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）是成年人中最具破坏性和侵袭性的脑肿瘤，患者存活时间为 平均14.6个月。胶质瘤细胞隐藏在血脑和血肿瘤屏障（BBTB）后面， 从肿瘤转移并侵入周围脑组织是复发的来源。的 大多数药物治疗剂不容易接近侵入性细胞，并且靶向这些细胞是必需的。 以达到更好的治疗效果。纳米颗粒有望用于药物输送，但它们的 BBTB的穿透是有限的，并且靶向侵入性细胞的效率仍然未知。我们最近 发现配制在聚乙二醇化脂质纳米颗粒（PLN）中的荧光吲哚羰花青脂质（ICL） 表现出高效的胶质瘤外渗，单次注射导致约60%的肿瘤蓄积 细胞和高达30%的注射剂量每克脑肿瘤。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的蓄积机制，提高药物释放 到侵袭性神经胶质瘤我们会致力达致以下的具体目的：1）研究非法入境者的贩卖机制 在BBTB和肿瘤中。在这个目标中，我们将检验脂质通过以下途径在肿瘤中迁移的假设： 细胞外囊泡; 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。这一目标将测试是否在侵入性细胞中积累， 免疫抑制细胞可以通过脂质化学、配制和靶向胶质瘤来进一步改进 标志物IL 13 R β 2; 3）利用ICL来理解和改善小分子递送至侵袭性肿瘤; 神经胶质瘤我们将探索我们以前开发的化学方法，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的递送、药物释放和在侵袭性 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。

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.