Tumor priming to promote nanoparticle gene delivery

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DESCRIPTION (provided by applicant): Insufficient delivery of gene vectors has been a major limiting factor in gene therapy of cancer. Hence, successful establishment of a technology that promotes gene vector delivery, especially the nonviral vectors that are less likely to elicit significant, potentially fatal host toxicities as have been observed with viral vectors, has the potential of advancing the use of gene therapy. Our laboratory recently demonstrated that the major determinants of penetration of large molecules in solid tumors are tissue structure and composition, and tumor cell density. We further showed that disruption of tumor structure and reduction of tumor cell density can be accomplished by using drugs such as paclitaxel and doxorubicin that induce apoptosis (referred to as tumor priming). This, in turn, results in expanded interstitial space and consequently greater and more even tumor penetration of large molecules (administered after apoptosis has occurred), both in 3-dimensional tumor histocultures and in tumors implanted in animals. We will test the hypothesis that tumor priming enhances nanoparticle delivery, by studying the delivery and spatial distribution of fluorescence-labeled latex beads and liposomes in solid tumors. Our preliminary results indicate that a single paclitaxel treatment improved the delivery of latex beads (100 nm in diameter) to solid tumors. Further, studies are proposed to define the particle characteristics giving the most favorable enhancement of delivery with the tumor priming approach, define the time course of changes in the tumor architecture, and determine the effect of priming in tumor regions with different perfusion characteristics. Studies will focus on liposomes, as these are effective nonviral gene vectors. This data is needed to determine the window of opportunity for delivering gene therapy after tumor priming and to determine the potential utility and limitations of the technology. Successful completion of the proposed studies would provide a new paradigm for delivery of nonviral gene vectors and other nanoparticles, and provide the background information on which we can formulate further studies into the mechanism of particle delivery to tumors.