glycolipid nanocarrier containing ROS-responsive peroxalate linkages (CSOPOSA) for ROS-triggered release of drugs and further modified it with Ex 26 (Ex 26-CSOPOSA), a selective sphingosine 1-phosphate receptor 1 (S1PR1) antagonist, to achieve the dual-targeted delivery of the c-Myc inhibitor JQ1 via S1PR1, which is overexpressed on both tumor cells and TAMs, thereby inducing apoptosis of tumor cells, and blocking M2 polarization of macrophages. More strikingly, our studies found that JQ1 could effectively inhibit the migration of tumor cells induced by M2 macrophages-derived exosomes via blocking Caveolin-1 related intercellular exosome exchange through lncRNA H19 and miR-107. The in vivo results revealed that this dual-targeted delivery strategy effectively inhibited tumor growth and metastasis with less systemic toxicity, providing a potential method for effective tumor treatment.
研究领域:
肿瘤学
·
药理学
·
细胞生物学
·
纳米技术
·
免疫学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
ACS Applied Nano Materials
·
2023
·
IF 5.9
Liuwei Zhang,Haonan Zheng,Hongyan Cui,Xiaolan Yin,Cheng Zhang,Yue Wang,Yan Zhao,Jiaqi Lin,Zheng Wang,Jingyun Wang,Qixian Chen
One of the challenges in antitumor therapy is the precise delivery of the therapeutic agent to cancerous cells. The delivery of chemotherapy agents can benefit from nanoformulation of prodrugs, which integrates the benefits of nanotechnology and prodrugs, including enhanced drug loading, increased drug bioavailability, and targeted accumulation within cancerous cells. In this work, we designed a redox-responsive polymeric dual-prodrug nanocarrier, PL-ss-(C&J), for codelivery of a potent chemotherapeutic camptothecin (CPT) and an immune checkpoint inhibitor JQ1. Further investigations confirmed that the developed nanomedicine was able to respond to the highly reductive environment within tumor cells. Additionally, due to their quick reactions to the intracellular reducing microenvironment, cytotoxic CPT and JQ1 were simultaneously activated and released, exhibiting significant cytotoxicity. This dual-prodrug activation approach also demonstrated high efficiency in inhibiting tumor growth with satisfactory biocompatibility, pharmacokinetics, and safety in vivo. These results indicated that this type of redox-sensitive dual-prodrug codelivery system based on polymeric prodrug nanomicelles would be a promising technology in chemotherapy and immunotherapy.
研究领域:
药学
·
肿瘤学
·
纳米技术
·
药物递送系统
·
癌症治疗
✓ 已验证
产品关联
DOI
高影响因子
JOURNAL OF NANOBIOTECHNOLOGY
·
2022
·Vol. 20
·期 1
·1-13
·
IF 9.429
Gu Jun,Zhao Gang,Yu Jiangkun,Xu Pei,Yan Jiabin,Jin Zhengshuai,Chen Sheng,Wang Yong,Zhang Leshuai W.,Wang Yangyun
Although combination chemoimmunotherapy shows promising clinical results for cancer treatment, this approach is largely restricted by variable objective response rate and severe systemic adverse effects of immunotherapeutic antibody and chemotherapeutic drugs. Therefore, an in situ-formed therapeutic silk-chitosan composite scaffold is fabricated in this study to allow local release of the chemotherapeutic drug doxorubicin (DOX) and JQ1 (small molecular inhibitor used for the extraterminal protein BRD4 and bromodomain) with control release kinetics. DOX-JQ1@Gel contains a pH-degradable group that releases therapeutics in a weak acidic tumor microenvironment. The released DOX could directly kill tumor cells or lead to immunogenic cell death, thereby triggering the response of antitumor immunity. Meanwhile, chemotherapy-triggered antigen release and JQ1-mediated PD-L1 checkpoint blockade cumulatively contribute to trigger the response of antitumor immunity. Finally, the DOX-JQ1@Gel is locally injected to evaluate its synergistic cancer therapeutic effect, which is expected to improve objective response rate of immunotherapy and minimize systemic side effects.Graphical Abstract
研究领域:
癌症治疗
·
药学
·
生物材料
·
免疫学
✓ 已验证
DOI
PubMed
高影响因子
JOURNAL OF CONTROLLED RELEASE
·
2023
·
IF 10.8
Maoyu Gao,Kai Feng,Xinmiao Zhang,Yiling Ruan,Guizhen Zhao,Huihui Liu,Xiaolian Sun
