Nanoparticle Based Cell Selective Modulation of SSAT1 Expression

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The regulation of polyamine levels in cells is highly regulated and dependent upon both the synthesis andcatabolism processes at work within the cell. As enzymes involved in both the synthesis (ornithinedecarboxylase) and catabolism (spermine/spermidine actyl transferase 1; SSAT1) of polyamines are known tobe altered under pathological conditions such as cancer, modulation of enzyme expression/activity has beenidentified as a potential therapeutic target for cancer. However, fundamental obstacles impede advancementsin this area. As polyamine concentrations within the cell drive many important biological functions, a keylimitation to scientific advancement of this field has been the inability to SELECTIVELY alter the expressionof key enzymes in polyamine metabolism within DISCRETE cellular populations. A potential solution to thisproblem is the use of nanoparticle systems to delivery the desired compounds to selected cell types. Byoptimizing lipid and polymer based coatings and attaching targeting vectors to the surface of the nanoparticle itis possible to "tune" the nanoparticle to interact with selected cells while minimizing interactions withoff-target cells. The objective of this research application is to design, characterize and provide initialproof-of-concept for targeted alteration of SSAT1 expression within a selected cell population. By optimizingthe nanoparticle surface through lipid and polymer composition, as well as through the attachment of celltargeting vectors, it is hypothesized that a more effective and cell selective approach to modulation of enzymeexpression can be achieved. Rationale for this particular enzyme and cell is based on the over-expression ofSSAT1 observed in brain tumors and recent studies suggesting alterations in SSAT1 expression in GB couldinfluence cell survival. The focus of this project is to identify survival advantages of SSAT1 in GB cells anddevelop a cellular "tuned" nanoparticle based delivery system tailored to modulate SSAT1 expression.Ultimately the goal is to optimize nanoparticle delivery to select tumor cells while avoiding delivery to normalcell populations.