Lipid-based Cancer Therapeutics

基于脂质的癌症治疗

• 批准号: 10415232
• 负责人: Johannes Morstein
• 金额: $ 8.6万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-06-01 至 2023-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10415232
• 关键词: Antineoplastic Agents; Biological; Biological Products; Biology; Cancer Biology; Cell Culture Techniques; Cell membrane; Chemistry; Clinical; Clinical Trials; Complement; Conceptions; Development; Doxorubicin Hydrochloride Liposome; Encapsulated; Enzymes; Goals; Human; In Vitro; Interdisciplinary Study; Ion Channel; KRAS2 gene; Knowledge; Light; Lipids; Malignant Neoplasms; Medicine; Membrane Proteins; Mutate; Oncogenes; Optics; Pharmaceutical Preparations; Pharmacology; Postdoctoral Fellow; Property; Research; Research Project Grants; Signal Transduction; Small RNA; Surface; System; Tail; Therapeutic; base; cancer immunotherapy; cancer therapy; clinical efficacy; design; improved; innovation; lipid metabolism; lipid nanoparticle; nanotherapy; novel; novel strategies; pharmacophore; receptor; small molecule; therapeutic RNA

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.

项目概要 过去十年人类癌症治疗取得的重大进展是由新概念推动的 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剂 和小分子。我的论文和博士后研究都将集中于开发 针对癌症的全新方法。 我的论文研究重点是用于脂质光学控制的光开关脂质的开发 新陈代谢和功能。除了针对特定受体、离子通道或酶之外，光诱导 脂质纳米颗粒（LNP）的结构变化可以作为封装药物释放的触发因素。 触发释放可以显着提高临床批准的基于 LNP 的癌症疗法的功效， 其中包括 Doxil/Caelyx、DaunoXome、Myocet、Lipo-Dox 或 Marqibo。我寻求设计和综合 用于“光可激活脂质纳米颗粒”的光可切换脂质，本文称为 paLNP，它允许有效的光 触发封装的抗癌药物的释放。将为小型企业制定两种互补的方法 分子药物和基于 RNA 的疗法以及 paLNP 的药理学特性将 在体外和细胞培养中进行了系统研究。 在我的博士后研究中，我寻求利用我在化学、脂质生物学和医学方面获得的知识来 开发针对在质膜信号热点发挥作用的生物靶标的脂质-药物缀合物。这 最初的目标将是突变的癌基因 KRAS G12C，它非常适合这种新方法。共轭 该癌基因与脂质的选择性共价修饰将在 KRAS 表面附加一个额外的脂质尾部 这可以在很大程度上改变其膜蛋白相互作用，并在最好的情况下完全抑制其功能。这 可以显着提高目前临床试验中共价药效团的功效。我寻求 在体外和细胞培养中合成并系统地研究这些脂质-药物缀合物。