Co-delivery of camptothecin and MiR-145 by lipid nanoparticles for MRI-visible targeted therapy of hepatocellular carcinoma.

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  • Additional Information
    • Source:
      Publisher: BioMed Central Country of Publication: England NLM ID: 8308647 Publication Model: Electronic Cited Medium: Internet ISSN: 1756-9966 (Electronic) Linking ISSN: 03929078 NLM ISO Abbreviation: J Exp Clin Cancer Res Subsets: MEDLINE
    • Publication Information:
      Publication: 2009- : London : BioMed Central
      Original Publication: [Roma] : APSIT,
    • Subject Terms:
      Carcinoma, Hepatocellular*/drug therapy ; Carcinoma, Hepatocellular*/pathology ; Carcinoma, Hepatocellular*/genetics ; Carcinoma, Hepatocellular*/metabolism ; MicroRNAs*/genetics ; MicroRNAs*/administration & dosage ; Liver Neoplasms*/drug therapy ; Liver Neoplasms*/pathology ; Liver Neoplasms*/metabolism ; Liver Neoplasms*/genetics ; Nanoparticles*/chemistry ; Camptothecin*/pharmacology ; Camptothecin*/analogs & derivatives ; Camptothecin*/administration & dosage ; Camptothecin*/therapeutic use; Animals ; Mice ; Humans ; Magnetic Resonance Imaging/methods ; Xenograft Model Antitumor Assays ; Cell Line, Tumor ; Apoptosis/drug effects ; Cell Proliferation/drug effects ; Lipids/chemistry ; Liposomes
    • Abstract:
      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) + CCl 4 -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.
      (© 2024. The Author(s).)
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    • Grant Information:
      2021xkjT105 Research Improvement Program of Anhui Medical University; 2023AH040370 Major Project of University Nature Science Research in Anhui Province; 82070629 National Natural Science Foundation of China; 82270660 National Natural Science Foundation of China
    • Contributed Indexing:
      Keywords: Combination therapy; Hepatocellular carcinoma; Lipid nanoparticles; Magnetic resonance imaging; Target delivery
    • Accession Number:
      0 (MicroRNAs)
      XT3Z54Z28A (Camptothecin)
      0 (MIRN145 microRNA, human)
      0 (Lipid Nanoparticles)
      0 (Lipids)
      0 (Liposomes)
    • Publication Date:
      Date Created: 20240830 Date Completed: 20240831 Latest Revision: 20240904
    • Publication Date:
      20240904
    • Accession Number:
      PMC11363558
    • Accession Number:
      10.1186/s13046-024-03167-9
    • Accession Number:
      39215325