MOLECULAR PHARMACEUTICS
·
2023
·
IF 4.9
Rui Chang,Rongrong Fu,Yujiao Huang,Jibing Zhang,Changshun Feng,Rui Wang,Hui Yan,Guangyong Li,Xiaohong Chu,Fengjiao Yuan,Dianlong Jia,Jun Li
Although tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) constitutes a promising antitumor drug, tumor resistance to TRAIL has become a major obstacle in its clinical application. Mitomycin C (MMC) is an effective TRAIL-resistant tumor sensitizer, which indicates a potential utility of combination therapy. However, the efficacy of this combination therapy is limited owing to its short half-life and the cumulative toxicity of MMC. To address these issues, we successfully developed a multifunctional liposome (MTLPs) with human TRAIL protein on the surface and MMC encapsulated in the internal aqueous phase to codeliver TRAIL and MMC. MTLPs are uniform spherical particles that exhibit efficient cellular uptake by HT-29 TRAIL-resistant tumor cells, thereby inducing a stronger killing effect compared with control groups. In vivo assays revealed that MTLPs efficiently accumulated in tumors and safely achieved 97.8% tumor suppression via the synergistic effect of TRAIL and MMC in an HT-29 tumor xenograft model while ensuring biosafety. These results suggest that the liposomal codelivery of TRAIL and MMC provides a novel approach to overcome TRAIL-resistant tumors.
研究领域:
药理学
·
肿瘤学
·
药物递送系统
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生物技术
✓ 已验证
产品关联
DOI
PubMed
高影响因子
PLANTA MEDICA
·
2022
·Vol. 88
·期 14
·1299-1310
·
IF 3.007
Xiaogang Peng,Qianxi Ouyang,Jiao Pei,Jinling Chang,Chunlun Qin,Hanli Ruan
Seven undescribed cytochalasins, multirostratins K – Q (2–8), together with one known analogue, cytochalasin Z3 (1), were isolated from the culture of Phoma multirostrata XJ-2-1, an endophytic fungus obtained from the root of Parasenecio albus. Their structures with absolute configurations were determined by 1D and 2D NMR, high-resolution electrospray ionization mass spectrometry (HRESIMS), electronic circular dichroism (ECD), single-crystal X-ray crystallography, and chemical methods. The structure of ascochalasin was revised from Δ13 to Δ21 by detailed analysis of the NMR data and by comparison with the data for 7. In a TRAIL (tumor necrosis factor related apoptosis inducing ligand)-resistance-overcoming experiment, co-treatment of 2 or 6 with TRAIL reduced the cell viability of A549 cells by 30.3% and 27.5% at 10 µM, respectively.
研究领域:
药理学
·
有机化学
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肿瘤学
✓ 已验证
DOI
PubMed
高影响因子
JOURNAL OF CONTROLLED RELEASE
·
2019
·
IF 7.901
Anwei Zhou,Junjie Du,Mengying Jiao,Daping Xie,Qianqian Wang,Lingjing Xue,Caoyun Ju,Zichun Hua,Can Zhang
The combined therapy of tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) and heat shock protein 70-targeting siRNA (siHSP70) has shown an improved anti-tumor effect on TRAIL-resistant tumor. However, vehicles to co-deliver these two biopharmaceuticals are challenging because of the distinct location of their targets on the cell surface and in the cytosol. Here we developed a hierarchically modular assembly formulation (TH-s-RSC) via the copper-free click reaction to co-encapsulate the positively-charged TRAIL and negatively-charged siHSP70 and release them in the extracellular space and cytoplasm. We demonstrate that TH-s-RSC can protect the packaged biopharmaceuticals through its hyaluronic acid shell in vivo , and sequentially release TRAIL in response to extracellular molecular including hyaluronidase (HAase) and matrix metalloproteinase 2 (MMP2), followed by the release of siHSP70 triggered by the reductive conditions in the cytoplasm. We showed that the complementary activity of TRAIL and siHSP70 exhibited superior synergistic anticancer efficacy in both A549 lung cancer xenograft models and 4T1 lung metastatic breast cancer models, compared to either treatment alone. Our strategy provides a promising platform for safe and effective co-delivery and dual-site targeting of biopharmaceuticals in cancer treatment that may be applicable in the future.
