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Theranostics for Pediatric Brain Cancer

小儿脑癌的治疗诊断学

基本信息

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
项目类别：
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

项目摘要

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.

小儿脑癌的治疗