Graduation Year

2008

Document Type

Dissertation

Degree

Ph.D.

Degree Granting Department

Chemical Engineering

Major Professor

Mark Jaroszeski, Ph.D.

Committee Member

Andrew Hoff, Ph.D.

Committee Member

Richard Gilbert, Ph.D.

Committee Member

Richard Heller, Ph.D.

Committee Member

William Lee, Ph.D.

Keywords

Plasma ions, Genetherapy, Electroporation, Molecular delivery, Tumors

Abstract

Application of corona ions produced in air to B16F10 murine melanoma cells in vitro and in animal models resulted in the transport of molecular therapeutics across the cell membrane. This work presents the development of new methods for drug and gene delivery based upon similar principles as the traditional electrode driven membrane destabilization processes known as electroporation. This was achieved with non-contact corona ion deposition that temporarily increased the permeability of cell membranes.

Interaction of corona charge with biological cells was studied and their potential for molecular delivery was established. Molecular delivery was first demonstrated in vitro using tracer molecules followed by in vitro delivery of the cytotoxic drug bleomycin. Building upon these results, the delivery of bleomycin coincident with ion deposition was xxi shown to significantly slow the growth of very aggressive solid tumors in animal models, compared to drug alone or no treatment. Delivery of plasmid DNA to cells in the skin of animal models indicated that application of corona ions (both positive and negative) to live tissue produced a four to six fold increase in gene expression. As this is the first significant study of the interaction and impact of corona ions on the delivery of drug and plasmid DNA to biological cells, numerous fundamental investigations were performed and discussed. A charge dose dependence was observed and physical mechanistic models were proposed. A model of cell resealing time constant following corona ion exposure was developed and demonstrated a reasonable prediction of experimental findings. The foundation laid by this work may enable continued exploration and use of corona ion deposition in the future as a new and promising physical method for drug and gene delivery.

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