Jing Rong, Tongtong Liu, Xiujuan Yin, Min Shao, Kun Zhu, Bin Li, Shiqi Wang, Yujie Zhu, Saisai Zhang, Likang Yin, Qi Liu, Xiao Wang, Lei Zhang
{"title":"通过脂质纳米颗粒联合递送喜树碱和 MiR-145,用于肝细胞癌的核磁共振可视靶向治疗。","authors":"Jing Rong, Tongtong Liu, Xiujuan Yin, Min Shao, Kun Zhu, Bin Li, Shiqi Wang, Yujie Zhu, Saisai Zhang, Likang Yin, Qi Liu, Xiao Wang, Lei Zhang","doi":"10.1186/s13046-024-03167-9","DOIUrl":null,"url":null,"abstract":"<p><strong>Background: </strong>Camptothecin (CPT) is one of the frequently used small chemotherapy drugs for treating hepatocellular carcinoma (HCC), but its clinical application is limited due to severe toxicities and acquired resistance. Combined chemo-gene therapy has been reported to be an effective strategy for counteracting drug resistance while sensitizing cancer cells to cytotoxic agents. Thus, we hypothesized that combining CPT with miR-145 could synergistically suppress tumor proliferation and enhance anti-tumor activity.</p><p><strong>Methods: </strong>Lactobionic acid (LA) modified lipid nanoparticles (LNPs) were developed to co-deliver CPT and miR-145 into asialoglycoprotein receptors-expressing HCC in vitro and in vivo. We evaluated the synergetic antitumor effect of miR-145 and CPT using CCK8, Western blotting, apoptosis and wound scratch assay in vitro, and the mechanisms underlying the synergetic antitumor effects were further investigated. Tumor inhibitory efficacy, safety evaluation and MRI-visible ability were assessed using diethylnitrosamine (DEN) + CCl<sub>4</sub>-induced HCC mouse model.</p><p><strong>Results: </strong>The LA modification improved the targeting delivery of cargos to HCC cells and tissues. The LA-CMGL-mediated co-delivery of miR-145 and CPT is more effective on tumor inhibitory than LA-CPT-L or LA-miR-145-L treatment alone, both in vitro and in vivo, with almost no side effects during the treatment period. Mechanistically, miR-145 likely induces apoptosis by targeting SUMO-specific peptidase 1 (SENP1)-mediated hexokinase (HK2) SUMOylation and glycolysis pathways and, in turn, sensitizing the cancer cells to CPT. In vitro and in vivo tests confirmed that the loaded Gd-DOTA served as an effective T1-weighted contrast agent for noninvasive tumor detection as well as real-time monitoring of drug delivery and biodistribution.</p><p><strong>Conclusions: </strong>The LA-CMGL-mediated co-delivery of miR-145 and CPT displays a synergistic therapy against HCC. The novel MRI-visible, actively targeted chemo-gene co-delivery system for HCC therapy provides a scientific basis and a useful idea for the development of HCC treatment strategies in the future.</p>","PeriodicalId":50199,"journal":{"name":"Journal of Experimental & Clinical Cancer Research","volume":null,"pages":null},"PeriodicalIF":11.4000,"publicationDate":"2024-08-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11363558/pdf/","citationCount":"0","resultStr":"{\"title\":\"Co-delivery of camptothecin and MiR-145 by lipid nanoparticles for MRI-visible targeted therapy of hepatocellular carcinoma.\",\"authors\":\"Jing Rong, Tongtong Liu, Xiujuan Yin, Min Shao, Kun Zhu, Bin Li, Shiqi Wang, Yujie Zhu, Saisai Zhang, Likang Yin, Qi Liu, Xiao Wang, Lei Zhang\",\"doi\":\"10.1186/s13046-024-03167-9\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p><strong>Background: </strong>Camptothecin (CPT) is one of the frequently used small chemotherapy drugs for treating hepatocellular carcinoma (HCC), but its clinical application is limited due to severe toxicities and acquired resistance. Combined chemo-gene therapy has been reported to be an effective strategy for counteracting drug resistance while sensitizing cancer cells to cytotoxic agents. Thus, we hypothesized that combining CPT with miR-145 could synergistically suppress tumor proliferation and enhance anti-tumor activity.</p><p><strong>Methods: </strong>Lactobionic acid (LA) modified lipid nanoparticles (LNPs) were developed to co-deliver CPT and miR-145 into asialoglycoprotein receptors-expressing HCC in vitro and in vivo. We evaluated the synergetic antitumor effect of miR-145 and CPT using CCK8, Western blotting, apoptosis and wound scratch assay in vitro, and the mechanisms underlying the synergetic antitumor effects were further investigated. Tumor inhibitory efficacy, safety evaluation and MRI-visible ability were assessed using diethylnitrosamine (DEN) + CCl<sub>4</sub>-induced HCC mouse model.