• The formulation of DNA therapeutic vaccines as stable, dry powders of DNA precipitated onto the surface of microscopic gold particles and contained within a cassette
   
• The gas-powered, single-use PMED device (Fig 1)

The DNA plasmid that forms the active component of the therapeutic vaccine is precipitated onto microscopic gold particles (typically 2µg DNA on 1mg gold). Microscopic elemental gold particles (mean particle diameter 1 - 3 microns) are used as the plasmid DNA carrier, because it is inert and has the appropriate density needed to deliver the vaccine directly into the target epidermal antigen-presenting cells (APCs). These microscopic particles appear as a stable dry powder. This powder is then filled into sealed cassettes. These cassettes act as the primary drug product container and are inserted into the PMED device during the final product assembly and packaging process.

The PMED device is a single-use, disposable device powered by high pressure helium (Figure 1). The cassette containing the powdered vaccine is loaded into the body of the device at the end of the manufacturing process. As the powdered vaccine is stable at ambient temperature and the cassette is sealed, PMED can be stored simply and cheaply.

Using the device itself requires minimal training. The nozzle end of the device is placed against the skin at the delivery site where the vaccine is to be delivered and the actuation button is then pressed to administer the vaccine.
 

On actuation, the release of helium from a self-contained micro-cylinder ruptures the cassette membrane and propels the particles from their stationary state in the cassette through the nozzle and towards the skin surface at high velocity. This results in the deposition of the microscopic DNA coated gold particles in the epidermal cells of the skin.

Figure 1 DNA-Particle Mediated Epidermal Delivery (PMED) Device

Why use PMED for DNA Immunotherapeutics
The object of DNA immunotherapy is to deliver the DNA into the nuclei of cells capable of presenting the encoded antigen to the immune reactive cells. These then elicit an immune response. The delivery of plasmid DNA can be achieved using traditional methods eg intramuscular injection or by using the PMED technology.

A key difference between direct injection and PMED delivery is the efficiency with which this is done:

Direct injection delivers the DNA to extracellular spaces and relies on an inefficient, non-specific uptake of the DNA by neighbouring cells or transport along lymphatic vessels to draining lymph nodes

Regardless of whether the DNA is taken up by cells at the site of delivery or by cells in the draining lymph nodes, the antigen encoded by those cells must be reprocessed by specialized APCs in order to elicit an immune response. In either case, the efficiency and quality of antigen presentation is greatly reduced due to the relative low natural uptake of extracellular DNA by cells and ineffective processing of low amounts of encoded antigen by the APCs.

In contrast, PMED delivers the DNA directly to the intracellular compartment. As a result, PMED™ delivery uses 1,000-fold less DNA than needle and injection administration, hence the cost per dose for PMED would be commercially attractive.