研究领域:
癌症治疗
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生物制药
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纳米技术
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药学
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分子生物学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
MOLECULAR PHARMACEUTICS
·
2024
·
IF 4.5
Xiaomeng Lu,Xinyu Zhan,Guozi Xia,Feifei Wang,Mingjia Lv,Renwei Liu,Yuxue Liu,Chen Zi,Guangyong Li,Rui Wang,Jun Li,Fengjiao Yuan,Dianlong Jia
Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is an attractive candidate for anticancer therapeutics due to its efficient pro-apoptotic activity against tumor cells and its well-tolerated safety profile. However, the in vivo antitumor efficacy of TRAIL is often limited by its poor tumor targeting capacity. Nowadays, the B7 homologue 3 (B7–H3) immune checkpoint has emerged as a promising target for tumor immunotherapy and drug delivery. Here, we report the achievement of tumor-targeted delivery of TRAIL by genetically fusing it with a B7H3-antagonistic affibody. The affibody–TRAIL fusion protein, named ACT, was easily expressed in Escherichia coli with a high yield and could form the active trimeric state. In vitro ACT showed significantly increased cellular binding to multiple B7H3-positive tumor cells and improved cytotoxicity by 2–3 times compared to the parent TRAIL. In vivo ACT demonstrated a 2.4-fold higher tumor uptake than TRAIL in mice bearing B7H3-positive A431 tumor grafts. More importantly, ACT exhibited significantly improved antitumor efficacy against tumors in vivo. In addition, ACT treatment did not cause body weight loss or histopathological changes in the major organs of mice, indicating its good safety profile. Overall, our findings demonstrate that targeting B7H3 to enhance TRAIL delivery is a viable approach to improve its therapeutic efficacy, and ACT may be a potential agent for targeted therapy of B7H3-positive tumors.
研究领域:
肿瘤学
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免疫治疗
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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 DRUG DELIVERY SCIENCE AND TECHNOLOGY
·
2025
·
IF 4.9
Feifei Wang,Dianlong Jia,Qingcui Song,Xiaomeng Lu,Guozi Xia,Jun Li,Xiaodong Jia,Mingliang Gu,Fengjiao Yuan,Zhengping Wang,Zhangyong Xia
Resistance against tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)-induced cell death of cancer cells is a major obstacle in clinical application of TRAIL. Bortezomib (BTZ) is the first-generation proteasome inhibitor to enhance TRAIL-mediated apoptosis and overcome tumor cell resistance to TRAIL, therefore we developed a novel nanodrug called LSBTZ-TRAIL to co-deliver TRAIL and BTZ via liposomes. TRAIL was coupled to the surface of the liposome by DSPE-PEG 2000 -NHS, while BTZ was encapsulated in the internal aqueous phase. LSBTZ-TRAIL was characterized with a particle size of 147.00 ± 1.300 nm, polydispersity index (PDI) of 0.056 ± 0.005 and zeta potential of -8.17 ± 0.600 mV. LSBTZ-TRAIL did not change the secondary structure of TRAIL, and LSBTZ-TRAIL was stable in 50% fetal bovine serum and tumor microenvironment. In vitro, the cell killing capacity of LSBTZ-TRAIL was 1.16-6.22 times that of TRAIL + BTZ. Mechanistically, LSBTZ-TRAIL induced apoptosis of tumor cells by up-regulating the death receptor (DR4/5) and activating the caspase signaling pathway. In vivo and in vitro uptake experiments, LS-TRAIL accumulated more in tumor cells or tissues than LS. In vivo , the antitumor effect of LSBTZ-TRAIL was 2.62 times that of TRAIL + BTZ, and prolonged the survival and blood circulation time of mice. In addition, safety evaluation showed that LSBTZ-TRAIL had no acute toxic effects in vivo . These results suggested that the liposomal co-delivery system of TRAIL and BTZ significantly enhance their antitumor effects and provide a new approach to overcome TRAIL-resistance.
