Inhibiting glioma invasion using targeted nanoparticles

描述(申请人提供)：使用定向纳米颗粒抑制胶质瘤侵袭高级别胶质瘤是完全致命的，即使在手术、替莫唑胺化疗和放疗之后也是如此。肿瘤复发是由胶质瘤细胞的再生引起的，胶质瘤细胞在正常大脑中渗透很长距离。胶质瘤样干细胞被认为会引发肿瘤复发，因为它们可以长时间保持静止；这使得它们能够抵抗依赖细胞分裂的细胞毒剂和治疗(即化疗、放射治疗)。对人类神经胶质瘤肿瘤(代表晚期症状性肿瘤)的神经病理标本的检查表明，胶质瘤细胞沿血管、白质束、细胞外间隙和脑实质下迁移。然而，很难在分子水平上对其进行表征。 以及人类肿瘤或实验性胶质瘤中个体迁移路径的细胞细节。为了了解胶质瘤细胞最初侵袭的细胞学基础，我们正在表征 脑胶质瘤生长和侵袭的解剖、生化和分子基础。我们最近发现，许多胶质瘤细胞和胶质瘤干细胞可以沿着肿瘤和瘤周血管系统提供的网络优先生长。随着离心性胶质瘤的侵袭沿着肿瘤和瘤周血管发生，我们现在的目标是针对维持胶质瘤细胞侵袭整个大脑的血管。我们的初步数据表明，F3靶向水凝胶纳米颗粒靶向于支持胶质瘤细胞生长和胶质瘤细胞侵袭的肿瘤血管，以及胶质瘤细胞。在这项R21应用中，我们建议测试生物相容和生物可降解的F3靶向水凝胶纳米粒加载治疗药物(即顺铂、替莫唑胺)是否会杀死那些维持胶质瘤从中央肿瘤肿块扩散到正常脑实质的血管，以及主要的胶质瘤肿瘤。F3肽与核仁蛋白结合，核仁蛋白是一种在肿瘤血管和胶质瘤中过度表达的蛋白质，但在正常大脑中不表达。我们假设选择性杀伤肿瘤血管(利用F3靶向纳米颗粒负载顺铂)将抑制胶质瘤的侵袭，结合F3靶向纳米颗粒负载替莫唑胺杀死主要胶质瘤肿块。这项提议将检验这样一种假设，即结合F3-纳米颗粒介导的肿瘤血管杀伤为胶质瘤侵袭提供底物的肿瘤血管和胶质瘤细胞，将减少胶质瘤的生长和肿瘤复发。我们之前在将基础科学进展转化为治疗人类恶性胶质瘤患者的早期临床试验(FDA IND-14574)方面的经验支持了我们的断言，即如果实验支持我们提出的假设，我们将能够有效地将这些结果转化为针对脑胶质瘤患者的I期临床试验。

DESCRIPTION (provided by applicant): Inhibiting glioma invasion using targeted nanoparticles High grade gliomas are uniformly lethal, even following surgery, temozolomide chemotherapy and radiotherapy. Tumor recurrence is caused by regrowth of glioma cells which infiltrate large distances throughout the normal brain. Glioma-like stem cells are thought to initiate tumor recurrence as they can remain quiescent for a long time; this allows them to resist cytotoxic agents and therapies that rely on cell division (i.e., chemotherapy, radiotherapy). Examination of neuropathological samples of human glioma tumors (representing advanced symptomatic tumors) suggest that glioma cells migrate along blood vessels, white matter tracts, the extracellular space, and subpially. However, it has been difficult to characterize in molecular and cellular detail the individual migration paths in either human tumors or in experimental gliomas. To understand the cellular basis of initial glioma cell invasion we are characterizing the anatomical, biochemical and molecular basis for glioma growth and invasion. We have recently discovered that many glioma cells and glioma stem cells can grow preferentially along the network provided by the tumoral and peritumoral vasculature. As centrifugal glioma invasion occurs along tumoral and peritumoral vessels we now aim to target the blood vessels that sustain glioma cell invasion throughout the brain. Our preliminary data indicate that F3-targeted hydrogel nanoparticles target the tumoral blood vessels that support glioma cell growth, and glioma cell invasion, as well as glioma cells. In this R21 application we propose to test if biocompatible and bio-degradable, F3-targeted hydrogel nanoparticles loaded with therapeutic drugs (i.e., cisplatin, temozolomide) will kill those vessels that sustain glioma dispersion from the central tumor mass into normal brain parenchyma, as well as the main glioma tumors. The peptide F3 binds to nucleolin, a protein overexpressed by tumor vasculature and by glioma tumors, but not by normal brain. We hypothesize that selective killing of tumor blood vessels (utilizing F3-targeted nanoparticles loaded with cisplatin) will inhibit glioma invasion, in combination with F3-targeted nanoparticles loaded with temozolomide to kill the main glioma mass. This proposal will test the hypothesis that combined F3-nanoparticle mediated killing of tumor blood vessels providing the substrate for glioma invasion, and of glioma cells, will reduce glioma growth and tumor recurrence. Our previous experience in the translation of basic science advances into early phase clinical trials for the treatment of human patients suffering from malignant glioma (FDA IND-14574), supports our assertion that, should experiments support our proposed hypothesis, we will be able to efficiently translate such results into Phase I clinica trials for GBM patients.