A “STICK” theranostic nanoplatform for image-guided drug delivery to brain malignancies

用于图像引导药物输送至脑部恶性肿瘤的“STICK”治疗诊断纳米平台

• 批准号: 10528326
• 负责人: Yuanpei Li
• 金额: $ 61.01万
• 依托单位: UNIVERSITY OF CALIFORNIA AT DAVIS
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-12-18 至 2026-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10528326
• 关键词: Acidosis; Acids; Address; Binding; Biodistribution; Blood; Blood - brain barrier anatomy; Blood Circulation; Boronic Acids; Brain; Brain Neoplasms; Cell surface; Characteristics; Child; Childhood; Childhood Glioma; Clinical; Clinical Management; Development; Diagnosis; Diffuse intrinsic pontine glioma; Disease; Drug Delivery Systems; Drug Kinetics; Drug Targeting; Endothelium; Engineering; Ensure; Epigenetic Process; Excision; Feasibility Studies; Genetic Engineering; Genetically Engineered Mouse; Glioblastoma; Glucose; Glucose Transporter; Glycoproteins; Goals; Grant; Heterogeneity; Histology; Histones; Immunotherapeutic agent; Lysine; Magnetic Resonance Imaging; Malignant Neoplasms; Mediating; Metastatic malignant neoplasm to brain; Methionine; Microdialysis; Modeling; Molecular; Monitor; Mus; Mutation; Nano delivery; Neuraxis; Normal tissue morphology; Outcome; Patients; Penetration; Pharmaceutical Preparations; Physiological; Radiation; Research; Scheme; Series; Sialic Acids; Site; Specificity; Surface; Survival Rate; Symptoms; Therapeutic; Therapeutic Index; Therapeutic Use Study; Time; Tissues; Toxic effect; Translations; Treatment Efficacy; Treatment-related toxicity; Tumor Burden; Tumor Tissue; base; biophysical techniques; blood-brain tumor barrier; clinical development; crosslink; design; diffuse midline glioma; epigenetic drug; epigenetic therapy; image guided; image-guided drug delivery; imaging agent; improved; in vivo; liquid chromatography mass spectrometry; molecular drug target; molecular imaging; nanoparticle; nanotechnology platform; nanotheranostics; neoplastic cell; nervous system disorder; neuro-oncology; novel; optical imaging; overexpression; patient derived xenograft model; premature; response; spatiotemporal; theranostics; therapeutically effective; three-dimensional modeling; transcytosis; tumor; tumor microenvironment; tumor progression; tumor specificity; tumor-specific gene delivery

Title: A “STICK” theranostic nanoplatform for image-guided drug delivery to brain malignancies Project Summary/Abstract Our long-term goal is to engineer a new and generalizable drug delivery platform to improve the delivery of various payloads to a series of brain malignancies and neurological disorders. The payloads can be imaging agents, chemotherapeutics, molecularly targeted drugs and immunotherapeutics. We identified the following major barriers for successful treatment of brain malignancies: 1) the blood-brain barrier/blood-brain tumor barrier (BBB/BBTB), 2) severe destabilizing effect in blood circulation that leads to a poor central nervous system (CNS) pharmacokinetics (PK) and 3) inability for agents to penetrate tumor tissue, and 4) lack of specificity for tumor cell delivery; resulting in poor treatment efficacy and off-target toxicity. To this end, we propose an integrated approach to mitigate these physiological barriers and mediate drug delivery to ensure disease targeting specificity. The goal of this revised R01 renewal application is to develop a new Sequential Targeting In CrosslinKing (STICK) nano-delivery platform to improve the drug delivery to brain malignancies. The characteristics of the proposed STICK nanoparticle (STICK NP) allow it to overcome the multiple barriers to penetrate deeply in brain malignancies. In Aim1, we will engineer new STICK NPs by designing new types of boronate crosslinkages to improve their CNS PK to maximize the time window to enhance the glucose transporter (GLUT1)-mediated transcytosis across the BBB/BBTB. The new crosslinkages also enhance the pH-responsive size transformation for improved tumor tissue penetration and sialic acid-targeting selectivity for enhanced tumor cell specificity. Our previous R01 grant focused on low grade brain tumors and as a logical but distinctive extension in this research topic, the target of our current project is diffuse midline glioma (DMG, previously called Diffuse Intrinsic Pontine Glioma (DIPG)), a high grade and the most aggressive form of pediatric glioma. DMG is the second most common type of primary, high grade brain tumor occurring in children with a median survival <1 year from diagnosis and the five-year survival rate of DMG is only around 2%. Discovery of the characteristic Histone 3-Lysine- 27-Methionine (H3K27M) mutation offers opportunity for development of targeted epigenetic therapies for this deadly disease. In Aim2, we will quantitatively determine the spatiotemporal distribution of the newly engineered STICK NPs in orthotopic DMG patient-derived xenograft (PDX) models and elucidate their delivery mechanisms by optical imaging, magnetic resonance imaging, liquid chromatography-mass spectrometry (LC- MS), and a series of biophysical approaches. In Aim3, two promising epigenetic drugs (panobinostat and ONC201) will be specifically delivered to DMG by encapsulations within selected STICK NPs for epigenetic therapy. The efficacy, toxicity, and molecular responses in tumor microenvironment will be investigated in orthotopic PDX models and genetically engineered murine (GEM) DMG models. This project has the great potential to significantly improve the clinical outcomes of DMG treatment. This concept can also be applied to improve the treatment of many other brain malignancies such as glioblastoma and brain metastases.