Cancer immunotherapy is an emerging cancer therapeutic method by activating the patient's immune system but suffers from low immunogenicity at tumor sites. Fever-like heat is known to modulate an immune-friendly tumor microenvironment . Here, temperature-responsive iron oxide nanoassemblies (IONAs) are developed by crosslinking iron oxide nanoparticles (IONPs) and loaded with JQ1 (JQ1/IONAs), an immuno-modulating agent known to down-regulate PD-L1. In the presence of an alternating magnetic field (AMF), the IONAs demonstrate a much more effective magnetic thermal effect than IONPs and are responsively disassembled to prevent overheating. Compared with IONPs + AMF (∼ 41 °C) and unresponsive nanoassemblies (uIONAs) + AMF (∼ 50 °C), the IONAs + AMF with a temperature heated around 45 °C show a much better immune response and anti-tumor effect. Further combining the mild thermal therapy with controlled release of JQ1, the JQ1/IONAs + AMF completely eradicate the primary tumors and trigger a strong immune effect to inhibit the distant tumor growth as well as prevent tumor recurrence and metastasis. Our JQ1/IONAs not only provide a magnetic thermal agent with effective heating and temperature self-regulation ability but also serve as a heat-triggered JQ1 carrier to spontaneously combine mild magnetic thermal therapy with immune checkpoint blockade therapy.
研究领域:
纳米技术
·
肿瘤学
·
免疫治疗
·
材料科学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Applied Materials Today
·
2020
·
IF 8.352
Qiongcong Xu,Liying Wang,Tong Tong,Xitai Huang,Chensong Huang,Fuxi Li,Qiao Su,Yichih Tien,Jun Wu,Wei Zhao,Xiaoyu Yin
Gallbladder cancer (GBC) is one of the most common and aggressive biliary tract diseases with limited therapeutic strategies and poor prognosis. Various therapeutic agents have been demonstrated effective in preclinical models, but high dose requirement and toxicity to normal cells limit their clinical applications. Considering the high concentration of glutathione (GSH) in GBC, we developed a GSH-responsive nanoparticle (NP) system based on biodegradable poly(disulfide amide) (Cys-8E Polymer) for targeted delivery of a BRD4 inhibitor (JQ1), which is known as a promising therapeutic agent for GBC treatment. JQ1-loaded Cys-8E nanoparticles ( [email protected] NPs) possessed a high JQ1 loading, preferable stability and redox-responsive release behavior. Additionally, the NPs showed good targeted delivery into GBC tumor spheroids and GBC patient-derived xenograft (PDX) tumors. Specifically, the intracellular GSH in tumors could trigger the release of JQ1, which induced the cell cycle arrest and apoptosis of GBC cells. RNA-sequencing analysis revealed that [email protected] NPs enhanced the effect of JQ1 through inhibiting NF-κB pathway. Importantly, [email protected] NPs significantly suppressed GBC tumor growth in the PDX model of early recurrence. No obvious systemic toxicity and organ damages were observed after treatment with [email protected] NPs. Our results demonstrate the promising therapeutic applications of [email protected] NPs for adjuvant therapy in GBC treatment.
研究领域:
肿瘤学
·
药学
·
分子生物学
·
纳米技术
✓ 已验证
产品关联
DOI
高影响因子
ACS Applied Materials & Interfaces
·
2022
·
IF 10.383
Meng Zhang,Yingzhi Chen,Dongdong Li,Zhidi He,Hairui Wang,Aihua Wu,Weidong Fei,Caihong Zheng,Ergang Liu,Yongzhuo Huang
Cancer immunotherapy represents a medical breakthrough, but there are still many patients unable to benefit from it because of the low response rate. The immunosuppressive tumor microenvironment (TME) is the main barrier to immunotherapy. Alleviating intratumoral immunosuppression is critical for improving the immune therapeutic efficacy. This work developed an in situ vaccination strategy by using gold nanocage (AuNC)-based photothermal effect in combination with an adjuvant and PD-L1 suppressor. In specific, this therapeutic strategy included three components: AuNCs as an inducer for tumor antigen production via photothermal ablation, CpG oligodeoxynucleotides as an adjuvant to amplify immune responses, and JQ1 as a PD-L1 suppressor to inhibit an immune checkpoint. The results showed that the in situ vaccination efficiently activated dendritic cells and primed T cells and exhibited a high therapeutic efficacy in the melanoma-bearing mice. This therapeutic strategy can increase the infiltration of cytotoxic T lymphocytes, suppress the PD-L1 expression in the tumor, and repolarize tumor-associated macrophages from pro-tumor M2 to the anti-tumor M1 phenotype, thereby remodeling the TME via regulating the innate immune and adaptive immune responses.
