Materials Today Bio
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2025
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IF 10.2
Yurong Xiang,Qiang Liu,Kang Liu,Liuxian Chen,Fengjiao Chen,Tao Li,Siqi Li,Qiang Yu,Quan Lv,Zheng Xiang
Multi-drug combination therapy is one of the most effective strategies for the treatment of drug-resistant and advanced tumors. Modern nanodrug delivery systems are crucial for multi-drug combination therapy and gene therapy. However, research on direct injection of RNAi has not yielded significant results. Artificial vectors are emerging as promising delivery systemts for RNA for gene therapy. In this study, a multi-drug therapy system was built based on a biodegradable exosome nano-platform exploiting the protective and low immunogenic properties of exosomes for RNA. This work aimed to accomplish the co-delivery of siRNA and 3-Bromopyruvic acid (3BP) on an exosome nanoplatform, enhancing targeting by coupling cetuximab (CTX) to exosome membranes, resulting in a new nanomedicine Exo@siRNA/3BP-CTX (ERBC) engineered exosomes. The synthesis conditions were optimized to obtain stable, safe, and effective nanomedicines. Successful targeting of tumors with CTX inhibited KRAS oncogene expression and significantly reduced glucose uptake by cancer cells. This enhanced the starvation therapy effect of the energy deprivation agent 3BP, thus promoting excessive autophagy activation in cells and doubling apoptosis. However, ERBC combined with CTX therapy restored cellular chemosensitivity to CTX. These findings indicate that engineered exosomes with dual therapeutic activities is a promising approach for treating refractory KRAS-mutant cancers.
研究领域:
肿瘤学
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基因治疗
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纳米医学
✓ 已验证
DOI
PubMed
高影响因子
PeerJ
·
2020
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IF 2.379
Xiaoyan Li,Yiyan Lu,Xiaojun Ou,Sijing Zeng,Ying Wang,Xiaoxiao Qi,Lijun Zhu,Zhongqiu Liu
Background This study aimed to systematically profile the alterations and sex- and age-related differences in the drug metabolizing enzymes (DMEs) in a KRAS-mutant mouse model of lung cancer (KRAS mice). Methodology In this study, the LC-MS/MS approach and a probe substrate method were used to detect the alterations in 21 isoforms of DMEs, as well as the enzymatic activities of five isoforms, respectively. Western blotting was applied to study the protein expression of four related receptors. Results The proteins contents of CYP2C29 and CYP3A11, were significantly downregulated in the livers of male KRAS mice at 26 weeks (3.7- and 4.4-fold, respectively, p < 0.05). SULT1A1 and SULT1D1 were upregulated by 1.8- to 7.0- fold at 20 ( p = 0.015 and 0.017, respectively) and 26 weeks ( p = 0.055 and 0.031, respectively). There were positive correlations between protein expression and enzyme activity for CYP2E1, UGT1A9, SULT1A1 and SULT1D1 ( r 2 ≥ 0.5, p < 0.001). Western blotting analysis revealed the downregulation of AHR, FXR and PPARα protein expression in male KRAS mice at 26 weeks. For sex-related differences, CYP2E1 was male-predominant and UGT1A2 was female-predominant in the kidney. UGT1A1 and UGT1A5 expression was female-predominant, whereas UGT2B1 exhibited male-predominant expression in liver tissue. For the tissue distribution of DMEs, 21 subtypes of DMEs were all expressed in liver tissue. In the intestine, the expression levels of CYP2C29, CYP27A1, UGT1A2, 1A5, 1A6a, 1A9, 2B1, 2B5 and 2B36 were under the limitation of quantification. The subtypes of CYP7A1, 1B1, 2E1 and UGT1A1, 2A3, 2B34 were detected in kidney tissue. Conclusions This study, for the first time, unveils the variations and sex- and age-related differences in DMEs in C57 BL/6 (WT) mice and KRAS mice.
研究领域:
药理学
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肿瘤学
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分子生物学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
MOLECULAR CARCINOGENESIS
·
2023
·
IF 4.6
Miao Deng,Jiaxin Guo,Zihang Ling,Chi Zhang,Lihong He,Zhaona Fan,Bin Cheng,Juan Xia
Gene mutations play an important role in head and neck squamous cell carcinoma (HNSCC) by not only promoting the occurrence and progression of HNSCC but also affecting sensitivity to treatment and prognosis. KRAS is one of the most frequently mutated oncogenes, which has been reported to have a mutation rate from 1.7% to 12.7% and may lead to poor prognosis in HNSCC, but its role remains unclear. Here, we found that the KRAS mutation can promote HNSCC generation through synergism with 4-Nitroquinoline-1-Oxide(4NQO). Mechanistically, KRAS mutations can significantly upregulate Runx1 to promote oral epithelial cell proliferation and migration and inhibit apoptosis. Runx1 inhibitor Ro 5-3335 can effectively inhibit KRAS -mutated HNSCC progression both in vitro and in vivo. These findings suggest that the KRAS mutation plays an important role in HNSCC and that Runx1 may be a novel therapeutic target for KRAS -mutated HNSCC.
