The design and evaluation of triazine dendrimers for gene delivery
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The interest in using gene therapy to target a variety of both inherited and acquired diseases has intensified over the last two decades. Because free DNA is easily degraded by serum nucleases in the bloodstream, the need for developing carrier systems that can compact and protect the DNA was quickly realized. Viral vector systems were some of the earliest carriers used, primarily because of the ease with which such systems can infect host cells. However, difficulties experienced when using viral vectors, including immunogenicity and the potential for genetic recombinations, forced researchers to design alternative delivery strategies. Non-viral vectors offer one alternative to overcome this dilemma. In addition to avoiding the biological problems experienced using viral carriers, non-viral vectors also offer the potential for large-scale production. Dendrimers are one non-viral carrier that has shown appreciable ability to deliver DNA into cells, a process called transfection. In the past, triazine dendrimers have shown biocompatibility, and the ability to synthesize these structures to contain cationic charges on the surface makes these structures potentially suitable for transfection studies. In this study, a small library of triazine dendrimers was synthesized in an attempt to understand how variations to both the periphery and core of triazine dendrimers affect the transfection efficiency of these dendriplexes. In the first subset of structures, a common core was used and various peripheral groups were appended to the dendrimer surface. The physicochemical and biological data, obtained in collaboration with Thomas Kissel at Philipps-Universitat Marburg, showed that the surface groups have a notable affect on transfection efficiency. Dendrimers with a higher amine number and neutral surface groups show high DNA binding affinity and higher transfection efficiency. In the second subset of dendrimers, variations to the core showed that transfection efficiency is improved both by increasing generation number and dendrimer flexibility. With this data in hand, triazine dendrimers with both higher generation number and higher flexibility have been synthesized. Two different triazine linker groups, trimethylene-dipiperidine and polyglycoldiamine, have been used. These structures will be evaluated to determine if increasing both flexibility and generation number together can further improve transfection efficiency.
Mintzer, Meredith Ann (2009). The design and evaluation of triazine dendrimers for gene delivery. Doctoral dissertation, Texas A&M University. Available electronically from