Blood-brain barrier delivery of protein and non-viral gene therapeutics with molecular Trojan horses

Abstract

The products of biotechnology, recombinant proteins, monoclonal antibodies, antisense, RNA interference, or non-viral gene transfer, cannot be developed as pharmaceuticals for the brain, unless these molecules are re-formulated to enable transport across the blood-brain barrier (BBB). Large molecule drugs, and plasmid DNA, can be delivered across the BBB with receptor-specific molecular Trojan horses. Trojan horse BBB delivery systems, coupled with one of 3 different technology platforms (fusion proteins, avidin-biotin, or Trojan horse liposomes), can enable the BBB transport of virtually any large molecule drug or plasmid DNA.

Figure 1

Molecular Trojan horses are incorporated into 1 of 3 technology platforms, depending on the type of pharmaceutical to be delivered to the brain. Recombinant proteins or monoclonal antibodies are delivered with the fusion protein technology [31, 32]. Peptides, antisense, or short interfering RNA (siRNA) are delivered with the avidin-biotin technology, wherein the drug is mono-biotinylated in parallel with the production of a fusion protein of avidin and the Trojan horse. Plasmid DNA, which can encode short interfering RNA (shRNA), is delivered across the BBB with Trojan horse liposomes [33, 39].