研究领域:
肿瘤学
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分子生物学
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癌症遗传学
✓ 已验证
DOI
PubMed
高影响因子
ACS Applied Nano Materials
·
2024
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IF 5.3
Ailing Su,Yuan Liu,Weihan Sun,Chongyang Liang,Weiqing Xu,Alison Rodger,James Piper,Yuling Wang,Shuping Xu
Specifically identifying one-base mismatched gene sequences is of significance for early diagnosis, prognosis, treatment, and evaluation. However, traditional polymerase chain reaction and next-generation sequencing methods require relatively long, carefully implemented analytical procedures. Here, we report a nanoconjugate that can synchronously discriminate two types of KRAS gene mutation due to the dual-recognition mechanism of the CRISPR/dCas system with the surface-enhanced Raman scattering (SERS) response output. This method applied two sets of CRISPR/dCas9 units to collect all KRAS genes via a magnetic force and the specific mutant sequence labeled through SERS nanotags, forming a dual-clamping architecture. This sensing conjugate was sufficient to quantify the amount of the two different mutations simultaneously with a low cross-reactivity. Consequently, we deem that this sensing assay satisfies the great characteristics of a genetic analytical tool with high specificity, accuracy, and simplicity, highlighting its potential as an alternative for screening multigene events and relevant genetic biomarkers.
研究领域:
分子生物学
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纳米技术
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基因工程
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生物医学工程
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癌症研究
✓ 已验证
产品关联
DOI
高影响因子
ACS Nano
·
2019
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IF 13.903
Chao Kong,Yang Li,Zhengsheng Liu,Junxiao Ye,Zhaohui Wang,Ling Zhang,Weijian Kong,Huiqin Liu,Chun Liu,Huanhuan Pang,Zeping Hu,Jinming Gao,Feng Qian
Survival of KRAS mutant pancreatic cancer is critically dependent on reprogrammed metabolism including elevated macropinocytosis, autophagy, and lysosomal degradation of proteins. Lysosomal acidification is indispensable to protein catabolism, which makes it an exploitable metabolic target for KRAS mutant pancreatic cancer. Herein we investigated ultra-pH-sensitive micelles (UPSM) with pH-specific buffering of organelle pH and rapid drug release as a promising therapy against pancreatic cancer. UPSM undergo micelle–unimer phase transition at their apparent pKa, with dramatically increased buffer capacity in a narrow pH range (<0.3 pH). Cell studies including amino acid profiling showed that UPSM inhibited lysosomal catabolism more efficiently than conventional lysosomotropic agents (e.g., chloroquine) and induced cell apoptosis under starved condition. Moreover, pH-triggered rapid drug release from triptolide prodrug-loaded UPSM (T-UPSM) significantly enhanced cytotoxicity over non-pH-sensitive micelles (T-NPSM). Importantly, T-UPSM demonstrated superior safety and antitumor efficacy over triptolide and T-NPSM in KRAS mutant pancreatic cancer mouse models. Our findings suggest that the ultra-pH-sensitive nanoparticles are a promising therapeutic platform to treat KRAS mutant pancreatic cancer through simultaneous lysosomal pH buffering and rapid drug release.
研究领域:
肿瘤学
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药学
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癌症生物学
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纳米技术
✓ 已验证
产品关联
DOI
PubMed
高影响因子
INTERNATIONAL JOURNAL OF PHARMACEUTICS
·
2024
·
IF 5.3
Gang Wang,Xiao-Na Xu,Zhu Zhi-Min,Kun Wang,Fei Li
This study tried to develop the α-Hederin/Oxaliplatin (OXA) dual-loaded rHDL (α-Hederin-OXA-rHDL) modified liposomes to improve the therapeutic index on colon adenocarcinoma (COAD). The α-Hederin-OXA-rHDL were prepared and evaluated for characterizations, accumulate to tumor tissues, and antitumor activity. A thorough investigation into oxaliplatin resistant and KRAS-mutant related hub keg genes were identified and performed to assess the prognosis role of the genetic signature in COAD. The potential immune signatures and molecular docking for verifing the predicted targets of α-Hederin-OXA-rHDL in tumor-bearing mice. Results suggested that α-Hederin-OXA-rHDL could enhance the sensitivity of oxaliplatin in HCT116/L-OHP cells via the regulation of KEAP1/NRF2 -mediated signaling and HO1 or GPX4 proteins. Furthermore, α-Hederin-OXA-rHDL regulated the predicted targets of PRDM1 interaction with miR-140-5p, efficient activing CD8 T cell to improve therapeutic response in vivo . Collectively, this work provides drug delivery with rHDL dual-loaded α-Hederin and oxaliplatin synergistically targets cancer cells and effectory T cells combating COAD.
