(110g) Multi-Targeted siRNA Delivery Liposomes Inhibit Metastatic Breast Cancer Cell Migration

Metastatic breast cancer (MBC) is the second leading cause of cancer-related fatalities in
women, accounting for more than 40,000 deaths each year. MBC has a five-year relative
survival rate of 23% compared with 99% for patients with non-metastatic breast cancer.
These statistics suggest an urgent and significant need for developing novel and effective
therapeutics for the treatment of MBC. In this study, we engineered a liposomal drug
delivery vehicle designed to inhibit both the C-X-C chemokine receptor type 4 (CXCR4)
and Lipocalin-2 (Lcn2) mediated migratory pathways. CXCR4 is a G protein-coupled
receptor that is responsible for cell migration along chemokine gradients. Lcn2 is a
secreted protein that mediates breast cancer cell EMT. pH-responsive liposomes were
designed to protect and trigger the release of Lcn2 siRNA. Liposomes were modified
with anti-CXCR4 to target MBC cells and block migration along the CXCR4-CXCL12
axis. This synergistic approach - coupling the CXCR4 axis blockade with Lcn2 silencing
- significantly reduced migration of triple-negative human breast cancer cells MDA-MB-
436 (-92%) and MDA-MB-231 (-88%). These results suggest that drug delivery vehicles
engineered to target multiple migratory pathways may effectively slow progression of
MBC.