A novel EGFR-targeted gene delivery system based on complexes self-assembled by EGF, DNA, and activated PAMAM dendrimers

Abstract

Epidermal growth factor receptor (EGFR)-targeted gene delivery is a promising approach in gene therapy against EGFR-positive cancer. In addition, macromolecules, such as polyamidoamine (PAMAM) dendrimers, are potential nonviral gene carriers in this therapy because of their biocompatibility and modifiable features. To achieve the goal of selectively enhancing the transfection efficiency in EGFR-positive cancer cells, the researchers developed chemical approaches of EGF-dendrimer conjugate, which were effective but complicated. Studies on liposomes reveal that self-assembly is another effective but simpler approach in EGF modification. Moreover, properly activated PAMAM dendrimers exhibit higher transfection efficiency, but little research has been done on its ligand-modification. In this study, we developed and characterized a novel gene-delivery system based on activated EGF-dendriplexes, which is formed via self-assembly by EGF and complexes prepared by activated PAMAM dendrimer and plasmid DNA. Such complexes exhibit desired features compared to nonmodified or nonactivated dendriplexes in vitro, including selective enhancement of transfection efficiency in EGFR-positive cells, decreased cytotoxicity, and low agonist effect. In vivo experimentation shows their EGFR-positive tumor targeted biodistribution and increased transfection efficiency at EGFR-positive tumors. Our results demonstrated that activated EGF-dendriplexes are safe and effective carriers for delivering gene drugs to EGFR-positive cells, which makes these complexes a promising targeted nonviral gene-delivery system for auxiliary cancer therapy.

Current Progress in Gene Delivery Technology Based on Chemical Methods and Nano-carriers

“…Polyamidoamine (PAMAM) dendrimers are highly branched spherical polymers that are highly soluble in aqueous solution and have a unique surface of primary amino groups 177 - 179 . Moreover, PAMAM dendrimers are a class of macromolecules that are uniformly dispersed in comparison with many other kinds of polymers investigated recently 180 - 183 .…”

Nanoparticle-based technologies for retinal gene therapy

“…PAMAM dendrimers were also effective in vivo [183, 186], although higher generation dendrimers were found to be cytotoxic due to their highly cationic structure [187]. PEI dendrimers on the other hand have been successfully used in vivo to deliver nucleic acids (plasmid DNA, siRNA, and long dsRNA) into various mouse tissues (e.g., lung, brain, liver, kidney, heart) [188–190].…”