title: Macrophage-specific RNA interference targeting via "click", mannosylated polymeric micelles.
abstract: Macrophages represent an important therapeutic target, because their activity has been implicated in the progression of debilitating diseases such as cancer and atherosclerosis. In this work, we designed and characterized pH-responsive polymeric micelles that were mannosylated using "click" chemistry to achieve CD206 (mannose receptor)-targeted siRNA delivery. CD206 is primarily expressed on macrophages and dendritic cells and upregulated in tumor-associated macrophages, a potentially useful target for cancer therapy. The mannosylated nanoparticles improved the delivery of siRNA into primary macrophages by 4-fold relative to the delivery of a nontargeted version of the same carrier (p < 0.01). Further, treatment for 24 h with the mannose-targeted siRNA carriers achieved 87 ± 10% knockdown of a model gene in primary macrophages, a cell type that is typically difficult to transfect. Finally, these nanoparticles were also avidly recognized and internalized by human macrophages and facilitated the delivery of 13-fold more siRNA into these cells than into model breast cancer cell lines. We anticipate that these mannose receptor-targeted, endosomolytic siRNA delivery nanoparticles will become an enabling technology for targeting macrophage activity in various diseases, especially those in which CD206 is upregulated in macrophages present within the pathologic site. This work also establishes a generalizable platform that could be applied for "click" functionalization with other targeting ligands to direct siRNA delivery.
authors: Department of Biomedical Engineering, Vanderbilt University , Nashville, Tennessee 37235, USA.
authors: Shann S
authors: SS
authors: Yu
authors: Cheryl M
authors: CM
authors: Lau
authors: Whitney J
authors: WJ
authors: Barham
authors: Halina M
authors: HM
authors: Onishko
authors: Christopher E
authors: CE
authors: Nelson
authors: Hongmei
authors: H
authors: Li
authors: Chelsey A
authors: CA
authors: Smith
authors: Fiona E
authors: FE
authors: Yull
authors: Craig L
authors: CL
authors: Duvall
authors: Todd D
authors: TD
authors: Giorgio
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D057930:Click Chemistry; D003713:Dendritic Cells / Q000378:metabolism; D005434:Flow Cytometry; D006801:Humans; D037181:Lectins, C-Type / Q000235:genetics; D008264:Macrophages / Q000378:metabolism; D000090323:Mannose Receptor; D037241:Mannose-Binding Lectins / Q000235:genetics; D008823:Micelles; D018613:Microscopy, Confocal; D053758:Nanoparticles / Q000008:administration & dosage / Q000737:chemistry; D011108:Polymers / Q000008:administration & dosage* / Q000737:chemistry*; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000008:administration & dosage / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D011956:Receptors, Cell Surface / Q000235:genetics
chemical_list: D037181:Lectins, C-Type; D000090323:Mannose Receptor; D037241:Mannose-Binding Lectins; D008823:Micelles; D011108:Polymers; D034741:RNA, Small Interfering; D011956:Receptors, Cell Surface