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) 是成人中最具破坏性和侵袭性的脑肿瘤，患者经过一段时间后仍能存活 中位数仅为 14.6 个月。神经胶质瘤细胞隐藏在血脑和血液肿瘤屏障（BBTB）后面 远离肿瘤并侵入周围脑组织是复发的根源。这 大多数药物疗法不容易接触到侵袭性细胞，因此靶向这些细胞是至关重要的 达到更好的治疗效果的目标。纳米颗粒有望用于药物输送，但它们的 BBTB 的穿透能力有限，并且靶向侵袭细胞的效率仍然未知。我们最近 发现在聚乙二醇化脂质纳米颗粒 (PLN) 中配制的荧光吲哚羰花青脂质 (ICL) 表现出高效的神经胶质瘤外渗，单次注射即可在约 60% 的肿瘤中积聚 细胞和每克脑肿瘤注射剂量的 30%。此外，高度侵入性模型中的数据 证明 PLN 到达肿瘤/脑边缘的侵袭性细胞。这些发现提供了一个独特的机会 全面了解脂质纳米粒蓄积机制，改善药物递送 侵袭性胶质瘤。我们将追求以下具体目标：1）研究ICL的贩运机制 穿过 BBTB 和肿瘤。为此，我们将检验脂质通过以下方式在肿瘤中迁移的假设： 细胞外囊泡； 2) 了解脂质结构和配方在靶向神经胶质瘤细胞中的作用 和肿瘤免疫微环境。该目标将测试侵袭性细胞中的积累是否和 通过脂质化学、制剂和靶向神经胶质瘤可以进一步改善免疫抑制细胞 标记IL13Rα2； 3) 利用 ICL 来了解和改进小分子向侵入性药物的递送 神经胶质瘤。我们将探索我们之前开发的化学方法，将小分子与 ICL 结合，以改善 细胞周期蛋白依赖性激酶抑制剂 dinaciclib 在侵入性治疗中的递送、药物释放和治疗效果 小鼠和患者来源的神经胶质瘤模型。这些研究将扩大我们对药物输送的理解 用脑肿瘤穿透纳米药物处理和指导侵袭性胶质瘤的治疗。