Nanoparticle Based Cell Selective Modulation of SSAT1 Expression

基于纳米颗粒的 SSAT1 表达细胞选择性调节

• 批准号: 519893-2017
• 负责人: Miller, Donald
• 金额: $ 1.82万
• 依托单位: University of Manitoba
• 依托单位国家: 加拿大
• 项目类别: Engage Grants Program
• 财政年份: 2017
• 资助国家: 加拿大
• 起止时间: 2017-01-01 至 2018-12-31
• 项目状态: 已结题
• 来源: https://www.nserc-crsng.gc.ca/ase-oro/Details-Detailles_eng.asp?id=640758
• 关键词: Nanoparticle; Based; Cell; Selective; Modulation

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.

细胞中多胺水平的调节是高度调节的，并且依赖于细胞内工作的合成和催化过程。由于已知参与多胺合成（鸟氨酸脱羧酶）和催化（精胺/亚精胺乙酰转移酶1; SSAT 1）的酶在病理条件下（如癌症）发生改变，因此酶表达/活性的调节已被确定为癌症的潜在治疗靶点。然而，根本性的障碍阻碍了这一领域的进展。由于细胞内多胺浓度驱动许多重要的生物学功能，该领域科学进步的一个关键限制是不能选择性地改变离散细胞群体内多胺代谢中关键酶的表达。这个问题的一个潜在的解决方案是使用纳米颗粒系统将所需的化合物递送到选定的细胞类型。通过优化基于脂质和聚合物的涂层并将靶向载体附着到纳米颗粒的表面，可以“调节”纳米颗粒与选定的细胞相互作用，同时最小化与脱靶细胞的相互作用。这项研究应用的目的是设计，表征和提供初步的概念验证，有针对性地改变SSAT 1的表达在选定的细胞群体。通过脂质和聚合物组成优化纳米颗粒表面，以及通过附着细胞靶向载体，假设可以实现更有效和细胞选择性的方法来调节酶表达。这种特殊的酶和细胞的原理是基于在脑肿瘤中观察到的SSAT 1的过度表达，最近的研究表明GB中SSAT 1表达的改变可能影响细胞存活。本项目的重点是确定SSAT 1在GB细胞中的生存优势，并开发一种细胞“调谐”的基于纳米颗粒的递送系统，以调节SSAT 1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体。