Mannosylated Polyion Complexes for In Vivo Gene Delivery into CD11c+ Dendritic Cells

Dendritic cells (DCs) possess unique abilities in initiating primary immune responses and thus represent prime targets for DNA-based vaccinations. Here, we describe the design and synthesis of mannosylated polyion complexes (PICs) composed of cationic polyethylenimine (PEI) and hydrophilic polyethyl...

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Bibliographic Details
Published in:Molecular pharmaceutics 2015-02, Vol.12 (2), p.453-462
Main Authors: Raviv, Lior, Jaron-Mendelson, Michal, David, Ayelet
Format: Article
Language:English
Subjects:
Animals
CD11c Antigen - genetics
Cell Line
Dendritic Cells - cytology
Gene Transfer Techniques
HeLa Cells
Humans
Mannose - chemistry
Mice
Polyethylene Glycols - chemistry
Polyethyleneimine - chemistry
Polymers - chemistry
Transfection - methods
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Summary:Dendritic cells (DCs) possess unique abilities in initiating primary immune responses and thus represent prime targets for DNA-based vaccinations. Here, we describe the design and synthesis of mannosylated polyion complexes (PICs) composed of cationic polyethylenimine (PEI) and hydrophilic polyethylene glycol (PEG) segments, and bearing mono- and trivalent mannose as a ligand for targeting mannose receptor (MR/CD206)-positive DCs. Amino-terminated mannose (Man)-containing ligands in mono- and trivalent presentations (Man- and Man3-, respectively) were prepared and conjugated to PEG via an N-hydroxysuccinimide (NHS)-activated terminal. Thiolated PEI was conjugated to the mannosylated PEG via the maleimide (MAL)-activated terminal. The resulting positively charged diblock copolymers bearing mannoses (Man-PEG-b-PEI and Man3-PEG-b-PEI) were self-assembled with DNA to form PICs with lower surface charge than did their PEI building block and mean hydrodynamic diameters in the range of 100–450 nm, depending on the N/P ratio. Man3-PEG-b-PEI demonstrated a 3–4-fold greater transfection efficiency in MR-positive dendritic cell lines (THP-1, DC2.4), relative to Man-PEG-b-PEI, exhibited low cytotoxicity when compared with PEI, and showed low transfection efficiency in nondendritic HeLa cells. In preliminary in vivo experiments, Man-PEG-b-PEI/DNA and Man3-PEG-b-PEI/DNA demonstrated 2–3-fold higher gene delivery efficiency into CD11c+ DCs collected from inguinal lymph nodes of C57/BL6 mice, when compared to PEI/DNA complexes, as shown by GFP expression measurements, 24 h post subcutaneous injection. The results indicate that the mannosylated PICs are a safe and effective gene delivery system, showing in vivo specificity toward CD11c+ DCs.
ISSN:1543-8384
1543-8392
DOI:10.1021/mp5005492