研究领域:
肿瘤学
·
药学
·
分子生物学
✓ 已验证
产品关联
DOI
高影响因子
PHARMACEUTICAL DEVELOPMENT AND TECHNOLOGY
·
2024
·
IF 2.6
Rongrong Fu,Rui Chang,Andong Peng,Changshun Feng,Weifan Zhu,Yi Chen,Xue Tian,Rui Wang,Hui Yan,Dianlong Jia,Jun Li
To solve the problem of resistance of tumor cells to TRAIL and the inevitable side effects of imatinib during treatment, we successfully prepared a kind of multifunctional liposome that encapsulated imatinib in its internal water phase and inserted TRAIL on its membrane in this study, which named ITLPs. The liposomes appeared uniform spherical and the particle size was approximately 150 nm. ITLPs showed high accumulation in TRAIL-resistance cells and HT-29 tumor-bearing mice model. In vitro cytotoxicity assay results showed that the killing activity of HT-29 cells treated with ITLPs increased by 50% and confirmed that this killing activity was mediated by the apoptosis pathway. Through mechanism studies, it was found that ITLPs arrested up to 32.3% of cells in phase M to exert anti-tumor effects. In vivo anti-tumor study showed that ITLPs achieved 61.8% tumor suppression and little toxicity in the HT-29 tumor-bearing mice model. Overall results demonstrated that codelivery of imatinib and TRAIL via liposomes may be a prospective method in the treatment of the TRAIL-resistance tumor.
研究领域:
肿瘤学
·
药学
·
生物技术
✓ 已验证
产品关联
DOI
PubMed
高影响因子
BIOORGANIC CHEMISTRY
·
2020
·
IF 4.831
Xiaogang Peng,Yangzhou He,Ying Gao,Fangfang Duan,Juan Chen,Hanli Ruan
Nine new ( 1 – 9 ) and four known ( 10 – 13 ) [13]cytochalasins, along with three known 24-oxa[14]cytochalasins ( 14 – 16 ), were isolated from the culture of Phoma multirostrata XJ-2-1, an endophytic fungus obtained from the fibrous root of Parasenecio albus . Their structures were elucidated by interpretation of the nuclear magnetic resonance (NMR) and high-resolution electrospray ionization mass spectroscopy (HRESIMS). The absolute configurations were assigned by single-crystal X-ray crystallography, modified Mosher′s method, and by analysis of their experimental electronic circular dichroism (ECD) spectra. Compound 6 could induce cell cycle arrest at G2-phase in CT26 and A549 cells, and displayed moderate cytotoxicity against CT26 and A549 cell lines with IC 50 values of 6.03 and 5.04 μM, respectively. Co-treatment of 7 – 9 , 13 and 16 with tumor necrosis factor related apoptosis inducing ligand (TRAIL) could significantly decrease the cell viability of A549, which revealed that cytochalasins could possibly be a new group of TRAIL sensitizers in lung cancer therapy.
