Biomolecules & Therapeutics

  • 제33권1호
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  • Pages.155-169
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  • 2025
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  • 1976-9148(pISSN)
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  • 2005-4483(eISSN)
한국응용약물학회 (The Korean Society of Applied Pharmacology)
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Design, Screening and Development of Asymmetric siRNAs Targeting the MYC Oncogene in Triple-Negative Breast Cancer

  • Negesse Mekonnen (Research Institute of Pharmaceutical Science, Department of Pharmacy, Seoul National University, College of Pharmacy) ;
  • Myeung-Ryun Seo (Department of Molecular Medicine and Biopharmaceutical Sciences, Seoul National University, Graduate School of Convergence Science and Technology) ;
  • Hobin Yang (College of Pharmacy, Kyungsung University) ;
  • Chaithanya Chelakkot (Research Institute of Pharmaceutical Science, Department of Pharmacy, Seoul National University, College of Pharmacy) ;
  • Jun Young Choi (R&D Center, ABION Inc.) ;
  • Sungyoul Hong (Research Institute of Pharmaceutical Science, Department of Pharmacy, Seoul National University, College of Pharmacy) ;
  • Kyoung Song (College of Pharmacy, Duksung Women's University) ;
  • Young Kee Shin (Research Institute of Pharmaceutical Science, Department of Pharmacy, Seoul National University, College of Pharmacy)
  • 투고 : 2024.05.04
  • 심사 : 2024.06.04
  • 발행 : 2025.01.01
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초록

Triple-negative breast cancer (TNBC) is a subtype of breast cancer that lacks hormone receptor and Her2 (ERBB2) expression, leaving chemotherapy as the only treatment option. The urgent need for targeted therapy for TNBC patients has led to the investigation of small interfering RNAs (siRNAs), which can target genes in a sequence-specific manner, unlike other drugs. However, the clinical translation of siRNAs has been hindered by the lack of an effective delivery system, except in the case of liver diseases. The MYC oncogene is commonly overexpressed in TNBC compared to other breast cancer subtypes. In this study, we used siRNA to target MYC in MDA-MB-231, MDA-MB-157, MDA-MB-436 and Hs-578T cells. We designed various symmetric and asymmetric (asiRNAs), screened them for in vitro efficacy, modified them for enhanced nuclease resistance and reduced off-target effects, and conjugated them with cholesterol (ChoL) and docosanoic acid (DCA) as a delivery system. DCA was conjugated to the 3' end of asiRNA by a cleavable phosphodiester linker for in vivo delivery. Our findings demonstrated that asiRNA-VP and Mod_asiRNA10-6 efficiently downregulated MYC and its downstream targets, including RRM2, RAD51 and PARP1. Moreover, in a tumor xenograft model, asiRNA-VP-DCA effectively knocked down MYC mRNA and protein expression. Remarkably, durable knockdown persisted for at least 46 days postdosing in mouse tumor xenografts, with no visible signs of toxicity, underscoring the safety of DCA-conjugated asiRNAs. In conclusion, this study developed novel asiRNAs, design platforms, validated modification patterns, and in vivo delivery systems specifically targeting MYC in TNBC.

키워드

과제정보

Authors would like to thank Dr. Na Young Kim and Dr. Hong Seok Choi for their cooperation in the order, procurement and synthesis of asymmetric siRNA from abroad. Ms. Kang Young Im for procuring the reagents and materials used in this study. This research was funded by the Basic Science Research Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Education (NRF-2022R1A6A1A03046247) and ABION BIO.

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