Polyamidoamine Dendrimer Grafted with an Acid-Responsive Charge-Reversal Layer for Improved Gene Delivery. Biomacromolecules 2020 Oct 12;21(10):4008-4016
Date
08/22/2020Pubmed ID
32820887Pubmed Central ID
PMC7583228DOI
10.1021/acs.biomac.0c00580Scopus ID
2-s2.0-85092803485 (requires institutional sign-in at Scopus site) 17 CitationsAbstract
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.
Author List
Wang J, Cooper RC, Yang HAuthor
Hu Yang PhD Chair, Professor in the Biomedical Engineering department at Medical College of WisconsinMESH terms used to index this publication - Major topics in bold
AnimalsDendrimers
Gene Transfer Techniques
Mice
NIH 3T3 Cells
Polyamines
