دورية أكاديمية
أعرض في EDS

Structural optimization of siRNA conjugates for albumin binding achieves effective MCL1-directed cancer therapy.

التفاصيل البيبلوغرافية
العنوان: Structural optimization of siRNA conjugates for albumin binding achieves effective MCL1-directed cancer therapy.
المؤلفون: Hoogenboezem EN; Department of Biomedical Engineering, Vanderbilt University, Nashville, TN, USA., Patel SS; Department of Biomedical Engineering, Vanderbilt University, Nashville, TN, USA., Lo JH; Department of Biomedical Engineering, Vanderbilt University, Nashville, TN, USA.; Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, USA., Cavnar AB; Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, USA., Babb LM; Department of Biomedical Engineering, Vanderbilt University, Nashville, TN, USA., Francini N; Department of Biomedical Engineering, Vanderbilt University, Nashville, TN, USA., Gbur EF; Department of Biomedical Engineering, Vanderbilt University, Nashville, TN, USA., Patil P; Department of Biomedical Engineering, Vanderbilt University, Nashville, TN, USA., Colazo JM; Department of Biomedical Engineering, Vanderbilt University, Nashville, TN, USA.; Medical Scientist Training Program, Vanderbilt University School of Medicine, Nashville, TN, USA., Michell DL; Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, USA., Sanchez VM; Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, USA., McCune JT; Department of Biomedical Engineering, Vanderbilt University, Nashville, TN, USA., Ma J; Department of Biomedical Engineering, Vanderbilt University, Nashville, TN, USA., DeJulius CR; Department of Biomedical Engineering, Vanderbilt University, Nashville, TN, USA., Lee LH; Department of Biomedical Engineering, Vanderbilt University, Nashville, TN, USA., Rosch JC; Department of Chemical and Biomolecular Engineering, Vanderbilt University, Nashville, TN, USA., Allen RM; Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, USA., Stokes LD; Department of Biomedical Engineering, Vanderbilt University, Nashville, TN, USA., Hill JL; Department of Biomedical Engineering, Vanderbilt University, Nashville, TN, USA., Vickers KC; Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, USA.; Department of Molecular Physiology and Biophysics, Vanderbilt University, Nashville, TN, USA., Cook RS; Department of Biomedical Engineering, Vanderbilt University, Nashville, TN, USA., Duvall CL; Department of Biomedical Engineering, Vanderbilt University, Nashville, TN, USA. craig.duvall@vanderbilt.edu.
المصدر: Nature communications [Nat Commun] 2024 Feb 21; Vol. 15 (1), pp. 1581. Date of Electronic Publication: 2024 Feb 21.
نوع المنشور: Journal Article
اللغة: English
بيانات الدورية: Publisher: Nature Pub. Group Country of Publication: England NLM ID: 101528555 Publication Model: Electronic Cited Medium: Internet ISSN: 2041-1723 (Electronic) Linking ISSN: 20411723 NLM ISO Abbreviation: Nat Commun Subsets: MEDLINE
أسماء مطبوعة: Original Publication: [London] : Nature Pub. Group
مواضيع طبية MeSH: Triple Negative Breast Neoplasms*/drug therapy , Triple Negative Breast Neoplasms*/genetics , Antineoplastic Agents*, Humans ; RNA, Small Interfering ; Myeloid Cell Leukemia Sequence 1 Protein/genetics ; Cell Line, Tumor ; Gene Silencing ; Lipids/chemistry ; Albumins/genetics
مستخلص: The high potential of siRNAs to silence oncogenic drivers remains largely untapped due to the challenges of tumor cell delivery. Here, divalent lipid-conjugated siRNAs are optimized for in situ binding to albumin to improve pharmacokinetics and tumor delivery. Systematic variation of the siRNA conjugate structure reveals that the location of the linker branching site dictates tendency toward albumin association versus self-assembly, while the lipid hydrophobicity and reversibility of albumin binding also contribute to siRNA intracellular delivery. The lead structure increases tumor siRNA accumulation 12-fold in orthotopic triple negative breast cancer (TNBC) tumors over the parent siRNA. This structure achieves approximately 80% silencing of the anti-apoptotic oncogene MCL1 and yields better survival outcomes in three TNBC models than an MCL-1 small molecule inhibitor. These studies provide new structure-function insights on siRNA-lipid conjugate structures that are intravenously injected, associate in situ with serum albumin, and improve pharmacokinetics and tumor treatment efficacy.
(© 2024. The Author(s).)
التعليقات: Update of: bioRxiv. 2023 Feb 15;:. (PMID: 36824780)
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معلومات مُعتمدة: T32 CA217834 United States CA NCI NIH HHS; K12 CA090625 United States CA NCI NIH HHS; P30 DK058404 United States DK NIDDK NIH HHS; R01 EB019409 United States EB NIBIB NIH HHS; R01 CA260958 United States CA NCI NIH HHS; R01 CA224241 United States CA NCI NIH HHS; R21 AR078636 United States AR NIAMS NIH HHS; P30 CA068485 United States CA NCI NIH HHS; F32 CA268705 United States CA NCI NIH HHS
المشرفين على المادة: 0 (RNA, Small Interfering)
0 (Myeloid Cell Leukemia Sequence 1 Protein)
0 (Antineoplastic Agents)
0 (Lipids)
0 (Albumins)
0 (MCL1 protein, human)
تواريخ الأحداث: Date Created: 20240221 Date Completed: 20240223 Latest Revision: 20240304
رمز التحديث: 20240304
مُعرف محوري في PubMed: PMC10881965
DOI: 10.1038/s41467-024-45609-0
PMID: 38383524
قاعدة البيانات: MEDLINE
الوصف
تدمد:2041-1723
DOI:10.1038/s41467-024-45609-0