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

基本信息

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
项目类别：
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

项目摘要

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：用于图像引导药物输送至脑恶性肿瘤的“STICK”治疗诊断纳米平台项目概要/摘要我们的长期目标是设计一个新的、通用的药物输送平台，以改善各种药物的输送有效载荷可以是一系列脑恶性肿瘤和神经系统疾病的有效载荷，我们发现化疗、分子靶向药物和免疫治疗存在以下主要障碍。成功治疗脑部恶性肿瘤：1）血脑屏障/血脑肿瘤屏障（BBB/BBTB），2）血液循环严重不稳定，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) 缺乏肿瘤细胞递送特异性；为此，我们提出了一种综合方法来减轻这些问题。生理学和介导药物递送以确保疾病靶向特异性是本次修订的目标障碍。 R01更新申请是开发新的Sequential Targeting In CrosslinKing (STICK)纳米递送改善脑恶性肿瘤药物输送的平台所提出的 STICK 的特点。纳米颗粒（STICK NP）使其能够克服多重障碍，深入渗透到脑部恶性肿瘤中。目标1，我们将通过设计新型硼酸酯交联键来设计新的 STICK NP，以改善其性能 CNS PK 最大化时间窗口以增强葡萄糖转运蛋白 (GLUT1) 介导的转胞吞作用新的交联还增强了 BBB/BBTB 的 pH 响应尺寸转换。改善肿瘤组织渗透性和唾液酸靶向选择性，从而增强肿瘤细胞特异性。之前的 R01 资助重点关注低级别脑肿瘤，并作为该领域合乎逻辑但独特的扩展研究课题，我们当前项目的目标是弥漫性中线胶质瘤（DMG，以前称为弥漫性内在性胶质瘤）脑桥胶质瘤 (DIPG) 是一种高级别且最具侵袭性的儿童 DMG。最常见的原发性高级别脑肿瘤，发生于中位生存期 <1 年的儿童中诊断和 DMG 的五年生存率仅为 2% 左右。 27-蛋氨酸 (H3K27M) 突变为开发针对这种致命疾病的靶向表观遗传疗法提供了机会在 Aim2 中，我们将定量确定新设计的疾病的时空分布。在原位 DMG 患者来源的异种移植 (PDX) 模型中粘贴 NP 并阐明其递送通过光学成像、磁共振成像、液相色谱-质谱（LC- MS），以及一系列生物物理方法，在 Aim3 中，两种有前途的表观遗传药物（panobinostat 和）。 ONC201）将通过封装在选定的 STICK NP 中专门递送至 DMG，以进行表观遗传治疗的功效、毒性和肿瘤微环境中的分子反应将在以下研究中进行研究。原位 PDX 模型和基因工程小鼠 (GEM) DMG 模型非常出色。显着改善 DMG 治疗临床结果的潜力这一概念也可应用于改善许多其他脑部恶性肿瘤的治疗，例如胶质母细胞瘤和脑转移瘤。