Intrathecal delivery of radiation sensitizing nanoparticles in pediatric neuro-oncology

放射增敏纳米颗粒在儿科神经肿瘤学中的鞘内递送

• 批准号: 10653853
• 负责人: Rachael W Sirianni
• 金额: $ 71.15万
• 依托单位: UNIV OF MASSACHUSETTS MED SCH WORCESTER
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-08-02 至 2024-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10653853
• 关键词: 3-Dimensional; Angiopoietin-2; Bar Codes; Binding; Blood; Brain; Catheters; Cells; Central Nervous System; Cerebrospinal Fluid; Charge; Child; Childhood; Childhood Brain Neoplasm; Childhood Malignant Brain Tumor; Clinic; Clinical; Clinical Data; Data; Development; Diagnosis; Diffuse; Disease; Dose; Drug Delivery Systems; Drug Kinetics; Drug or chemical Tissue Distribution; Encapsulated; Endocrine System Diseases; Engineering; Excision; Exhibits; Foundations; Genetic Engineering; Glioma; Growth; Histones; Human; Image; Infiltration; Infratentorial Neoplasms; Infusion procedures; Intrathecal Space; Label; Lesion; Libraries; Ligands; Macaca mulatta; Malignant neoplasm of brain; Maps; Measures; Metabolic Clearance Rate; Metastatic Neoplasm to the Leptomeninges; Methods; Modeling; Multimodal Imaging; Nanotechnology; Neoplasm Metastasis; Nervous System; Operative Surgical Procedures; Patients; Penetration; Peptide Receptor; Pharmaceutical Preparations; Pharmacodynamics; Polymers; Positron-Emission Tomography; Predisposition; Quantum Dots; Radiation; Radiation Dose Unit; Radiation induced damage; Radiation therapy; Radiosensitization; Research Personnel; Resected; Resolution; Safety; Secondary to; Spatial Distribution; Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization; Spinal Cord; Subarachnoid Space; Surface; Surface Properties; Survival Rate; System; Therapeutic; Tissues; Toxic effect; Vascularization; Water; Work; biocompatible polymer; biodegradable polymer; biomaterial compatibility; burden of illness; cancer cell; chemotherapy; cisterna magna; clinical application; clinical translation; cognitive function; design; drug action; drug distribution; drug efficacy; effective therapy; efficacy evaluation; experience; fractionated radiation; imaging approach; improved; inhibitor; medulloblastoma; miniaturize; mouse model; nanolabel; nanoparticle; nanoparticle delivery; nanoscale; neuro-oncology; neurosurgery; nonhuman primate; novel; novel strategies; pre-clinical; radiation delivery; reconstruction; safety assessment; small molecule

PROJECT SUMMARY / ABSTRACT Although survival rates for children diagnosed with a primary malignant brain tumor have improved, radiation induced damage to the developing nervous system remains a significant problem. Few treatment options are available once malignant cells have metastasized to the leptomeninges that surround the brain and spinal cord. Leptomeningeal metastasis (LM) cannot be surgically resected, and systemic chemotherapy is hindered by the presence of the blood-brain and blood-spinal cord barriers, leaving high dose craniospinal radiation as the only effective treatment option. Some investigators have administered therapeutics directly into the intrathecal space with the hope that locally administered drugs will better reach LM. However, action of intrathecally administered agents is limited by rapid clearance and inadequate tissue penetration as cerebrospinal fluid (CSF) turns over. Furthermore, most traditional chemotherapeutics are poorly water soluble and cannot be administered to the CSF at relevant concentrations. We have recently developed a novel approach for encapsulating the histone deacetyle inhibitor (HDACI) quisinostat within biodegradable and biocompatible NPs (QNPs). Our preliminary data demonstrate that intrathecally administered NPs distribute readily across the surfaces of the brain and spinal cord, are well retained within the subarachnoid space, and localize with lesions to slow the growth of LM in a murine model of metastatic medulloblastoma. Here, we propose a comprehensive approach for optimizing the design of radiation sensitizing NPs for intrathecal drug delivery to treat LM. These NPs serve not just as a stationary depot to prolong drug presence in the central nervous system but as mobile carriers that we predict will selectively sensitize metastatic lesions to radiation. We will, (1) engineer the surface of NPs to further improve their localization with LM, (2), determine the relationship between drug delivery and efficacy in models of medulloblastoma, and, (3), establish species scaling of direct-to-CSF nanoparticle delivery. Treatments will be evaluated in patient derived and genetically engineered models of medulloblastoma exhibiting LM. Fluorescent barcoding, matrix assisted laser desorption ionization (MALDI), and positron emission tomography (PET) imaging approaches will be used to precisely localize NP and drug delivery to LM with quantitative, cellular-level resolution. By directly pairing multiple measures of delivery, activity, and efficacy, we expect to develop a comprehensive understanding of barriers to effective drug delivery within the subarachnoid space. Most importantly, these studies will advance new nanotechnology toward the clinic for better treatment of pediatric brain tumors.

