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

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瘤，患者的存活率为 中位数仅为14.6个月。隐藏在血脑和血肿瘤屏障(BBTB)后面的是胶质瘤细胞 远离肿瘤和侵犯周围脑组织是复发的来源。这个 侵袭性细胞不容易被大多数药物治疗所获得，而靶向这些细胞是必不可少的 实现更好的治疗结果的目标。纳米颗粒有望实现药物输送，但它们的 BBTB的渗透性有限，靶向侵袭细胞的效率尚不清楚。我们最近 发现在聚乙二醇化脂质纳米粒(PLN)中形成的荧光吲哚菁脂(ICL) 表现出高效的胶质瘤外渗，单次注射可导致约60%的肿瘤积聚 细胞和高达每克脑瘤注射剂量的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来 全面了解脂质纳米粒蓄积机制，改善药物释放 到侵袭性胶质瘤。我们将追求以下具体目标：1)研究ICL的贩运机制 在BBTB和肿瘤中。在这个目标中，我们将检验这样一种假设，即脂类通过 细胞外小泡；2)了解脂质结构和制剂在靶向胶质瘤细胞中的作用 和肿瘤免疫微环境。这一目标将测试侵袭性细胞和 免疫抑制细胞可以通过脂质化学、制剂和针对胶质瘤的靶向来进一步改进 标记物IL13R2；3)利用ICL了解和改进对侵袭性小分子的递送 神经胶质瘤。我们将探索我们以前开发的将小分子偶联到ICL的化学方法，以改进 细胞周期蛋白依赖性激酶抑制剂地那昔利在侵袭性治疗中的给药、释药和疗效 小鼠和患者来源的胶质瘤模型。这些研究将扩大我们对药物传递的理解 脑肿瘤穿透性纳米药物治疗侵袭性胶质瘤的过程和指导。

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.