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: 10684109
• 负责人: Yuanpei Li
• 金额: $ 61.2万
• 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/10684109
• 关键词: Acidosis; Acids; Address; Binding; Biodistribution; Blood; Blood - brain barrier anatomy; Blood Circulation; Boronic Acids; Brain; Brain Neoplasms; Cell surface; Central Nervous System; Characteristics; Child; Childhood; Childhood Glioma; Circulation; Clinical; Clinical Management; Development; Diagnosis; Diffuse intrinsic pontine glioma; Disease; Drug Delivery Systems; Drug Kinetics; Drug Targeting; Encapsulated; Endothelium; Engineering; Ensure; Epigenetic Process; Excision; Feasibility Studies; 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; Mutation; Nanodelivery; 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; biophysical techniques; blood-brain barrier crossing; blood-brain tumor barrier; clinical development; crosslink; design; diffuse midline glioma; epigenetic drug; epigenetic therapy; glycemic control; image guided; image-guided drug delivery; imaging agent; improved; in vivo; liquid chromatography mass spectrometry; molecular drug target; molecular imaging; mouse model; 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; uptake

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：用于脑恶性肿瘤图像引导药物递送的“STICK”治疗诊断纳米平台 项目总结/摘要 我们的长期目标是设计一个新的和可推广的药物输送平台，以改善各种药物的输送。 一系列脑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， 化学治疗剂、分子靶向药物和免疫治疗剂。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）药剂不能穿透肿瘤组织，和4）缺乏肿瘤细胞递送的特异性;导致 治疗效果差和脱靶毒性。为此，我们提出了一个综合的方法来减轻这些 生理屏障和介导药物递送，以确保疾病靶向特异性。本次修订的目标 R 01更新申请是为了开发一种新的交联序贯靶向（STICK）纳米递送 平台，以改善药物输送到脑恶性肿瘤。建议的STICK的特性 纳米颗粒（STICK NP）使其能够克服多重障碍，深入穿透脑恶性肿瘤。在 目标1，我们将通过设计新型的硼酸酯交联来设计新的STICK NP，以改善它们的性能。 CNS PK，以最大化时间窗，增强葡萄糖转运蛋白（GLUT 1）介导的胞吞转运 通过BBB/BBTB。新的交联还增强了pH响应性大小转化， 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 以前的R 01拨款集中在低级别脑肿瘤，作为一个逻辑，但独特的延伸，在这方面 研究课题，我们目前的项目的目标是弥漫性中线胶质瘤（DMG，以前称为弥漫性内在 脑桥胶质瘤（DIPG）），一种高级别和最具侵袭性的儿科胶质瘤。DMG是第二个 最常见的原发性高级别脑肿瘤发生在儿童中，中位生存期<1年， DMG的五年生存率仅为2%左右。组蛋白3-赖氨酸的发现- 27-甲硫氨酸（H3 K27 M）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。 疾病在目标2中，我们将定量确定新工程的时空分布， STICK NP在原位DMG患者来源的异种移植物（PDX）模型中的作用并阐明其递送 通过光学成像、磁共振成像、液相色谱-质谱（LC-MS） MS）和一系列生物物理方法。在Aim 3中，两种有前途的表观遗传药物（帕比司他和 ONC 201）将通过在所选STICK NP内的修饰特异性地递送至DMG，用于表观遗传修饰。 疗法肿瘤微环境中的疗效、毒性和分子反应将在 原位PDX模型和基因工程鼠（GEM）DMG模型。这个项目有很大的 有可能显著改善DMG治疗的临床结局。这个概念也可以应用于 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。

项目成果

Sub-100nm, long tumor retention SN-38-loaded photonic micelles for tri-modal cancer therapy.

• DOI: 10.1016/j.jconrel.2017.07.014
• 发表时间: 2017-09-10
• 期刊: Journal of controlled release : official journal of the Controlled Release Society
• 作者: Yang X;Xue X;Luo Y;Lin TY;Zhang H;Lac D;Xiao K;He Y;Jia B;Lam KS;Li Y
• 通讯作者: Li Y

A facile strategy for fine-tuning the stability and drug release of stimuli-responsive cross-linked micellar nanoparticles towards precision drug delivery.

刺激反应性交联的胶束纳米颗粒的稳定性和药物释放的轻松策略，以递送精确药物。

• DOI: 10.1039/c7nr02530k
• 发表时间: 2017-06-14
• 期刊: Nanoscale
• 影响因子: 6.7
• 作者: Xiao K;Lin TY;Lam KS;Li Y
• 通讯作者: Li Y

"One-Pot" Fabrication of Highly Versatile and Biocompatible Poly(vinyl alcohol)-porphyrin-based Nanotheranostics.

• DOI: 10.7150/thno.20190
• 发表时间: 2017
• 期刊: Theranostics
• 影响因子: 12.4
• 作者: Luo Y;Wu H;Feng C;Xiao K;Yang X;Liu Q;Lin TY;Zhang H;Walton JH;Ajena Y;Hu Y;Lam KS;Li Y
• 通讯作者: Li Y

HSP90 Inhibitor Encapsulated Photo-Theranostic Nanoparticles for Synergistic Combination Cancer Therapy.

• DOI: 10.7150/thno.14882
• 发表时间: 2016
• 期刊: Theranostics
• 影响因子: 12.4
• 作者: Lin TY;Guo W;Long Q;Ma A;Liu Q;Zhang H;Huang Y;Chandrasekaran S;Pan C;Lam KS;Li Y
• 通讯作者: Li Y

Extremely long tumor retention, multi-responsive boronate crosslinked micelles with superior therapeutic efficacy for ovarian cancer.

• DOI: 10.1016/j.jconrel.2017.08.028
• 发表时间: 2017-10-28
• 期刊: Journal of controlled release : official journal of the Controlled Release Society
• 作者: Xiao W;Suby N;Xiao K;Lin TY;Al Awwad N;Lam KS;Li Y
• 通讯作者: Li Y