研究领域:
癌症免疫疗法
·
纳米技术
·
生物医学工程
·
免疫学
·
肿瘤学
✓ 已验证
DOI
PubMed
高影响因子
Acta Pharmaceutica Sinica B
·
2022
·
IF 14.903
Lujing Geng,Tong Lu,Huaqing Jing,Yue Zhou,Xiaoyang Liang,Jiao Li,Nan Li
Ferroptosis (FPT), a novel form of programmed cell death, is characterized by overwhelming iron/reactive oxygen species (ROS)-dependent accumulation of lipid peroxidation (LPO). However, the insufficiency of endogenous iron and ROS level limited the FPT therapeutic efficacy to a large extent. To overcome this obstacle, the bromodomain-containing protein 4 (BRD 4 )-inhibitor (+)-JQ1 (JQ1) and iron-supplement ferric ammonium citrate (FAC)-loaded gold nanorods (GNRs) are encapsulated into the zeolitic imidazolate framework-8 (ZIF-8) to form matchbox-like [email protected] /ZIF-8 for the amplified FPT therapy. The existence of matchbox (ZIF-8) is stable in physiologically neutral conditions but degradable in acidic environment, which could prevent the loaded agents from prematurely reacting. Moreover, GNRs as the drug-carriers induce the photothermal therapy (PTT) effect under the irradiation of near-infrared II (NIR-II) light owing to the absorption by localized surface plasmon resonance (LSPR), while the hyperthermia also boosts the JQ1 and FAC releasing in the tumor microenvironment (TME). On one hand, the FAC-induced Fenton/Fenton-like reactions in TME can simultaneously generate iron (Fe 3+ /Fe 2+ ) and ROS to initiate the FPT treatment by LPO elevation. On the other hand, JQ1 as a small molecule inhibitor of BRD 4 protein can amplify FPT through downregulating the expression of glutathione peroxidase 4 (GPX4), thus inhibiting the ROS elimination and leading to the LPO accumulation. Both in vitro and in vivo studies reveal that this pH-sensitive nano-matchbox achieves obvious suppression of tumor growth with good biosafety and biocompatibility. As a result, our study points out a PTT combined iron-based/BRD 4 -downregulated strategy for amplified ferrotherapy which also opens the door of future exploitation of ferrotherapy systems.
研究领域:
癌症研究
·
纳米技术
·
治疗学
·
生物医学工程
·
材料科学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
JOURNAL OF CONTROLLED RELEASE
·
2023
·
IF 10.8
Yanyun Hao,Hui Li,Xiaoyan Ge,Yang Liu,Jialin Yin,Xia Li,Yutong Liu,Hongfei Chen,Lingling Huang,Jing Zou,Shiying Zhang,Hao Wu,Zhiyue Zhang
Immunotherapy has fundamentally altered cancer treatment; however, its effectiveness is clinically hampered by insufficient intratumoral T lymphocyte infiltration and failed T lymphocyte priming. Additionally, inducing cancer-specific immune responses while sparing normal cells remains challenging. Herein, we developed a redox-activatable polymeric nanoswitch (c-N@IM/JQ) that remained ‘off’ status in circulation but rapidly switched ‘on' after entering the tumor. Toll-like receptor (TLR) 7/8 agonist (imidazoquinoline, IMQ) and bromodomain and extraterminal inhibitor (JQ1) are locked in c-N@IM/JQ with a redox-cleavable linker (switch off). Upon systemic administration , c-N@IM/JQ with c-RGD peptide modification preferentially accumulated at tumor sites and responded to the high glutathione levels to release native IMQ for fully mobilizing T lymphocyte army, and JQ1 for removing the programmed death ligand (PD-L)-1 protection on tumor cells (switch on). These strengthened T lymphocyte armies are easily accessible to these de-protected tumor cells, revitalizing the immune response against tumors.
研究领域:
癌症免疫疗法
·
纳米技术
·
药学
·
分子生物学
✓ 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）