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Stem cell-based ovarian cancer suicide gene therapy

机译：基于干细胞的卵巢癌自杀基因治疗

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摘要

Cancer is a leading cause of death worldwide, resulting in 8.2 million deaths in 2012. Tumor suicide gene therapy is among the novel targeted therapeutics that has demonstrated promising results. There are two important factors that specify the efficiency and safety of the suicide gene therapy systems. One is vector safety and efficiency and the other enzyme/prodrug anticancer efficacy. Among the vectors employed for delivery of therapeutics, mesenchymal stem cells (MSCs) have attracted tremendous amount of attention due to their unique features such as inherent tumor tropism and low immunogenicity. The objective of this research was to take advantage of MSCs as cell-based vectors to develop an efficient and safe suicide gene therapy system for cancer. As a first step towards achieving the objective, I engineered a panel of MSCs that were genetically modified to express five different suicide genes and compared their anti-tumor efficiency in vitro and in vivo. Among the enzyme/prodrug systems tested, genetically modified MSCs that expressed yeast cytosine deaminase enzyme (yCD-UPRT) in combination with prodrug 5-fluorocytosine (5FC) demonstrated the highest anti-tumor efficacy. In the next step we focused on developing a safe and efficient method for stem cell engineering. Since current commercially available transfection agents are inefficient and toxic to MSCs, I made an attempt to develop a safe and efficient gene delivery system suitable for MSC engineering. Using a previously developed vector in Dr. Hatefi's lab as a template, I recombinantly engineered a new vector for MSC transfection. This vector is comprised of a cell penetrating peptide for penetration into MSCs, four histone H2A repeats to condense plasmid DNA (pDNA) into nanosize particles and a fusogenic peptide named GALA to facilitate endosomal escape. The results of this study illustrated that the newly developed recombinant vector could efficiently and safely transfect MSCs. In conclusion we not only successfully developed a safe and efficient method for stem cell engineering but also identified an enzyme/prodrug system that could be used for effective treatment of ovarian cancer.
机译：癌症是全球主要的死亡原因，2012年导致820万人死亡。肿瘤自杀基因疗法是新颖的靶向疗法之一，已证明有希望的结果。有两个重要因素指定了自杀基因治疗系统的效率和安全性。一种是载体的安全性和效率，另一种是酶/前药的抗癌功效。在用于递送治疗剂的载体中，间充质干细胞（MSC）由于其独特的特性（例如固有的肿瘤嗜性和低免疫原性）而引起了极大的关注。这项研究的目的是利用MSCs作为基于细胞的载体来开发一种有效且安全的癌症自杀基因治疗系统。作为实现该目标的第一步，我设计了一组经过遗传修饰以表达五个不同自杀基因的MSC，并比较了它们在体内和体外的抗肿瘤效率。在测试的酶/前药系统中，表达酵母胞嘧啶脱氨酶（yCD-UPRT）与前药5-氟胞嘧啶（5FC）组合的转基因MSC表现出最高的抗肿瘤功效。在下一步中，我们专注于开发一种安全有效的干细胞工程方法。由于目前市售的转染剂对MSC无效且有毒性，因此我尝试开发一种适用于MSC工程的安全有效的基因递送系统。使用Hatefi博士实验室中先前开发的载体作为模板，我重组设计了一种用于MSC转染的新载体。该载体由可穿透MSC的细胞穿透肽，四个将质粒DNA（pDNA）浓缩成纳米级颗粒的组蛋白H2A重复序列和名为GALA的融合肽组成，可促进内体逃逸。这项研究的结果表明，新开发的重组载体可以有效，安全地转染MSC。总之，我们不仅成功开发了一种安全，有效的干细胞工程方法，而且还确定了可用于有效治疗卵巢癌的酶/前药系统。

著录项

  • 作者

    Salman Noori, Faranak.;

  • 作者单位

    Rutgers The State University of New Jersey - New Brunswick.;

  • 授予单位 Rutgers The State University of New Jersey - New Brunswick.;
  • 学科 Pharmaceutical sciences.
  • 学位 Ph.D.
  • 年度 2015
  • 页码 156 p.
  • 总页数 156
  • 原文格式 PDF
  • 正文语种 eng
  • 中图分类
  • 关键词

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