Structural Optimization of siRNA Conjugates for Albumin Binding Achieves Effective MCL1-Targeted Cancer Therapy

Area of Science:

• Biotechnology
• Molecular Biology
• Oncology

Background:

• siRNAs hold therapeutic promise for silencing oncogenic drivers but face delivery challenges.
• Targeting traditionally undruggable cancer genes requires effective tumor cell delivery strategies.

Approach:

• siRNAs were modified with C18 lipids for albumin binding and improved pharmacokinetics.
• Systematic variation of lipid structures identified a lead conjugate with specific divalent C18 lipid and linker properties.
• Optimized conjugate design focused on proximal branching for albumin association and minimized self-assembly.

Key Points:

• The lead siRNA-lipid conjugate demonstrated a 12-fold increase in tumor siRNA accumulation in triple-negative breast cancer models.
• Achieved approximately 80% MCL-1 silencing in orthotopic breast tumors.
• Outperformed an MCL-1 small molecule inhibitor in improving survival outcomes in preclinical models.

Conclusions:

• Structure-function insights guide the optimization of siRNA-lipid conjugates for albumin-mediated tumor delivery.
• This approach offers a promising strategy for molecular-targeted cancer therapy against challenging oncogenes.
• Optimized albumin-binding siRNA conjugates represent a significant advancement in cancer treatment delivery.