Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 104, Issue 10, Pages 4095-4100Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.0608491104
Keywords
affinity up-regulation; antiinflammation; cell adhesion molecule; drug delivery; AL-57 and TS1/22
Categories
Funding
- NIAID NIH HHS [AI 63421, AI 58695, R01 AI045587, R21 AI058695, R56 AI045587, AI 45587, R01 AI063421] Funding Source: Medline
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Silencing gene expression by RNAi is a powerful method for exploring gene function and validating drug targets and potentially for therapy. Lymphocytes and other primary blood cells are resistant to lipid-based transfection in vitro and are difficult to target in vivo. We show here that antibody-protamine fusion proteins targeting the human integrin lymphocyte function-associated antigen-1 (LFA-1) efficiently deliver siRNAs and specifically induce silencing in primary lymphocytes, monocytes, and dendritic cells. Moreover, a fusion protein constructed from an antibody that preferentially recognizes activation-dependent conformational changes in LFA-1 selectively targets activated leukocytes and can be used to suppress gene expression and cell proliferation only in activated lymphocytes. The siRNA-fusion protein complexes do not cause lymphocyte activation or induce IFN responses. K562 cells expressing latent WT or constitutively activated LFA-1 engrafted in the lungs of SCID mice are selectively targeted by intravenously injected fusion protein-siRNA complexes, demonstrating the potential in vivo applicability of LFA-1-directed siRNA delivery.
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