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

标题：一种用于图像引导药物输送治疗脑部恶性肿瘤的棒状纳米治疗平台 项目摘要/摘要 我们的长期目标是设计一种新的、可推广的药物输送平台，以改善各种不同药物的输送 一系列脑部恶性肿瘤和神经系统疾病的有效载荷。有效载荷可以是成像剂， 化疗药物、分子靶向药物和免疫治疗药物。我们确定了以下主要障碍 脑恶性肿瘤的成功治疗：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)药代动力学较差 (PK)和3)药物不能穿透肿瘤组织，以及4)肿瘤细胞输送缺乏特异性；导致 治疗效果差，且有脱靶毒性。为此，我们提出了一种综合方法来缓解这些问题 生理障碍和中介药物输送，以确保疾病靶向特异性。这次修订的目标是 R01的更新应用是在交联(棒)纳米递送中开发一种新的顺序靶向 改善脑部恶性肿瘤药物输送的平台。拟议中的棍棒的特点 纳米粒子(棒状NP)使其能够克服多种障碍，深入渗透到脑部恶性肿瘤中。在……里面 目的1、我们将通过设计新型的硼酸盐交联剂来设计新的棒状NPs，以改善其性能 CNS PK最大时间窗增强葡萄糖转运蛋白(GLUT1)介导的细胞转运 横跨BBB/BBTB。新的交联剂还增强了对pH响应的尺寸转换 改善肿瘤组织穿透性和唾液酸靶向选择性，以增强肿瘤细胞特异性。我们的 之前的R01基金专注于低级别脑瘤，并作为这一领域合乎逻辑但独特的延伸 研究主题，我们目前项目的目标是弥漫性中线胶质瘤(DMG，以前称为弥漫性本征 桥脑胶质瘤(DIPG)，是一种高级别和最具侵袭性的儿童胶质瘤。DMG是第二个 最常见的原发性高级别脑瘤发生在儿童，中位生存期为1年。 DMG的诊断和五年存活率仅为2%左右。组蛋白3-赖氨酸的发现 27-甲硫氨酸(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 疾病。在AIM2中，我们将定量确定新工程的时空分布 原位DMG患者来源异种移植(PDX)模型中粘贴NPs及其释放的研究 通过光学成像、磁共振成像、液-质联用(LC-MS)研究机理 MS)，以及一系列生物物理方法。在Aim3中，两种有希望的表观遗传药物(Panobinostat和Panobinostat) ONC201)将通过在选定的棒状NPs内包裹的方式专门传递到DMG，用于表观遗传 心理治疗。在肿瘤微环境中的有效性、毒性和分子反应将在 原位PDX模型和基因工程小鼠DMG模型。这个项目有很大的优势 有可能显著改善DMG治疗的临床结果。这一概念也可以应用于 改善许多其他脑恶性肿瘤的治疗，如胶质母细胞瘤和脑转移瘤。

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.