Theranostics for Pediatric Brain Cancer

小儿脑癌的治疗诊断学

• 批准号: 10393485
• 负责人: Heike Elizabeth Daldrup-Link
• 金额: $ 66.86万
• 依托单位: STANFORD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-04-15 至 2026-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10393485
• 关键词: Adult; Affect; Animals; Apoptosis; Binding Sites; Biosensor; Blood - brain barrier anatomy; Blood Vessels; Brain; Brain Neoplasms; Cell Death; Cells; Child; Childhood; Childhood Malignant Brain Tumor; Colchicine; Data; Development; Diagnosis; Diagnostic; Disease; Disease remission; Dose; Dose-Limiting; Drug Delivery Systems; Drug Monitoring; Endothelial Cells; Endothelium; Enzymes; FDA approved; Fluorescein-5-isothiocyanate; Fluorescence Microscopy; Formulation; Generations; Glioblastoma; Glioma; Goals; High Prevalence; Horseradish Peroxidase; Intravenous; Label; Lead; Link; Location; MMP14 gene; Magnetic Resonance Imaging; Malignant Neoplasms; Malignant neoplasm of brain; Mean Survival Times; Measures; Mediating; Microtubules; Mitosis; Modeling; Mus; Nature; Nutritional; Organ; Outcome; Pediatric Neoplasm; Peptide Hydrolases; Perivascular Neoplasm; Permeability; Pharmaceutical Preparations; Pharmacotherapy; Placebos; Positioning Attribute; Problem Solving; Prodrugs; Prognosis; Proteins; Radiation; Rattus; Recurrence; Research; Site; Starvation; System; Therapeutic; Therapeutic Agents; Therapeutic Effect; Toxic effect; Treatment Efficacy; Tubulin; Tumor Suppression; Tumor Tissue; Visceral; antiangiogenesis therapy; antitumor effect; base; cancer therapy; cell killing; clinical translation; clinically translatable; conventional therapy; curative treatments; cytotoxic; density; design; improved; improved outcome; in vivo; interest; intravital microscopy; iron oxide nanoparticle; macromolecule; nanocarrier; nanoparticle; neoplastic cell; neuro-oncology; novel; novel drug class; novel strategies; novel therapeutics; overexpression; real time monitoring; side effect; success; theranostics; therapy resistant; tumor; tumor growth

THERANOSTICS FOR PEDIATRIC BRAIN CANCER Glioblastoma (GBM) is the most frequently diagnosed primary malignant brain tumor in children with median survival of less than one year. Disease recurrence is common and is caused by the presence of glioma-initiating cells (GICs) that are unreceptive to conventional therapies, underscoring the urgent need for new therapeutic options. We aim to develop a novel strategy to specifically disrupt the lifeline of GICs, without causing toxic effects to the normal brain. The highly vascularized nature of GBMs and the critical function of the perivascular niche for nutritional supply of GICs have spurred much interest in novel vascular-disruptive agents (VDAs). Intravenously administered VDAs easily reach GBM vessels and do not rely on the enhanced permeability and retention effect, which can limit the delivery of macromolecules to the tumor tissue. VDA-mediated blood vessel disruption causes efficient drug delivery to the GIC niche and starvation of many tumor cells. In contrast to classical anti-angiogenesis drugs, VDAs not only disrupt the tumor vasculature, but also cause significant GIC apoptosis through direct cytotoxic effects. While being highly effective for cancer treatment, initial VDA formulations also caused significant toxicity to the normal brain. This is particularly concerning for children, as the developing brain is more vulnerable to toxic side effects compared to the adult brain. To solve this problem, we developed novel VDA-loaded theranostic (combined therapeutic and diagnostic) nanoparticles, which are specifically activated in brain tumors by matrix metalloproteinases 14 (MMP-14). The normal brain does not express MMP-14 and therefore, does not activate the theranostic drug, thereby creating highly effective cancer therapy without side effects. The major goal of our project is to develop MMP-14-activatable theranostic nanoparticles (TNPs) for curative treatment of GBM, without causing toxicity to the normal brain. The approach relies on the high prevalence of MMP-14 in GBM, a proven MMP-14-activatable prodrug strategy, and a nanocarrier platform based on FDA-approved iron oxide nanoparticles. We hypothesize that our TNPs will be converted to an active therapeutic agent only within MMP-14-expressing tumors, releasing the therapeutic drug azademethylcolchicine and causing significant antitumor effects. In addition, we postulate that the iron oxide nanoparticle moiety will allow real-time monitoring of drug accumulation and localization at tumors with magnetic resonance imaging (MRI). In aim 1, we will evaluate whether TNP dose and VDA payload affect VDA mediated vascular disruption, blood brain barrier (BBB) breakdown and cancer-specific toxicity. In aim 2, we will investigate the link between VDA-mediated tumor microvessel disruption, microvascular endothelial cell death and GIC death. TNPs hold the potential to substantially improving therapeutic efficacy whilst simultaneously reducing dose-limiting toxicities. Realizing our goal will uncover new targets and mechanisms for successful GBM therapy, eliminate or substantially reduce off-target toxicities and provide children with brain cancers with a much needed new treatment option.

