Surface-Engineered Dendrimers with a Diaminododecane Core Achieve Efficient Gene Transfection and Low Cytotoxicity

Abstract

Cationic dendrimers are widely used as gene vectors; however, these materials are usually associated with unsatisfied transfection efficiency and biocompatibility. In this study, we used an aliphatic hydrocarbon-cored polyamidoamine (PAMAM) dendrimer as an alternative to traditional cationic PAMAM dendrimers in the design of efficient gene vectors. Diaminododecane-cored generation 4 (C12G4) PAMAM dendrimer showed dramatically higher efficacy in luciferase and EGFP gene transfection than diaminoethane-cored generation 4 (C2G4) and diaminohexane-cored generation 4 (C6G4) PAMAM dendrimers. The viability of cells incubated with C12G4 at transfection concentrations is above 90%. The significantly improved gene transfection efficacy of C12G4 is attributed to the hydrophobic core of C12G4 which increases the cellular uptake of dendrimer/DNA polyplexes. Further modification of C12G4 with functional ligands such as arginine, 2,4-diamino-1,3,5-triazine, and fluorine compounds significantly increase its transfection efficiency on several cell lines. These results suggest that diaminododecane-cored dendrimers can be developed as a versatile scaffold in the design of efficient gene vectors.

Amino Acid-Modified Polyethylenimines with Enhanced Gene Delivery Efficiency and Biocompatibility

“…As anticipated, these modified-PEI conjugates exhibited obviously lower cytotoxicity than PEI, especially in normal cells HEK293. Leu-PEI with hydrophobic side chains showed higher cytotoxicity than other polymers, suggesting that hydrophobic modification is prone to induce toxicity, which may come from the enhanced interaction with the cell membrane [33][34][35]. Among the five polymers, Ga-PEI showed the lowest cytotoxicity.…”

Defined Polymeric Materials for Gene Delivery

“…This is due to the increased cellular uptake of dendrimer/pDNA polyplexes. Further surface modification of C12G4 dendrimer using arginine, 2,4‐diamino‐1,3,5‐triazine and fluorine compounds as the functional group greatly improve the transfection efficiency in several cell lines . Uekama and colleagues developed cyclodextrin‐modified PAMAM dendrimers for pDNA delivery.…”

Linear TACN-based cationic polymers as non-viral gene vectors

“…35 In order to evaluate the cytotoxicity of title polymers, the viability of three different cell lines was tested in the presence of polymers with various concentrations, and 25 kDa PEI was used for comparison. 36 On the contrary, polymers with heteroatoms-contained spacers exhibited much lower toxicity, and P6 gave highest cell viability. 3, for the polymers with hydrophobic spacers (P1-P3), the cytotoxicity dramatically increased with the extension of hydrophobic chain, and P3 gave even higher toxicity than PEI in both cell lines.…”

“…Fig. 36 Thus an optimized chain length is signicant for the hydrophobic modied vectors. 37 It is known that hydrophobic chains may not only promote cellular uptake 38 and the stability toward competitive interaction of polyanions, 39-41 but also induce cell cytotoxicity.…”