Lipid-based Cancer Therapeutics

项目摘要 在过去的十年里，人类癌症治疗的重大进步是由新的概念推动的 针对癌症的方法，包括癌症免疫疗法、癌症纳米疗法或新型生物制品 和小分子。我的论文和博士后研究都将集中在 针对癌症的根本性新方法。 本论文的主要研究内容是光控脂类的研究进展。 新陈代谢和功能。除了靶向特定的受体、离子通道或酶外，光诱导 脂质纳米粒(LNP)的结构变化可以触发包囊药物的释放。 触发释放可显著提高临床批准的基于LNP的癌症治疗药物的疗效， 其中包括Doxil/Caelyx、DaunoXome、Myocet、Lipo-Dox或Marchibo。我试图设计和合成 光敏性脂质纳米粒，这里称为paLNPs，它允许有效的光- 引发了胶囊抗癌药物的释放。将为小型企业开发两种互补的方法 分子药物和基于RNA的疗法以及paLNPs的药理学特性将是 在体外和细胞培养中进行了系统的研究。 在我的博士后研究中，我试图利用我在化学、脂质生物学和医学方面获得的知识来 开发作用于质膜信号热点的生物靶标的脂类药物结合物。这个 最初的目标将是突变的癌基因KRAS G12C，它非常适合这种新的方法。共轭 该癌基因与脂类的选择性共价修饰物将在KRAS表面附加一条脂尾 这可能会在很大程度上改变它的膜-蛋白质相互作用，在最好的情况下，完全抑制它的功能。这 可以显著提高目前正在进行临床试验的共价药物载体的疗效。我想要 在体外和细胞培养中合成并系统研究这些脂类药物偶联物。

Project Summary Significant progress in human cancer therapy in the last decade has been driven by conceptionally new approaches to targeting cancer, including cancer immunotherapy, cancer nanotherapy, or new types of biologics and small molecules. Both my dissertation and postdoc research will be focused on the development of fundamentally new approaches to targeting cancer. My dissertation research is focused on the development of photoswitchable lipids for the optical control of lipid metabolism and function. In addition to targeting specific receptors, ion-channels, or enzymes, light-induced structural changes in a lipid nanoparticle (LNP) could serve as trigger for the release of encapsulated drugs. Triggered release could markedly improve the efficacy of clinically approved LNP-based cancer therapeutics, which include Doxil/Caelyx, DaunoXome, Myocet, Lipo-Dox, or Marqibo. I seek to design and synthesize photoswitchable lipids for `photoactivable lipid nanoparticles', herein termed paLNPs, that allow for effective light- triggered release of encapsulated cancer drugs. Two complementary approaches will be developed for small molecule drugs and RNA-based therapeutics and the pharmacological properties of paLNPs will be systematically investigated in vitro and in cell culture. In my postdoctoral research I seek to use my acquired knowledge in chemistry, lipid-biology, and medicine to develop lipid-drug conjugates for biological targets that function at plasma-membrane signaling hotspots. The initial target will be the mutated oncogene KRAS G12C, which is ideally suited for this new approach. Conjugating selective covalent modifier of this oncogene with a lipid will attach an additional lipid tail to the surface of KRAS that could largely alter its membrane-protein interaction and in the best case completely inhibit its function. This could markedly increase the efficacy of the covalent pharmacophores currently in clinical trials. I seek to synthesize and systematically study these lipid-drug conjugates in vitro and in cell culture.