Structure–activity relationship of novel low-generation dendrimers for gene delivery

Abstract

Structure-activity relationship (SAR) studies are very critical to design ideal gene vectors for gene delivery. However, It is difficult to obtain SAR information of low-generation dendrimers due to the lack of easy structural modification ways. Here, we synthesized a novel family of rigid aromatic backbone-based low-generation polyamidoamine (PAMAM) dendrimers. According to the number of primary amines, they were divided into two types: four-amine-containing PAMAM (DL1-DL5) and eight-amine-containing PAMAM (DL6-DL10). Due to the introduction of a rigid aromatic backbone, the low-generation PAMAM could be modified easier by different hydrophobic aliphatic chains. Several assays were used to study the interactions of the PAMAM dendrimers with plasmid DNA, and the results revealed that they not only had good DNA binding ability but also could efficiently condense DNA into spherical-shaped nanoparticles with suitable sizes and zeta potentials. The SAR studies indicated that the gene-transfection efficiency of the synthesized materials depended on not only the structure of their hydrophobic chains but also the number of primary amines. It was found that four-amine-containing PAMAM prepared from oleylamine (DL5) gave the best transfection efficiency, which was 3 times higher than that of lipofectamine 2000 in HEK293 cells. The cellular uptake mechanism mediated by DL5 was further investigated, and the results indicated that DL5/DNA complexes entered the cells mainly via caveolae and clathrin-mediated endocytosis. In addition, these low-generation PAMAMs modified with a single hydrophobic tail showed lower toxicity than lipofectamine 2000 in MC3T3-E1, MG63, HeLa, and HEK293 cells. These results reveal that such a type of low-generation polyamidoamines might be promising non-viral gene vectors, and also give us clues for the design of safe and high-efficiency gene vectors.

Endocytosis: The Nanoparticle and Submicron Nanocompounds Gateway into the Cell

“…Furthermore, PAMAM G4 dendrimers, both cationic and neutral, seem to be internalized by a caveolin-and clathrin-independent pathway in human lung carcinoma A549 cells [53] while low generation (G2) amine-terminated dendrimers are also taken up mainly by CME pathway in human colon adenocarcinoma Caco-2 cells [54] and by CME and CVME in HEK293 human embryonic kidney epithelial cells [53]. On the other hand, anionic, -COOH and -OH terminated dendrimers, are taken up by CVME [41] even though some researchers suggest that CME could also play a role [55].…”

Overcoming barriers: a review on innovations in drug delivery to the middle and inner ear

“…Dendrimers are nanoparticles characterized by long, branched polymer chains and are readily customizable in terms of their molecular architecture, which confers the ability to carry a wider variety of drugs and allows surface functionalization, for example for conjugating permeation or targeting moieties ( Kheiriabad et al, 2021 ). One study demonstrated greater gene transfection efficiency of a polyamidoamine dendrimer over the commercially available transfection reagent, Lipofectamine 2000, a lipid nanoparticle ( Gao et al, 2018b ). Another polyamindoamine-based dendrimer was used to deliver an ATOH1 -containing plasmid to the rat inner ear.…”

Nanoscale Self-Assembly for Therapeutic Delivery

“…Further, Gao et al studied structure activity relationship to design efficient gene delivery vectors. They demonstrated that both hydrophobic modification and density of amines modulate the gene transfer ability of synthetic vectors (Gao et al, 2018).…”