Triazine Dendrimers as Nonviral Vectors for in Vitro and in Vivo RNAi: The Effects of Peripheral Groups and Core Structure on Biological Activity

Abstract

A family of triazine dendrimers, differing in their core flexibility, generation number, and surface functionality, was prepared and evaluated for its ability to accomplish RNAi. The dendriplexes were analyzed with respect to their physicochemical and biological properties, including condensation of siRNA, complex size, surface charge, cellular uptake and subcellular distribution, their potential for reporter gene knockdown in HeLa/Luc cells, and ultimately their stability, biodistribution, pharmacokinetics and intracellular uptake in mice after intravenous (iv.) administration. The structure of the backbone was found to significantly influence siRNA transfection efficiency, with rigid, second generation dendrimers displaying higher gene knockdown than the flexible analogues while maintaining less off-target effects than Lipofectamine. Additionally, among the rigid, second generation dendrimers, those with either arginine-like exteriors or peripheries containing hydrophobic functionalities mediated the most effective gene knockdown, thus showing that dendrimer surface groups also affect transfection efficiency. Moreover, these two most effective dendriplexes were stable in circulation upon intravenous administration and showed passive targeting to the lung. Both dendriplex formulations were taken up into the alveolar epithelium, making them promising candidates for RNAi in the lung. The ability to correlate the effects of triazine dendrimer core scaffolds, generation number, and surface functionality with siRNA transfection efficiency yields valuable information for

Polycation-siRNA nanoparticles can disassemble at the kidney glomerular basement membrane

“…Like most cationic polymer-based siRNA delivery systems (5)(6)(7)(8)(9), the siRNA/CDP nanoparticle is rapidly eliminated from circulation (shown in mice, monkeys, and humans) (10)(11)(12). In fact, polymer complexation often does not extend the circulation time of siRNA.…”

Low Molecular Weight pDMAEMA-block-pHEMA Block-Copolymers Synthesized via RAFT-Polymerization: Potential Non-Viral Gene Delivery Agents?

“…Each sample was measured in 5 runs. For both measurements, N/P ratios of 5, 10, 15, and 20 were tested and analyzed with the Zetasizer Nano ZS Software 6.20 (Malvern, Herrenberg, Germany) as reported previously [37].…”

Polyester Dendrimers: Smart Carriers for Drug Delivery

“…However, because the drug is delivered to the site of action extremely rapidly with IV injection, there is a risk of overdose if the dose has been calculated incorrectly, and there is an increased risk of side effects if the drug is administered too rapidly. Numerous reports of IV administered dendrimer-drug complexes have appeared [85][86][87][88][89]. For example, 2'-(benzo[1,2-c] 1,2,5-oxadiazol-5(6)-yl(N 1 -oxide) methylidene)-1-methoxy methane hydrazide presents antichagasic activity but has low water solubility.…”