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

Ella N. Hoogenboezem, Shrusti S. Patel, Justin H. Lo, Ashley B. Cavnar, Lauren M. Babb, Nora Francini, Eva F. Gbur, Prarthana Patil, Juan M. Colazo, Danielle L. Michell, Violeta M. Sanchez, Joshua T. McCune, Jinqi Ma, Carlisle R. DeJulius, Linus H. Lee, Jonah C. Rosch, Ryan M. Allen, Larry D. Stokes, Jordan L. Hill, Kasey C. Vickers, Rebecca S. Cook and Craig L. Duvall ()
Additional contact information
Ella N. Hoogenboezem: Vanderbilt University
Shrusti S. Patel: Vanderbilt University
Justin H. Lo: Vanderbilt University
Ashley B. Cavnar: Vanderbilt University Medical Center
Lauren M. Babb: Vanderbilt University
Nora Francini: Vanderbilt University
Eva F. Gbur: Vanderbilt University
Prarthana Patil: Vanderbilt University
Juan M. Colazo: Vanderbilt University
Danielle L. Michell: Vanderbilt University Medical Center
Violeta M. Sanchez: Vanderbilt University Medical Center
Joshua T. McCune: Vanderbilt University
Jinqi Ma: Vanderbilt University
Carlisle R. DeJulius: Vanderbilt University
Linus H. Lee: Vanderbilt University
Jonah C. Rosch: Vanderbilt University
Ryan M. Allen: Vanderbilt University Medical Center
Larry D. Stokes: Vanderbilt University
Jordan L. Hill: Vanderbilt University
Kasey C. Vickers: Vanderbilt University Medical Center
Rebecca S. Cook: Vanderbilt University
Craig L. Duvall: Vanderbilt University

Nature Communications, 2024, vol. 15, issue 1, 1-20

Abstract: Abstract 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.

Date: 2024
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DOI: 10.1038/s41467-024-45609-0

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