Targeted gene delivery to pulmonary endothelium by anti-PECAM antibody
Targeted gene delivery to pulmonary endothelium by anti-PECAM antibody
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DOI：
10.1152/ajplung.2000.278.3.l504
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发表时间：
2000-03-01
影响因子：
4.9
通讯作者：
Huang, L
中科院分区：
文献类型：
--
作者：
Li, S;Tan, YD;Huang, L
为了以最小的毒性实现有效的全身基因传递到肺部，通过将阳离子聚合物聚乙烯亚胺(PEI)与抗血小板内皮细胞黏附分子(PECAM)抗体进行化学偶联，开发了一种载体。含荧光素酶基因表达载体(PCMVL)与抗PECAM-PEI结合物复合后对小鼠肺内皮细胞的转染率明显高于PEI-pCMVL复合体。此外，抗PECAM单抗-PEI偶联物可在较低的电荷正负比下介导有效的转染率。PEI与对照免疫球蛋白(仓鼠免疫球蛋白)的偶联不能促进小鼠肺内皮细胞的转染率，这表明细胞对抗PECAM抗体-PEI-DNA复合物的摄取和随后的基因表达是由受体介导的过程控制的，而不是由非特异性电荷相互作用控制的。PEI与抗PECAM抗体的偶联也显著改善了静脉给药后完整小鼠的肺基因转移。与PEI-pCMVL相比，肺转染率的增加与循环促炎细胞因子(肿瘤坏死因子-α)水平的降低有关。这些结果表明，靶向肺内皮细胞的基因传递是一种有效的策略，可以在降低毒性的同时增强基因对肺循环的传递。
To achieve efficient systemic gene delivery to the lung with minimal toxicity, a vector was developed by chemically conjugating a cationic polymer, polyethylenimine (PEI), with anti-platelet endothelial cell adhesion molecule (PECAM) antibody (Ab). Transfection of mouse lung endothelial cells with a plasmid expression vector with cDNA to luciferase (pCMVL) complexed with anti-PECAM Ab-PEI conjugate was more efficient than that with PEI-pCMVL complexes. Furthermore, the anti-PECAM Ab-PEI conjugate mediated efficient transfection at lower charge plus-to-minus ratios. Conjugation of PEI with a control IgG (hamster IgG) did not enhance transfection of mouse lung endothelial cells, suggesting that the cellular uptake of anti-PECAM Ab-PEI-DNA complexes and subsequent gene expression were governed by a receptor-mediated process rather than by a nonspecific charge interaction. Conjugation of PEI with anti-PECAM Ab also led to significant improvement in lung gene transfer to intact mice after intravenous administration. The increase in lung transfection was associated with a decrease compared with PEI-pCMVL with respect to circulating proinflammatory cytokine (tumor necrosis factor-alpha) levels. These results indicate that targeted gene delivery to the lung endothelium is an effective strategy to enhance gene delivery to the pulmonary circulation while simultaneously reducing toxicity.