TY - JOUR
T1 - Mannosylated Cationic Copolymers for Gene Delivery to Macrophages
AU - Lopukhov, Anton V.
AU - Yang, Zigang
AU - Haney, Matthew J.
AU - Bronich, Tatiana K.
AU - Sokolsky-Papkov, Marina
AU - Batrakova, Elena V.
AU - Klyachko, Natalia L.
AU - Kabanov, Alexander V.
N1 - Funding Information:
This study was supported in part by the Eshelman Institute for Innovation grant “Systemic Targeting of Mononuclear Phagocytes for Parkinson's Disease Gene Therapy” (AVK), National Cancer Institute grant 1R21CA220148 (AVK), Russian Foundation for Basic Research grants 17‐54‐33027 (NLK), and the Russian Science Foundation grant 20‐63‐46029 (AVK, NLK, AVL).
Publisher Copyright:
© 2021 Wiley-VCH GmbH
PY - 2021/4
Y1 - 2021/4
N2 - 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.
AB - 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.
KW - cationic block copolymer
KW - macrophage transfection
KW - mannose
KW - targeted gene delivery
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U2 - 10.1002/mabi.202000371
DO - 10.1002/mabi.202000371
M3 - Article
C2 - 33615675
AN - SCOPUS:85101134284
VL - 21
JO - Macromolecular Bioscience
JF - Macromolecular Bioscience
SN - 1616-5187
IS - 4
M1 - 2000371
ER -