小儿脑肿瘤的治疗 胶质母细胞瘤（GBM）是儿童中最常见的原发性恶性脑肿瘤， 生存时间不到一年。疾病复发是常见的，并且是由神经胶质瘤启动的肿瘤细胞的存在引起的。 细胞（GIC）不接受传统疗法，强调迫切需要新的治疗方法。 选项.我们的目标是开发一种新的策略，专门破坏GIC的生命线，而不会导致有毒的 对正常大脑的影响GBM的高度血管化性质和血管周围的关键功能 GIC的营养供应的利基已经激发了对新型血管破坏剂（VDA）的极大兴趣。 血管内给药的VDA容易到达GBM血管，并且不依赖于增强的渗透性， 保留效应，其可以限制大分子向肿瘤组织的递送。VDA介导的血管 破坏导致有效的药物递送到GIC小生境和许多肿瘤细胞的饥饿。相比 经典的抗血管生成药物VDA不仅破坏肿瘤血管，而且引起显著的GIC， 细胞凋亡通过直接的细胞毒性作用。虽然对癌症治疗非常有效，但最初的VDA 制剂也对正常脑产生显著的毒性。这对儿童尤其重要，因为 与成人大脑相比，发育中的大脑更容易受到毒副作用的影响。为了解决这个问题， 我们开发了新型的VDA负载治疗诊断（联合治疗和诊断）纳米颗粒， 在脑肿瘤中被基质金属蛋白酶14（MMP-14）特异性激活。正常的大脑不会 表达MMP-14，因此不会激活治疗诊断药物，从而产生高效的癌症 无副作用的治疗。本课题的主要目标是开发MMP-14激活的治疗诊断剂， 纳米颗粒（TNP）用于GBM的治愈性治疗，而不会对正常大脑造成毒性。的 方法依赖于MMP-14在GBM中的高流行率，这是一种经证实的MMP-14可激活的前药策略， 基于FDA批准的氧化铁纳米颗粒的纳米载体平台。我们假设我们的TNP将是 仅在表达MMP-14的肿瘤中转化为活性治疗剂，释放治疗药物 azademethylcolchicine并引起显著的抗肿瘤作用。此外，我们假设氧化铁 纳米颗粒部分将允许实时监测药物在肿瘤处的积聚和定位， 磁共振成像（MRI）。在目的1中，我们将评估TNP剂量和VDA有效载荷是否影响VDA介导的细胞凋亡。 血管破坏、血脑屏障（BBB）破坏和癌症特异性毒性。在目标2中，我们将研究 VDA介导的肿瘤微血管破坏、微血管内皮细胞死亡和GIC之间的联系 死亡TNP具有显著提高治疗效果的潜力，同时减少 剂量限制性毒性。实现我们的目标将揭示成功GBM治疗的新靶点和机制， 消除或大大减少脱靶毒性，并为患有脑癌的儿童提供急需的 新的治疗方案