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Mannosylated Cationic Copolymers for Gene Delivery to Macrophages
Author(s) -
Lopukhov Anton V.,
Yang Zigang,
Haney Matthew J.,
Bronich Tatiana K.,
SokolskyPapkov Marina,
Batrakova Elena V.,
Klyachko Natalia L.,
Kabanov Alexander V.
Publication year - 2021
Publication title -
macromolecular bioscience
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.924
H-Index - 105
eISSN - 1616-5195
pISSN - 1616-5187
DOI - 10.1002/mabi.202000371
Subject(s) - gene delivery , mannose receptor , mannose , transfection , asialoglycoprotein receptor , chemistry , peg ratio , cytotoxicity , polyethylene glycol , microbiology and biotechnology , genetic enhancement , biochemistry , macrophage , biology , in vitro , gene , hepatocyte , finance , economics
Abstract Macrophages are desirable targets for gene therapy of cancer and other diseases. Cationic diblock copolymers of polyethylene glycol (PEG) and poly‐L‐lysine (PLL) or poly{N‐[N‐(2‐aminoethyl)‐2‐aminoethyl]aspartamide} (pAsp(DET)) are synthesized and used to form polyplexes with a plasmid DNA (pDNA) that are decorated with mannose moieties, serving as the targeting ligands for the C type lectin receptors displayed at the surface of macrophages. The PEG‐ b ‐PLL copolymers are known for its cytotoxicity, so PEG‐ b ‐PLL‐based polyplexes are cross‐linked using reducible reagent dithiobis(succinimidyl propionate) (DSP). The cross‐linked polyplexes display low toxicity to both mouse embryonic fibroblasts NIH/3T3 cell line and mouse bone marrow‐derived macrophages (BMMΦ). In macrophages mannose‐decorated polyplexes demonstrate an ≈8 times higher transfection efficiency. The cross‐linking of the polyplexes decrease the toxicity, but the transfection enhancement is moderate. The PEG‐ b ‐pAsp(DET) copolymers display low toxicity with respect to the IC‐21 murine macrophage cell line and are used for the production of non‐cross‐linked pDNA‐contained polyplexes. The obtained mannose modified polyplexes exhibit ca. 500‐times greater transfection activity in IC‐21 macrophages compared to the mannose‐free polyplexes. This result greatly exceeds the targeting gene transfer effects previously described using mannose receptor targeted non‐viral gene delivery systems. These results suggest that Man‐PEG‐ b ‐pAsp(DET)/pDNA polyplex is a potential vector for immune cells‐based gene therapy.