研究领域:
药理学
·
生物化学
·
肿瘤学
✓ 已验证
DOI
PubMed
高影响因子
BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR BASIS OF DISEASE
·
2019
·
IF 4.328
Qian Chen,Dehong Yan,Qingmei Zhang,Guizhong Zhang,Meng Xia,Junxin Li,Wugen Zhan,Enyun Shen,Zhihuan Li,Lilong Lin,Youhai H. Chen,Xiaochun Wan
Acetaminophen (APAP) is one of the most commonly used drugs worldwide, and APAP-induced liver injury is the most frequent cause of acute liver failure in developed countries. However, the mechanisms of APAP-induced hepatotoxicity are not well understood, and treatment options for the disorder are very limited. Here, we show that TRAIL (tumor necrosis factor-related apoptosis-inducing ligand) is a major mediator of APAP-induced liver injury in mice, and its blockade markedly ameliorates the liver failure. In APAP-treated mice, TRAIL was expressed in the liver, spleen, and peripheral blood primarily by CD11b + Gr1 + neutrophils. The concentration of soluble TRAIL in the blood, and the frequencies of TRAIL + leukocytes in the spleen and liver positively correlated with the severity of liver injury. APAP sensitized hepatocytes to TRAIL-induced apoptosis by upregulating the expression of the TRAIL receptor DR5 (death receptor 5), presumably through its transcription factor CHOP (C/EBP homologous protein). Importantly, blocking TRAIL with a soluble DR5-Fc fusion protein (sDR5-Fc) significantly attenuated APAP-induced liver injury, the hepatic infiltration of leukocytes, the levels of inflammatory cytokines, and the mortality of mice. When administered alongside N -acetylcysteine, sDR5-Fc further protected against APAP-induced acute liver injury. Thus, the TRAIL-DR5 signaling pathway plays a key role in APAP-induced liver inflammation and failure, and its blockade represents an effective new strategy to treat the liver disease.
研究领域:
药理学
·
肝病学
·
免疫学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
CHEMICO-BIOLOGICAL INTERACTIONS
·
2022
·
IF 5.168
Yudong Yin,Li Sun,Lixin Sheng,Liqiong Zhang,Jingjing Liu,Xiaoan Wen,Weibin Mo,Quande Wang,Keguang Cheng
In order to discover more effective and less toxic drugs in the field of anti-tumor, the backbone structure of 17 β -estradiol was modified, and 11 target compounds were synthesized. Compounds 5 and 10 , which exhibited better anti-tumor activity and higher selectivity (more than 10-fold), were chosen for further biological investigation. Flow cytometry results indicated that 5 and 10 could arrest MCF-7 cells in the G2 phase and induce apoptosis . Immunohistochemical analysis revealed that 5 and 10 could bind to the estradiol receptor alpha in MCF-7 cells. Western blotting and real-time PCR assays were performed to detect the effects of compounds on apoptosis-related targets at the protein and gene levels. These results showed that both 5 and 10 could dosed-dependently increase the expression of Apaf-1, Bax, caspase-3,8,9 and reduce the expression levels of the anti-apoptotic factors Bcl-2 and Bcl-xL. Besides, the Human apoptosis array assay demonstrated the expression level of death receptor Trail R2/DR5 was upregulated obviously while the expression of TNF R1, IAPs and Hsp27/60/70 were downregulated. On the whole, 5 induced MCF-7 cell death through the endogenous pathway in mitochondria and the exogenous pathway with death receptor Trail R2/DR5.
研究领域:
肿瘤学
·
药理学
·
细胞生物学
·
分子生物学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
JOURNAL OF DRUG TARGETING
·
2018
·
IF 3.408
Xuefei Zhou,Zimo Liu,Huifang Wang,Xin Liu,Zhuxian Zhou,Jianbin Tang,Xiangrui Liu,Min Zheng,Youqing Shen
Non-viral gene delivery is an attractive approach for the treatment of many diseases including cancer, benefiting from its safety and large-scale production concerns. However, the relatively low transfection efficacy compared with viral vectors restricts the clinical applications of non-viral gene vectors. Reactive oxygen species (ROS) triggered charge reversal polymers (named B-PDEAEA) presented improved transfection efficacy, because of fast release of plasmid DNA responding to enhanced oxidative stress in cancer cells. But inadequate dissociation can still occur owing to the insufficient intracellular ROS generation. Here, we report SAHA (vorinostat), which is a clinical histone deacetylase inhibitor and anticancer drug, induces the ROS accumulation in cancer cells, and facilitates the charge reversal process of B-PDEAEA and the cellular dissociation of the delivered gene from the vectors. As a result, SAHA remarkably increases the gene transfection efficacy in an ROS-dependent manner. Importantly, SAHA synergizes with B-PDEAEA mediated therapeutic gene TNF-related apoptosis-inducing ligand (TRAIL) delivery in inducing apoptosis of cancer cells. These findings support the first concept of improving the gene delivery efficacy of stimuli-responsive vectors through upregulating the cellular ROS via an FDA approved anticancer agent. Additionally, combination of SAHA and TRAIL gene therapy could be a potential strategy for cancer treatment.
