Inhibiting glioma invasion using targeted nanoparticles

使用靶向纳米粒子抑制神经胶质瘤侵袭

• 批准号: 8666093
• 负责人: Pedro R Lowenstein
• 金额: $ 22.8万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-07-01 至 2016-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8666093
• 关键词: Address; Amino Acids; Animals; Anoikis; Apoptosis; Back; Basic Science; Binding; Biochemical; Biocompatible; Blood Vessels; Brain; Brain Neoplasms; Cell division; Cell membrane; Cells; Cisplatin; Clinical Treatment; Clinical Trials; Cytoplasm; Cytotoxic Chemotherapy; Cytotoxic agent; Cytotoxin; Data; Endothelial Cells; Extracellular Space; Galectin 1; Glioma; Glycoproteins; Growth; High Mobility Group Proteins; Homing; Human; Hydrogels; Implant; In Vitro; Individual; Malignant Glioma; Malignant neoplasm of brain; Mediating; Molecular; Neoplasms in Vascular Tissue; Nucleolar Proteins; Operative Surgical Procedures; Patients; Peptides; Pharmaceutical Preparations; Phase; Proteins; Radiation therapy; Recurrence; Rodent; Sampling; Stem cells; Structure; Testing; Therapeutic; Time; Translating; Translations; U251; base; beryllium trifluoride; cell growth; cell motility; chemotherapy; cytotoxicity; cytotoxicity test; experience; in vivo Model; killings; migration; nanoparticle; neoplastic cell; novel strategies; nucleolin; overexpression; public health relevance; research study; stem; temozolomide; therapy resistant; tumor; tumor growth; white matter

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.

描述（由申请人提供）：使用靶向纳米颗粒抑制神经胶质瘤侵袭高级神经胶质瘤也是均匀致命的，即使是手术，替莫唑胺化疗和放疗。肿瘤复发是由神经胶质瘤细胞的再生长引起的，胶质瘤细胞在整个正常大脑中渗透了较大的距离。胶质瘤样干细胞被认为会引起肿瘤复发，因为它们可以长期保持静止。这使他们能够抵抗依赖细胞分裂的细胞毒性剂和疗法（即化学疗法，放疗）。检查人神经胶质瘤肿瘤的神经病理学样本（代表晚期症状肿瘤）表明胶质瘤细胞沿血管，白质区，细胞外空间和细胞外空间迁移。但是，很难在分子中表征 和细胞细节人类肿瘤或实验胶质瘤中的个体迁移路径。为了了解初始神经胶质瘤细胞侵袭的细胞基础，我们正在表征 胶质瘤生长和侵袭的解剖学，生化和分子基础。我们最近发现，许多神经胶质瘤细胞和神经胶质瘤干细胞可以沿肿瘤和周围脉管系统提供的网络优先生长。随着离心神经瘤侵袭发生在肿瘤和周围血管上，我们现在旨在靶向维持整个大脑中神经胶质瘤细胞侵袭的血管。我们的初步数据表明，F3靶向的水凝胶纳米颗粒的靶向支持神经胶质瘤细胞生长和神经胶质瘤细胞侵袭的肿瘤血管以及神经胶质瘤细胞。在此R21应用中，我们建议测试装有治疗药物的可生物相容性和生物降解，f3靶向的水凝胶纳米颗粒（即，顺铂，替莫唑胺）将杀死那些维持中枢性肿瘤质量的胶质瘤量的容器，并杀死主要脑肿瘤中的正常脑肿瘤，以及主要的glioma肿瘤。肽F3与核仁蛋白结合，核酸素蛋白是一种由肿瘤脉管系统和神经胶质瘤肿瘤过表达的蛋白质，但不受正常脑的蛋白质。我们假设选择性杀死肿瘤血管（利用带有顺铂的F3靶向纳米颗粒）将抑制神经胶质瘤的侵袭，并结合F3靶向的纳米颗粒，含有替诺佐剂的纳米颗粒，以杀死主腹膜瘤质量。该提案将检验以下假设：F3-纳米粒子介导的肿瘤血管杀死提供胶质瘤侵袭的肿瘤血管和神经胶质瘤细胞，将减少神经胶质瘤的生长和肿瘤复发。我们以前在将基础科学进步转化为早期临床试验中的经验，用于治疗患有恶性神经胶质瘤患者的患者（FDA IND-14574），支持我们的断言，即如果实验支持我们提出的假设，我们将能够将这种结果有效地转化为GBM患者的I期临床试验。

项目成果

Hydrogel Nanoparticles with Thermally Controlled Drug Release.

• DOI: 10.1021/mz500231e
• 发表时间: 2014-07-15
• 期刊: ACS macro letters
• 影响因子: 7.015
• 作者: Shirakura T;Kelson TJ;Ray A;Malyarenko AE;Kopelman R
• 通讯作者: Kopelman R

Matrix Density Engineering of Hydrogel Nanoparticles with Simulation-Guided Synthesis for Tuning Drug Release and Cellular Uptake.

水凝胶纳米粒子的基质密度工程与模拟引导合成用于调节药物释放和细胞摄取。

• DOI: 10.1021/acsomega.7b00590
• 发表时间: 2017
• 期刊: ACS omega
• 影响因子: 4.1
• 作者: Shirakura,Teppei;Smith,Christof;Hopkins,ThomasJohnJames;KooLee,Yong-Eun;Lazaridis,Filippos;Argyrakis,Panos;Kopelman,Raoul
• 通讯作者: Kopelman,Raoul