The treatment of head and neck cancer is a complicated task which requires that many factors be considered before the best option can be chosen. The best treatment, providing the greatest efficacy with minimal side effects, is likely to be a localized nonsurgical treatment. Such a treatment would allow resolution of the primary tumor without the devastating systemic side effects associated with chemotherapy nor the social and psychological side effects associated with scarring and disfigurement resulting from surgical resection. Locally delivered gene therapy with viral vectors is a promising approach due to advances in delivery-enhancing materials. One such material is genetically engineered silk-elastinlike protein polymer (SELP), which due to its repeating structure and method of synthesis can be precisely modified to produce desired properties, such as pore size, swelling ratio, release rate, and mechanical strength. In this dissertation, it is shown that one particular analog of this polymer exhibits superior performance in the enhancement of adenoviral gene delivery, with enhancement of localization of gene expression of up to 55-fold, and reduction in acute immune response as measured by differential white blood cell count and hepatotoxicity due to viral administration. Further improvement of this material has been to include matrix-metalloproteinase (MMP)-sensitive sites in the polymer to provide it the capability to biodegrade more rapidly. Advantages to an MMP-responsive material include the ability to respond to changes in the tumor environment, as increased MMP activity can correlate with increased invasiveness and, in many cases, metastasis. The insertion of the MMP-responsive sequence caused sensitivity to both MMP-2 and MMP-9, with 63% and 44% increases in protein loss from sensitive hydrogels exposed to MMP-2 and MMP-9, respectively, compared to unexposed control. Further, MMP-2 and MMP-9 exposure caused 41% and 24% reduction in compressive modulus, and 95% and 66% increased release of 100nm polystyrene nanoparticles, respectively. These results show the potential of SELPs in increasing the safety and efficacy of adenoviral gene therapy.
|Commitee:||Cappello, Joseph, Grainger, David, Hunt, Jason, Kopecek, Jindrich|
|School:||The University of Utah|
|School Location:||United States -- Utah|
|Source:||DAI-B 74/04(E), Dissertation Abstracts International|
|Subjects:||Biomedical engineering, Pharmacy sciences|
|Keywords:||Adenoviral gene delivery, Cancer therapy, Gene delivery, Genetically engineered polymers, Head and neck cancer, Hydrogels, Protein polymers, Silk|
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