Design, synthesis, and evaluation of synthetic particulate delivery systems in DNA and protein vaccine delivery

Vaccination is not only a medical marvel in terms of unparalleled importance in safeguarding health but also considered to be one of the most economical and safe medical intervention strategies. Radical changes have taken place in vaccine development in recent times with modern approaches laying heavy emphasis on safety and rapid turn around times for new vaccines. Recombinant subunit protein vaccines and DNA vaccines are considered to be the future generation of vaccines. Genetic immunization which involves host inoculation of bacterially derived plasmid DNA encoding for proteins (antigens) derived from disease causing pathogens has emerged as a safer, cost effective alternative to the use of recombinant viruses. Experts believe that genetic immunization could be the first application towards the use of nucleic acids as a biopharmaceutical drug. Although extensive research in animal models has shown significant promise in terms of generating strong and potent balance of humoral and cell mediated immunity, the translation to human clinical trials has been disappointing. The use of synthetic delivery systems to enhance the potency of nucleic acid based (DNA) vaccines and recombinant purified protein vaccines have opened new directions in safer, yet effective modalities of vaccination. The overall goal of this project was to engineer synthetic polymer based delivery systems to enhance the potency of protein and DNA vaccines. We have synthesized hybrid polymeric PLGA microparticles; surface modified by chemical conjugation of polycations such as branched and linear poly (ethyleneimine) PEI and with solvent free Atmospheric Plasma Glow discharge (APG) based approaches. Extensive characterization demonstrates that our formulations; a) have excellent reproducibility, b) are efficiently taken up by phagocytic cells, c) have endo/phagosomal escape facilitating properties, d) are non toxic to cells, and e) have improved transfection efficiencies at early time points in phagocytic cells in vitro. We have also demonstrated that these formulations considerably enhance potency of cancer genetic vaccines without the use of known immune potentiators in mice models in vivo. The potential to include known soluble adjuvants in our design can have far reaching effects in realizing combinatorial vaccine and adjuvant delivery systems for cures in cancer and infectious diseases.