项目摘要 /摘要 尽管诊断为原发性恶性脑肿瘤的儿童的存活率有所改善，但辐射 诱发对发展中神经系统的损害仍然是一个重大问题。很少有治疗选择是 一旦恶性细胞转移到围绕大脑和脊髓的瘦素转移。 瘦脑脑转移（LM）无法通过手术切除，并且全身化疗受到 血脑和血脊髓屏障的存在，使高剂量的颅脊髓辐射作为唯一 有效的治疗选择。一些研究人员已将治疗药直接用于鞘内空间 希望本地使用的药物可以更好地达到LM。但是，暂时给予的行动 当脑脊液（CSF）翻转时，药物受到快速清除和组织穿透不足的限制。 此外，大多数传统的化学治疗药都是水溶性的，不能给予 CSF相关浓度。我们最近开发了一种封装组蛋白的新方法 甲状腺抑制剂（HDACI）在可生物降解和生物相容性NP（QNP）中。我们的初步 数据表明，固定的固定施用的NP在大脑的表面上很容易分布 脊髓良好保留在蛛网膜下腔空间内，并用病变定位以减慢LM的生长 在转移性髓母细胞瘤的鼠模型中。在这里，我们提出了一种全面的优化方法 辐射敏化NP的设计用于鞘内药物递送以治疗LM。这些NP不仅是 固定仓库以延长中枢神经系统中的药物存在，但作为移动载体，我们预测 将有选择地将转移性病变敏感到辐射。我们将（1）设计NP的表面以进一步改进 它们与LM（2）的本地化确定药物输送与功效之间的关系 髓母细胞瘤和（3），建立直接到CSF纳米粒子递送的物种缩放。治疗将是 在表现出LM的髓母细胞瘤的患者衍生和基因工程模型中评估。荧光 条形码，基质辅助激光解吸电离（MALDI）和正电子发射断层扫描（PET） 成像方法将使用定量，细胞级的精确定位NP和药物输送到LM 解决。通过直接配对多种交付，活动和功效的度量，我们希望开发一个 全面理解在亚蛛网膜下腔内有效药物输送的障碍。最多 重要的是，这些研究将使新的纳米技术向诊所推进，以更好地治疗小儿 脑肿瘤。

项目成果

Infusion of 5-Azacytidine (5-AZA) into the fourth ventricle or resection cavity in children with recurrent posterior Fossa Ependymoma: a pilot clinical trial.

将 5-氮杂胞苷 (5-AZA) 输注到患有复发性后窝室管膜瘤的儿童的第四脑室或切除腔中：一项试点临床试验。

• DOI: 10.1007/s11060-018-03055-1
• 发表时间: 2019
• 期刊: Journal of neuro-oncology
• 影响因子: 3.9
• 作者: Sandberg,DavidI;Yu,Bangning;Patel,Rajan;Hagan,John;Miesner,Emilie;Sabin,Jennifer;Smith,Sarah;Fletcher,Stephen;Shah,ManishN;Sirianni,RachaelW;Taylor,MichaelD
• 通讯作者: Taylor,MichaelD

High-dose MTX110 (soluble panobinostat) safely administered into the fourth ventricle in a nonhuman primate model.

• DOI: 10.3171/2020.2.peds19786
• 发表时间: 2020-08-01
• 期刊: Journal of neurosurgery. Pediatrics
• 作者: Sandberg DI;Kharas N;Yu B;Janssen CF;Trimble A;Ballester LY;Patel R;Mohammad AS;Elmquist WF;Sirianni RW
• 通讯作者: Sirianni RW