| Cancer targeted gene delivery requires a fundamental understanding of the hallmarks of the disease in order to devise innovative strategies for improving efficacy. Such improvements depend upon advancement in the design of the genetic cargo administered as well as the formulation aspects resulting in an effective delivery system. Molecular level understanding of tumor-induced angiogenesis, cell signaling, and protein expression have aided in the development of novel therapeutic strategies. However, the rate limiting step in implementing these approaches revolves around the efficiency of the delivery system employed. With the advent of nanobiotechnology, various nano-sized delivery vehicles have been introduced with the intention of inducing selective nucleic acid delivery to tumor cells or tumor endothelium. Recent efforts have been focused on the design of vehicles whose properties or functionalities allow them to overcome the various extra- and intracellular barriers en route to their target cells. One class of materials, polycationic polymers, has been used to package DNA and other nucleic acids within sub-micron sized particles, offering protection from shear-induced or enzymatic degradation. However, the practical implementation of such materials remains limited due to the lack of particle uniformity and target cell specificity. This dissertation focuses on the improved formulation design of polycation-DNA complexes and their corresponding biological activity. Specific milestones for this work include evaluation of the structural and functional consequence of poly(ethylene glycol), development of materials responsive to cancer specific biochemical cues, and improved cellular targeting approaches for enhanced chemotherapy. The fields of cancer therapy and nanobiotechnology hold great potential for future identification of effective therapeutic targets and the development of efficient drug/gene therapies. Gene therapy, in particular, holds great promise for impacting the pathways involved in tumor growth, containment, and metastasis. Ultimately, the clinical realization of anti-cancer gene therapies will depend upon the development of delivery vehicles whose physical and biochemical properties enable them to appropriately navigate the intracellular and extracellular landscapes. This dissertation highlights key design considerations and efforts toward this goal. |
