Fluorescent Indocarbocyanine PEGylated Lipid Nanoparticles for Understanding and Overcoming Barriers to Drug Delivery in Invasive Glioblastoma

荧光吲哚羰花青聚乙二醇化脂质纳米颗粒用于了解和克服侵袭性胶质母细胞瘤药物输送障碍

• 批准号: 10649571
• 负责人: Irina V Balyasnikova
• 金额: $ 56.33万
• 依托单位: UNIVERSITY OF COLORADO DENVER
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-08-01 至 2027-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10649571
• 关键词: Abbreviations; Adult; Animals; Antibodies; Antigens; Apoptosis; Biodistribution; Blood; Blood Vessels; Brain; Brain Neoplasms; CRISPR/Cas technology; Cells; Chemistry; Cyclin-Dependent Kinase Inhibitor; Cyclin-Dependent Kinases; Data; Dextrans; Diffusion; Disease; Dose; Drug Delivery Systems; Drug Kinetics; Endocytosis; Endothelial Cells; Endothelium; Exhibits; Exocytosis; Extravasation; Flow Cytometry; Formulation; Foundations; Genetically Engineered Mouse; Glioblastoma; Glioma; Goals; Image; In Situ; In Vitro; Injections; Invaded; Libraries; Ligands; Lipid Chemistry; Lipids; Liposomes; Mediating; Modeling; Mus; Myeloid Cells; Organoids; Pathway interactions; Patients; Penetration; Perfusion; Pharmaceutical Preparations; Pharmacotherapy; Phospholipids; Population; Process; Prodrugs; Radiation therapy; Recurrence; Reporting; Resistance; Role; Solid Neoplasm; Source; Specificity; Structure; Testing; Therapeutic; Treatment Efficacy; Treatment outcome; blood-brain tumor barrier; brain tissue; cell motility; clinical translation; delivery vehicle; extracellular vesicles; fluorescence lifetime imaging; fluorophore; improved; in vivo; inhibitor; innovation; knock-down; lipid nanoparticle; lipid structure; lipophilicity; migration; nanoformulation; nanomedicine; nanoparticle; nanoparticle delivery; neoplastic cell; novel; novel strategies; particle; small molecule; spatiotemporal; success; tool; trafficking; transcytosis; tumor; tumor-immune system interactions; uptake

Project Abstract Glioblastoma (GBM) is the most devastating and aggressive brain tumor in adults, with patients surviving a median of only 14.6 months. Hidden behind the blood-brain and blood tumor-barrier (BBTB), the glioma cells migrating away from the tumor and invading surrounding brain tissue, are the source of recurrence. The invasive cells are not readily accessible to most drug therapeutics, and targeting these cells is an essential goal for achieving better treatment outcomes. Nanoparticles hold promise for drug delivery, but their penetration of the BBTB is limited, and the efficiency of targeting invasive cells remains unknown. We recently discovered that fluorescent indocarbocyanine lipids (ICLs) formulated in PEGylated Lipid Nanoparticles (PLNs) exhibit highly efficient glioma extravasation, with a single injection resulting in accumulation in ~60% of tumor cells and up to 30% of injected dose per gram of brain tumor. Furthermore, data in highly invasive models demonstrate PLNs reach invasive cells at the tumor/brain margin. These findings offer a unique opportunity to comprehensively understand the mechanism of accumulation of lipid nanoparticles and improve drug delivery to invasive gliomas. We will pursue the following specific aims: 1) Study the trafficking mechanism of ICLs across the BBTB and in tumors. In this aim, we will test the hypothesis that lipids migrate in tumors via extracellular vesicles; 2) Understand the role of lipid structure and formulation in targeting glioma cells and the tumor immune microenvironment. This aim will test if accumulation in invasive cells and immunosuppressive cells can be further improved through lipid chemistry, formulation and targeting to glioma marker IL13R2; 3) Exploit ICLs to understand and improve small molecule delivery to invasive gliomas. We will explore our previously developed chemistry to conjugate small molecules to ICLs to improve their delivery, drug release, and therapeutic efficacy of cyclin-dependent kinase inhibitor dinaciclib in invasive mouse and patient-derived glioma models. These studies will expand our understanding of the drug delivery process and guide treatment of invasive gliomas with brain tumor-penetrating nanomedicine.

项目摘要 胶质母细胞瘤（GBM）是成年人中最具破坏性和侵略性的脑肿瘤，患者存活 中位数仅为14.6个月。胶质瘤细胞隐藏在血脑和血肿瘤障碍物（BBTB）后面 从肿瘤迁移并侵入周围的脑组织，是复发的根源。这 大多数药物疗法都无法轻易获取侵入性细胞，而将这些细胞靶向是必不可少的 实现更好的治疗结果的目标。纳米颗粒有望提供药物，但 BBTB的渗透是有限的，靶向浸润细胞的效率仍然未知。我们最近 发现荧光吲哚氨基脂质（ICLS）在质脂质纳米颗粒（PLN）中配制 表现出高效的神经胶质瘤渗出，单个注射导致肿瘤的积累 细胞和每克脑肿瘤的注射剂量的30％。此外，高度侵入性模型中的数据 证明PLN在肿瘤/脑缘处达到浸润细胞。这些发现为 全面了解脂质纳米颗粒积累的机制并改善药物输送 侵入性神经胶质瘤。我们将追求以下具体目标：1）研究ICL的贩运机制 跨BBTB和肿瘤。在此目标中，我们将测试以下假设，即脂质通过 细胞外蔬菜； 2）了解脂质结构和配方在靶向神经胶质瘤细胞中的作用 和肿瘤免疫环境。此目标将测试是否积累在侵入性细胞和 通过脂质化学，可以进一步改善免疫抑制细胞，对神经胶质瘤进行配方和靶向 标记IL13R2; 3）利用ICL来理解和改善小分子递送到侵入性 神经胶质瘤。我们将探索我们先前开发的化学反应，以将小分子结合到ICLs以改进 它们的分娩，药物释放和细胞周期蛋白依赖性激酶抑制剂dinaciclib在侵入性中 小鼠和患者衍生的神经胶质瘤模型。这些研究将扩大我们对药物输送的理解 用脑肿瘤纳米医学的过程和指导侵入性神经胶质瘤的处理。