Abstract
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.
| Original language | English |
|---|---|
| Article number | 1900018 |
| Journal | Advanced Functional Materials |
| Volume | 29 |
| Issue number | 20 |
| DOIs | |
| Publication status | Published - 2019 May 16 |
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All Science Journal Classification (ASJC) codes
- Electronic, Optical and Magnetic Materials
- Biomaterials
- Chemistry(all)
- Materials Science(all)
- Condensed Matter Physics
- Electrochemistry
Cite this
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Binary Targeting of siRNA to Hematologic Cancer Cells In Vivo Using Layer-by-Layer Nanoparticles. / Choi, Ki Young; Correa, Santiago; Min, Jouha; Li, Jiahe; Roy, Sweta; Laccetti, Kristiana H.; Dreaden, Erik; Kong, Stephanie; Heo, Roun; Roh, Young Hoon; Lawson, Edward C.; Palmer, Peter A.; Hammond, Paula T.
In: Advanced Functional Materials, Vol. 29, No. 20, 1900018, 16.05.2019.Research output: Contribution to journal › Article
TY - JOUR
T1 - Binary Targeting of siRNA to Hematologic Cancer Cells In Vivo Using Layer-by-Layer Nanoparticles
AU - Choi, Ki Young
AU - Correa, Santiago
AU - Min, Jouha
AU - Li, Jiahe
AU - Roy, Sweta
AU - Laccetti, Kristiana H.
AU - Dreaden, Erik
AU - Kong, Stephanie
AU - Heo, Roun
AU - Roh, Young Hoon
AU - Lawson, Edward C.
AU - Palmer, Peter A.
AU - Hammond, Paula T.
PY - 2019/5/16
Y1 - 2019/5/16
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85063501903&partnerID=8YFLogxK
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U2 - 10.1002/adfm.201900018
DO - 10.1002/adfm.201900018
M3 - Article
VL - 29
JO - Advanced Functional Materials
JF - Advanced Functional Materials
SN - 1616-301X
IS - 20
M1 - 1900018
ER -