Nanoparticle Based Cell Selective Modulation of SSAT1 Expression

细胞内多胺水平的调节受到高度调控，依赖于细胞内的合成和分解代谢过程。由于参与多胺合成（鸟嘌呤脱羧酶）和分解代谢（精胺/亚精胺酰基转移酶1；SSAT1）的酶在癌症等病理条件下都会发生改变，因此调节酶的表达/活性已被确定为癌症的潜在治疗靶点。然而，一些根本性的障碍阻碍了这一领域的进展。由于细胞内的多胺浓度驱动许多重要的生物功能，该领域科学进步的一个关键限制是无法选择性地改变离散细胞群体中多胺代谢关键酶的表达。这个问题的一个潜在解决方案是使用纳米粒子系统将所需的化合物输送到选定的细胞类型中。通过优化脂质和聚合物涂层，并将靶向载体附着在纳米颗粒表面，可以“调整”纳米颗粒与选定细胞的相互作用，同时最大限度地减少与非靶细胞的相互作用。本研究申请的目的是设计、表征和提供SSAT1在选定细胞群中表达的靶向改变的初步概念证明。通过脂质和聚合物组合以及细胞靶向载体的附着来优化纳米颗粒表面，假设可以实现更有效和细胞选择性的酶表达调节方法。这种特殊的酶和细胞的基本原理是基于在脑肿瘤中观察到的SSAT1过表达，最近的研究表明，GB中SSAT1表达的改变可能影响细胞存活。该项目的重点是确定SSAT1在GB细胞中的生存优势，并开发一种细胞“调谐”纳米颗粒为基础的递送系统，以调节SSAT1的表达。最终目标是优化纳米颗粒递送，以选择肿瘤细胞，同时避免递送到正常细胞群。

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.