The overall objective of the proposed study is to develop and validate an in vitro multicellular layer (MCL) model that can be used to gain a better understanding of transport mechanisms and to facilitate testing a large number of experimental parameters that are pertinent to in vivo applications of electric field-mediated gene delivery. As a technique, electric field-mediated gene delivery is likely to be far from optimal since DNA transport in tumors is a complicated process. It is unpractical to optimize the technique using tumor tissues nor can it be optimized by using polymeric gels because of the absence of cells in gels. Therefore, I propose to develop and validate the MCL model (Specific Aim 1) since it is less expensive than tumor tissues and more relevant than polymeric gels. Using this model, I will identify effective pulse sequences forDNA transport (Specific Aim 1) and investigate effects of extracellular matrix (ECM) and cells on DNA mobility (Specific Aim 2). In addition, I will investigate the impact of DNA electrophoresis on transfection efficiency in electric field-mediated gene transfer (Specific Aim 3). Results from this study may lead to the identification of the most effective procedures for electric field-mediated gene transfer in solid tumors.
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