Polyamidoamine Dendrimer Grafted with an Acid-Responsive Charge-Reversal Layer for Improved Gene Delivery.,Biomacromolecules

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Polyamidoamine Dendrimer Grafted with an Acid-Responsive Charge-Reversal Layer for Improved Gene Delivery.
Biomacromolecules ( IF 5.5 ) Pub Date : 2020-08-21 , DOI: 10.1021/acs.biomac.0c00580
Juan Wang _{1,

2} , Remy C Cooper ₃ , Hu Yang _{2,

4,

5}

Affiliation

We report on a heterogeneous dendrimer (G3-acetal-NH₂) derivative possessing an acid-responsive charge-reversal layer. The synthesis of G3-acetal-NH₂ starts with a polyamidoamine (PAMAM) dendrimer G3 core and follows the aza-Michael addition with N-(2-(1-(allyloxy)ethoxy)ethyl)acrylamide synthesized by us and the thiol-ene click chemistry with cysteamine hydrochloride in sequence. In a weakly acidic environment, the surface of this newly formed dendrimer can turn from amine-terminated to hydroxyl-terminated due to the cleavage of the acetal groups. This charge conversion from 34.3 ± 2.7 to 18.0 ± 0.3 mV in 24 h at pH 5.3 enables its capacity as a gene delivery vehicle. G3-acetal-NH₂ with a positively charged surface can condense pMAX GFP plasmid at similar weight ratios as native G4-NH₂ (above 2:1), allowing for its protected uptake into cells and endosomal escape. Meanwhile, in the endosome, the drop in vesicle pH cleaves the acetal bond, releasing the genetic payload and limiting its recondensation by the reduction in the dendrimer surface charge. When the vector/plasmid weight ratio was 2:1, G3-acetal-NH₂ improved transfection of pMAX GFP plasmid by 5-fold over native G4-NH₂ in NIH3T3 cells in terms of GFP protein expression. Taken together, we show that this surface charge conversion performance makes the synthesized heterogeneous dendrimer an improved vehicle for gene transfection.

中文翻译：

接枝有酸响应电荷反转层的聚酰胺胺树枝状聚合物以改善基因传递。

我们报告了具有酸响应电荷反转层的异质树枝状聚合物（G3-乙缩醛-NH ₂）衍生物。G3-缩醛-NH ₂的合成以聚酰胺胺 (PAMAM) 树枝状聚合物 G3 核心开始，然后与我们合成的N- (2-(1-(烯丙氧基)乙氧基)乙基)丙烯酰胺和硫醇-烯点击化学与半胱胺盐酸盐依次进行。在弱酸性环境中，由于缩醛基团的裂解，这种新形成的树枝状聚合物的表面可以从胺端基转变为羟基端基。在 pH 5.3 的情况下，这种电荷在 24 小时内从 34.3 ± 2.7 到 18.0 ± 0.3 mV 的转换使其具有作为基因传递载体的能力。G3-缩醛-NH₂与带正电的表面能缩合PMAX GFP质粒以相似的重量比为天然G4-NH ₂（上面的2：1），从而允许其受保护的摄取入细胞和内体逃逸。同时，在内体中，囊泡 pH 值的下降会裂解缩醛键，释放遗传载荷并通过树枝状聚合物表面电荷的减少来限制其再凝聚。当载体/质粒重量比为 2:1 时，就 GFP 蛋白表达而言，G3-乙缩醛-NH ₂将 pMAX GFP 质粒的转染提高了NIH3T3 细胞中天然 G4-NH ₂的 5 倍。总之，我们表明这种表面电荷转换性能使合成的异质树枝状大分子成为基因转染的改进载体。

更新日期：2020-10-12

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