Binary Targeting of siRNA to Hematologic Cancer Cells In Vivo Using Layer-­by-­Layer Nanoparticles

Binary Targeting of siRNA to Hematologic Cancer Cells In Vivo Using Layer-­by-­Layer Nanoparticles
최기영Santiago Correa민주하Jiahe LiSweta RoyKristiana H. LaccettiErik DreadenStephanie Kong허로운노영훈Edward C. LawsonPeter A. PalmerPaula T. Hammond
Issue Date
Advanced functional materials
VOL 29, NO 20-1900018-13
Using siRNA therapeutics to treat hematologic malignancies has been unsuccessful because blood cancer cells exhibit remarkable resistance to standard transfection methods. Herein, the successful delivery of siRNA therapeutics with a dual-targeted, layer-by-layer nanoparticle (LbL-NP) is reported. The LbL-NP protects siRNA from nucleases in the bloodstream by embedding it within polyelectrolyte layers that coat a polymeric core. The outermost layer consists of hyaluronic acid (a CD44-ligand) covalently conjugated to CD20 antibodies. The CD20/CD44 dual-targeting outer layer provides precise binding to blood cancer cells, followed by receptormediated endocytosis of the LbL-NP. This siRNA delivery platform is used to silence B-cell lymphoma 2 (BCL-2), a pro-survival protein, in vitro and in vivo. The dual-targeting approach significantly enhances internalization of BCL-2 siRNA in lymphoma and leukemia cells, which leads to significant downregulation of BCL-2 expression. Systemic administration of the dual-targeted, siRNA-loaded nanoparticle induces apoptosis and hampers proliferation of blood cancer cells, both in cell culture and in orthotopic non-Hodgkin’s lymphoma animal models. These results provide the basis for approaches to targeting blood-borne cancers and other diseases and suggest that LbL nanoassemblies are a promising approach for delivering therapeutic siRNA to hematopoetic cell types that are known to evade transfection by other means.
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