(681b) siRNA-Loaded Lipidoid Nanoparticles for the Treatment of Mantle Cell Lymphoma

Mantle cell lymphoma (MCL), an incurable form of non-Hodgkin lymphoma, is marked by overexpression of proteins that allow cells to proliferate and avoid cell death. Proteins that are overexpressed in MCL include members of D-type cyclins and the Bcl-2 family, proteins that regulate cell cycle progression and apoptosis, respectively. Vehicles that deliver short interfering ribonucleic acid (siRNA) to the cytoplasm of cells leading to gene-specific silencing have shown promise in treating a variety of diseases and conditions. Nanoparticles formed using lipid-like materials called lipidoids have been shown to potently deliver siRNA to the liver and immune cells. Here, we use siRNA-loaded lipidoid nanoparticles to target several Cyclin D and anti-apoptotic Bcl-2 proteins to treat MCL. Sustained silencing of Mcl-1 in JeKo-1 human MCL cells was observed through 7 days with a large increase in the number of cells going through apoptosis beginning at day 3. LNPs delivering siRNA targeting several anti-apoptotic members of the Bcl-2 family led to ~30% of cells undergoing apoptosis after 3 days of treatment at doses as low as 10 nM siRNA. When siRNAs targeting multiple Bcl-2 family members were delivered simultaneously, a further increase in the fraction of cell undergoing apoptosis at 3 days was observed. Simultaneous targeting of D-type cyclins and Bcl-2 family members also led to a larger fraction of cells undergoing apoptosis than siRNAs targeting single Bcl-2 family members or D-type cyclins. The results in this study indicate that cocktails of siRNAs targeting multiple genes in multiple pathways involved with regulating programmed cell death and the cell cycle may lead to enhanced cell death of MCL cells compared to targeting only one pathway.