标题：用于图像引导的脑恶性肿瘤的“棍子” Theranotic纳米植物术 项目摘要/摘要 我们的长期目标是设计一个新的且可推广的药物输送平台，以改善各种的交付 有效载荷会导致一系列大脑恶性肿瘤和神经系统疾病。有效载荷可以是成像代理， 化学治疗药，分子靶向药物和免疫治疗药。我们确定了以下主要障碍 大脑恶性肿瘤的成功治疗：1）血脑屏障/血脑肿瘤屏障（BBB/BBTB），2） 在血液循环中的严重不稳定作用，导致中枢神经系统（CNS）药代动力学不良 （PK）和3）药物无法穿透肿瘤组织，4）缺乏针对肿瘤细胞递送的特异性；导致 治疗效率不佳和靶向毒性。为此，我们提出了一种减轻这些方法的综合方法 生理障碍并介导药物递送，以确保针对疾病的特异性。这个修订的目标 R01更新应用是在交联（棒）纳米交叉中开发新的顺序定位 改善药物输送到大脑恶性肿瘤的平台。拟议棍子的特征 纳米颗粒（Stick NP）使其可以克服多个屏障，以深入脑恶性肿瘤。在 AIM1，我们将通过设计新型的硼酸交联以改善其新型NPS NP CNS PK最大化时间窗口以增强葡萄糖转运蛋白（GLUT1）介导的跨经细胞增多症 跨BBB/BBTB。新的交联还增强了pH响应尺寸的转换 改善了肿瘤组织的穿透性和唾液酸靶向选择性，可增强肿瘤细胞特异性。我们的 以前的R01赠款重点是低级脑肿瘤，并作为逻辑但独特的扩展 研究主题，我们当前项目的目标是弥漫性中线神经胶质瘤（DMG，以前称为弥漫性固有性 蓬托神经胶质瘤（DIPG）），一种高级和最具侵略性的小儿神经胶质瘤。 DMG是第二个 最常见类型的原发性，高级脑肿瘤发生在中位生存率<1年的儿童中 DMG的诊断和五年生存率仅约2％。发现特征性组蛋白3-赖氨酸的发现 27-甲硫代（H3K27M）突变为为此致命开发有针对性的表观遗传疗法提供了机会 疾病。在AIM2中，我们将定量确定新设计的时空分布 将NPS贴在原位DMG患者衍生的Xenographic（PDX）模型中，并阐明其输送 通过光学成像，磁共振成像，液相色谱 - 质量光谱法（LC-）的机制（LC- MS）和一系列生物物理方法。在AIM3中，两种有前途的表观遗传药物（Panobinobinostat和 ONC201）将通过选定的Stick NP中的表观遗传学中的封装来专门传递到DMG 治疗。肿瘤微环境中的效率，毒性和分子反应将在 原位PDX模型和一般设计的鼠（GEM）DMG模型。这个项目很棒 显着改善DMG治疗的临床结果的潜力。这个概念也可以应用于 改善许多其他脑恶性肿瘤的治疗，例如胶质母细胞瘤和脑转移。