研究领域:
癌症研究
·
基因治疗
·
药理学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Theranostics
·
2019
·
IF 8.063
Kerong Chen,Xiaoqing Cao,Min Li,Yujie Su,Huipeng Li,Mengying Xie,Ziqi Zhang,Hongbin Gao,Xiangting Xu,Yi Han,Jianping Zhou,Wei Wang
Genetically engineered mesenchymal stem cells (MSCs), as non-viral gene delivery platforms, are rapidly evolving in tumor therapy due to their low immunogenicity and natural tumor-homing capacity. Methods: In this paper, we selected reconstituted high-density lipoprotein (rHDL), a lipoprotein-bioinspired nanovector with specific binding ability to scavenger receptor B type I (SR-BI) expressed on MSCs, as a transfection agent to genetically modify MSCs. pDNA encoding tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) was used as a functional gene to be transfected into the nucleus of MSCs for TRAIL expression. Lauric acid-coupled polyethyleneimine (PEI-LA) as an amphiphilic cationic polymer was synthesized to electrostatically bind to pDNA, and then incorporated into rHDL to form rHDL/PEI-LA/pDNA nanoparticles. Results: The nanoparticles exhibited homogenous particle size and excellent serum stability in vitro . Meanwhile, this SR-BI-targeted rHDL performed efficient intracellular gene delivery, specific lysosome-independent mechanism of cellular uptake and high transfection of pDNA towards MSCs. Moreover, high TRAIL expression in MSCs was detected after rHDL-mediated transfection. In vitro and in vivo results indicated that genetically engineered MSCs could accurately target to B16F10 cells, thereby producing significant apoptosis-inducing effect on aggressive melanoma. Conclusion: TRAIL-expressing MSCs engineered by rHDL nanovector was an efficient and hypotoxic method for stem cells-based pulmonary melanoma metastasis-targeting therapy.
研究领域:
癌症生物学
·
基因治疗
·
纳米技术
·
干细胞研究
✓ 已验证
DOI
PubMed
高影响因子
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
·
2020
·Vol. 21
·期 9
·3385
·
IF 4.556
Xin Meng,Jinrui Zhang,Hao Wu,Dahai Yu,Xuexun Fang
Mucin2 (Muc2) is the main component of the intestinal mucosal layer and is highly expressed in mucous colorectal cancer. Previous studies conducted by our lab found that the recombinant protein Amuc_1434 (expressed inEscherichia coliprokaryote cell system, hereinafter termed Amuc_1434*), derived fromAkkermansia muciniphila, can degrade Muc2. Thus, the main objective of this study was to explore the effects of Amuc_1434* on LS174T in colorectal cancer cells expressing Muc2. Results from this study demonstrated that Amuc_1434* inhibited the proliferation of LS174T cells, which was related to its ability to degrade Muc2. Amuc_1434* also blocked the G0/G1 phase of the cell cycle of LS174T cells and upregulated the expression of tumor protein 53 (p53), which is a cell cycle-related protein. In addition, Amuc_1434* promoted apoptosis of LS174T cells and increased mitochondrial ROS levels in LS174T cells. The mitochondrial membrane potential of LS174T cells was also downregulated by Amuc_1434*. Amuc_1434* can activate the death receptor pathway and mitochondrial pathway of apoptosis by upregulating tumor-necrosis-factor-related apoptosis-inducing ligand (TRAIL). In conclusion, our study was the first to demonstrate that the protein Amuc_1434* derived fromAkkermansia muciniphilasuppresses LS174T cell viability via TRAIL-mediated apoptosis pathway.Keywords:Amuc_1434*;colorectal cancer cells;proliferation;apoptosis;TRAIL
研究领域:
癌症生物学
·
分子生物学
·
细胞生物学
✓ 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）