研究领域:
药学
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癌症生物学
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分子生物学
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免疫学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
ACS Nano
·
2023
·
IF 17.1
Yukun Huang,Yu Chen,Songlei Zhou,Laozhi Xie,Kaifan Liang,Jianpei Xu,Qian Zhang,Huan Chen,Dayuan Wang,Qingxiang Song,Gan Jiang,Ni Mei,Fenfen Ma,Huiping Lu,Xiaoling Gao,Jun Chen
Metabolic therapy targeting the metabolic addictions driven by gain-of-function mutations in KRAS is promising in fighting cancer through selective killing of malignant cells without hurting healthy cells. However, metabolic compensation and heterogeneity make current metabolic therapies ineffective. Here, we proposed a biomimetic “Nutri-hijacker” with “Trojan horse” design to induce synthetic lethality in KRAS-mutated (mtKRAS) malignant cells by hitchhiking and reprogramming the metabolic addictions. Nutri-hijacker consisted of the biguanide-modified nanoparticulate albumin that impaired glycolysis and a flavonoid that restrained glutaminolysis after the macropinocytosis of Nutri-hijacker by mtKRAS malignant cells. Nutri-hijacker suppressed the proliferation and spread of mtKRAS malignant cells while lowering tumor fibrosis and immunosuppression. Nutri-hijacker significantly extended the lifespan of pancreatic ductal adenocarcinoma (PDAC)-bearing mice when combined with the hydroxychloroquine-based therapies that failed in clinical trials. Collectively, our findings demonstrated that Nutri-hijacker is a strong KRAS mutation-customized inhibitor and the synthetic lethality based on mtKRAS-driven metabolic addictions might be a promising strategy against PDAC.
研究领域:
肿瘤学
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分子生物学
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癌症治疗
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药理学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Advanced Science
·
2025
·
IF 14.1
Hongrui Fan,Hongyi Chen,Haolin Song,Chufeng Li,Yu Wang,Zhenhao Zhao,Qin Guo,Xuwen Li,Mingxuan Liu,Tao Sun,Chen Jiang
KRAS mutations are find in over 90% of pancreatic ductal adenocarcinoma (PDAC) cases, making PDAC exhibit intrinsic resistance to chemotherapy and reshape the immunosuppressive tumor microenvironment (TME), disappointing the clinically preferred chemotherapy-immunotherapy combination. Standing on the cross point of therapeutic resistance, the aberrant adenosine metabolism contributes greatly to chemo- and immunotherapy tolerance. KRAS mutation-induced over-expression of key enzyme CD39 is believed to be involved in shaping the immunosuppressive TME, as it catalyzes the hydrolysis of extracellular ATP into immunosuppressive adenosine. Meanwhile, the loss of equilibrative nucleoside transporters (ENTs) leads to the accumulation of adenosine and the intracellular delivery difficulty of gemcitabine, further vanishing patients’ hope of benefiting from either chemotherapy or immunotherapy. The key challenge is to modulate the aberrant metabolism, also enhance gemcitabine intracellular delivery. Therefore, ROS-responsive positively-charged polymer B-PDEA is prepared and assembled into polyplexes for loading CD39-down-regulating small interfering RNA. Gemcitabine-loaded albumin is coupled with the polyplexes through enzyme-cleavable peptide, forming the intact nanoparticles for the co-delivery of the first-line chemotherapeutic drug and CD39-regulating nucleic acid, showing enhanced gemcitabine intracellular delivery and adenosine metabolism regulating capacity. This approach activated antitumor immunity while achieving chemosensitization by changing the metabolic-immune crosstalk of TME, showcasing great potential for PDAC treatment.
研究领域:
纳米医学
·
肿瘤学
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药剂学
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分子生物学
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免疫治疗
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药物递送
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生物化学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
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