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 receptor-mediated 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.
Bibliographical noteFunding Information:
The authors thank the Swanson Biotechnology Center Core Facilities and the David H. Koch Institute, and particularly thank Drs. D. S. Yun and M. R. Griffin for their technical support. This research was supported by the Janssen Incubator Program through Janssen Research and Development, LLC, National Institutes of Health (NIBIB1F32EB017614), Basic Science Research Program (2015R1A6A3A04059033, 2018R1D1A1A02085552) through the National Research Foundation of Korea (NRF) funded by the Ministry of Education, Republic of Korea, and a Korea Institute of Science and Technology intramural research grant.
© 2019 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
All Science Journal Classification (ASJC) codes
- Materials Science(all)
- Condensed Matter Physics