Inhibiting glioma invasion using targeted nanoparticles

描述（由申请人提供）：使用靶向纳米颗粒抑制胶质瘤侵袭高级别胶质瘤是一致致命的，即使在手术、替莫唑胺化疗和放疗后。肿瘤复发是由神经胶质瘤细胞的再生长引起的，神经胶质瘤细胞在正常脑中大范围浸润。神经胶质瘤样干细胞被认为引发肿瘤复发，因为它们可以长时间保持静止;这使得它们能够抵抗依赖于细胞分裂的细胞毒性剂和疗法（即，化疗、放疗）。对人类神经胶质瘤肿瘤（代表晚期症状性肿瘤）的神经病理学样本的检查表明，神经胶质瘤细胞沿着血管、白色束、细胞外间隙和软膜下迁移。然而，很难在分子水平上对其进行表征。 以及细胞细节，在人类肿瘤或实验性神经胶质瘤中的个体迁移路径。为了了解胶质瘤细胞初始侵袭的细胞基础，我们对胶质瘤细胞的特征进行了分析。 胶质瘤生长和侵袭的解剖学、生物化学和分子基础。我们最近发现许多胶质瘤细胞和胶质瘤干细胞可以优先沿着肿瘤和瘤周血管系统提供的网络生长。由于神经胶质瘤的离心侵袭是沿着肿瘤和瘤周血管发生的，我们现在的目标是靶向维持神经胶质瘤细胞侵袭整个大脑的血管。我们的初步数据表明，F3靶向的水凝胶纳米颗粒靶向支持胶质瘤细胞生长的肿瘤血管，胶质瘤细胞侵袭，以及胶质瘤细胞。在该R21应用中，我们提出测试生物相容性和生物可降解的、F3靶向的水凝胶纳米颗粒是否负载有治疗药物（即，顺铂、替莫唑胺）将杀死那些维持神经胶质瘤从中央肿瘤块分散到正常脑实质中的血管，以及主要的神经胶质瘤肿瘤。肽F3与核仁素结合，核仁素是一种由肿瘤血管系统和神经胶质瘤肿瘤过度表达的蛋白质，但不被正常大脑所表达。我们假设，选择性杀死肿瘤血管（利用F3靶向纳米粒子负载顺铂）将抑制胶质瘤的侵袭，与F3靶向纳米粒子负载替莫唑胺杀死主要的胶质瘤质量相结合。该提议将检验以下假设：组合的F3纳米颗粒介导的对提供胶质瘤侵袭底物的肿瘤血管和胶质瘤细胞的杀伤将减少胶质瘤生长和肿瘤复发。我们之前将基础科学进展转化为治疗恶性胶质瘤患者的早期临床试验（FDA IND-14574）的经验支持我们的断言，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GBM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.