Mannosylated Cationic Copolymers for Gene Delivery to Macrophages.
Mannosylated Cationic Copolymers for Gene Delivery to Macrophages.
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DOI：
10.1002/mabi.202000371
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发表时间：
2021-04
影响因子：
4.6
通讯作者：
Kabanov AV
中科院分区：
文献类型：
--
作者：
Lopukhov AV;Yang Z;Haney MJ;Bronich TK;Sokolsky-Papkov M;Batrakova EV;Klyachko NL;Kabanov AV
巨噬细胞是癌症和其他疾病基因治疗的理想靶点。本文合成了聚乙二醇（PEG）与聚l -赖氨酸（PLL）或聚{N-[N-（2-氨基乙基）-2-氨基乙基]阿斯巴酰胺}（pAsp(DET)）的阳离子二嵌段共聚物，并与甘露糖修饰的质粒DNA （pDNA）形成多聚体，作为巨噬细胞表面C型凝集素受体的靶向配体。PEG-b-PLL共聚物以其细胞毒性而闻名，因此基于PEG-b-PLL的多聚物使用可还原试剂二硫铋（琥珀酰丙酸酯）（DSP）交联。交联复合物对小鼠胚胎成纤维细胞NIH/3T3细胞系和小鼠骨髓源性巨噬细胞均显示低毒性（BMMΦ）。在巨噬细胞中，甘露糖修饰的复合物表现出约8倍的转染效率。多聚物交联可降低毒性，但转染增强作用适中。PEG-b-pAsp（DET）共聚物对IC-21小鼠巨噬细胞系显示出低毒性，并用于生产非交联的含有dna的复合物。与无甘露糖复合物相比，获得的甘露糖修饰复合物在IC-21巨噬细胞中的转染活性提高了约500倍。这一结果大大超过了先前使用甘露糖受体靶向非病毒基因传递系统描述的靶向基因转移效果。这些结果表明，Man-PEG-b-pAsp(DET)/pDNA复合体是一种潜在的免疫细胞基因治疗载体。
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.
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影响因子：
4.8
作者：
Feinberg, H;Park-Snyder, S;Weis, WI
通讯作者：
Weis, WI
影响因子：
4.9
作者：
Chamberlain, Lisa M.;Holt-Casper, Dolly;Grainger, David W.
通讯作者：
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影响因子：
4.8
作者：
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通讯作者：
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影响因子：
4.8
作者：
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通讯作者：
Zenke, M
影响因子：
3.3
作者：
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通讯作者：
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