A synthetic solution to gene delivery

Abstract

A self-assembling polymer-DNA nanoparticle serves as a vehicle for highly efficient gene delivery to cells.

Main

There is great medical interest in developing safe and effective delivery systems for gene therapy. Although modified viruses have shown promise as delivery vehicles, they are not an ideal solution as their specificity can be difficult to manipulate and they can cause severe immune reactions. Synthetic polymers have also been test driven, but it has proven a challenge to adjust their chemical properties to achieve efficient gene delivery while avoiding cellular toxicity.

Toward an innovative synthetic solution, Paula Hammond, in collaboration with Robert Langer (both of MIT), recently reported a self-assembling hybrid block copolymer system that targets plasmid DNA to cells with high efficiency, serum stability, low toxicity and, perhaps most importantly, chemical tunability. The block copolymer (so named because chemicaly distinct repeating units, or 'blocks', are linked together) consists of a cationic branched polymer to bind DNA, a biocompatible hydrophilic linear polymer to prevent nonspecific uptake, and a sugar ligand for cell-surface receptor targeting. Each of these blocks is synthetically addressable, as Hammond explains: “We can take elements that we know work extremely effectively for a delivery system and isolate them using the block copolymer format.”

The hybrid polymer and plasmid DNA self-assemble into a 'polyplex' (Fig. 1), as lead author Kris Wood explains: “The cationic hybrid polymer condenses negatively charged DNA to form nanoparticles with a series of concentric, functional 'shells' possessing independently tunable properties.” As proof that the polyplex could be efficiently endocytosed, they introduced the gene encoding firefly luciferase into two cell lines, and 72 hours later, the cells were glowing.

Figure 1

Self-assembling polyplex of DNA and hybrid polymer.

Wood, Langer and Hammond are not quite finished yet, however. They plan to test their gene delivery system in vivo, which may require tuning of the targeting ligand to recognize surface receptors on specific cell types. They also envision that the block copolymer format could be modified to deliver other molecules into cells, such as hydrophobic drugs. “We have a lot of chemical space to work in,” says Hammond.