</p><p><strong>Results: </strong>The LA modification improved the targeting delivery of cargos to HCC cells and tissues. The LA-CMGL-mediated co-delivery of miR-145 and CPT is more effective on tumor inhibitory than LA-CPT-L or LA-miR-145-L treatment alone, both in vitro and in vivo, with almost no side effects during the treatment period. Mechanistically, miR-145 likely induces apoptosis by targeting SUMO-specific peptidase 1 (SENP1)-mediated hexokinase (HK2) SUMOylation and glycolysis pathways and, in turn, sensitizing the cancer cells to CPT. In vitro and in vivo tests confirmed that the loaded Gd-DOTA served as an effective T1-weighted contrast agent for noninvasive tumor detection as well as real-time monitoring of drug delivery and biodistribution.</p><p><strong>Conclusions: </strong>The LA-CMGL-mediated co-delivery of miR-145 and CPT displays a synergistic therapy against HCC. The novel MRI-visible, actively targeted chemo-gene co-delivery system for HCC therapy provides a scientific basis and a useful idea for the development of HCC treatment strategies in the future.</p>\",\"PeriodicalId\":50199,\"journal\":{\"name\":\"Journal of Experimental & Clinical Cancer Research\",\"volume\":null,\"pages\":null},\"PeriodicalIF\":11.4000,\"publicationDate\":\"2024-08-30\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11363558/pdf/\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Journal of Experimental & Clinical Cancer Research\",\"FirstCategoryId\":\"3\",\"ListUrlMain\":\"https://doi.org/10.1186/s13046-024-03167-9\",\"RegionNum\":1,\"RegionCategory\":\"医学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q1\",\"JCRName\":\"ONCOLOGY\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Journal of Experimental & Clinical Cancer Research","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1186/s13046-024-03167-9","RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"ONCOLOGY","Score":null,"Total":0}
Co-delivery of camptothecin and MiR-145 by lipid nanoparticles for MRI-visible targeted therapy of hepatocellular carcinoma.
Background: Camptothecin (CPT) is one of the frequently used small chemotherapy drugs for treating hepatocellular carcinoma (HCC), but its clinical application is limited due to severe toxicities and acquired resistance. Combined chemo-gene therapy has been reported to be an effective strategy for counteracting drug resistance while sensitizing cancer cells to cytotoxic agents. Thus, we hypothesized that combining CPT with miR-145 could synergistically suppress tumor proliferation and enhance anti-tumor activity.
Methods: Lactobionic acid (LA) modified lipid nanoparticles (LNPs) were developed to co-deliver CPT and miR-145 into asialoglycoprotein receptors-expressing HCC in vitro and in vivo. We evaluated the synergetic antitumor effect of miR-145 and CPT using CCK8, Western blotting, apoptosis and wound scratch assay in vitro, and the mechanisms underlying the synergetic antitumor effects were further investigated. Tumor inhibitory efficacy, safety evaluation and MRI-visible ability were assessed using diethylnitrosamine (DEN) + CCl4-induced HCC mouse model.
Results: The LA modification improved the targeting delivery of cargos to HCC cells and tissues. The LA-CMGL-mediated co-delivery of miR-145 and CPT is more effective on tumor inhibitory than LA-CPT-L or LA-miR-145-L treatment alone, both in vitro and in vivo, with almost no side effects during the treatment period. Mechanistically, miR-145 likely induces apoptosis by targeting SUMO-specific peptidase 1 (SENP1)-mediated hexokinase (HK2) SUMOylation and glycolysis pathways and, in turn, sensitizing the cancer cells to CPT. In vitro and in vivo tests confirmed that the loaded Gd-DOTA served as an effective T1-weighted contrast agent for noninvasive tumor detection as well as real-time monitoring of drug delivery and biodistribution.
Conclusions: The LA-CMGL-mediated co-delivery of miR-145 and CPT displays a synergistic therapy against HCC. The novel MRI-visible, actively targeted chemo-gene co-delivery system for HCC therapy provides a scientific basis and a useful idea for the development of HCC treatment strategies in the future.
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