Theranostics for Pediatric Brain Cancer

儿童脑癌的治疗方案 胶质母细胞瘤(GBM)是儿童中最常见的原发恶性脑肿瘤。 存活不到一年。疾病复发是常见的，是由胶质瘤引起的。 不能接受传统疗法的细胞(GIC)，强调了对新疗法的迫切需要 选择。我们的目标是开发一种新的策略，专门扰乱GIC的生命线，而不会造成有毒 对正常大脑的影响。肾小球基底膜的高度血管化特性和血管周围的关键功能 GICs营养供应的利基市场激发了人们对新型血管干扰剂(VDA)的兴趣。 静脉注射VDA很容易到达GBM血管，不依赖于增强的通透性和 滞留效应，可限制大分子向肿瘤组织的输送。VDA介导的血管 破坏会导致有效的药物输送到GIC利基，并导致许多肿瘤细胞饥饿。与之形成鲜明对比的是 经典的抗血管生成药物VDA不仅破坏了肿瘤的血管系统，而且引起了显著的GIC 通过直接的细胞毒作用进行的细胞凋亡。虽然对癌症治疗非常有效，但最初的VDA 制剂也对正常大脑造成了显著的毒性。这对儿童来说尤其令人担忧，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治疗(结合治疗和诊断)纳米颗粒，它们是 在脑肿瘤中由基质金属蛋白酶14(MMP14)特异性激活。正常的大脑则不会 表达基质金属蛋白酶-14，因此，不会激活治疗药物，从而产生高效的癌症 无副作用的治疗。我们项目的主要目标是开发可激活的基质金属蛋白酶-14治疗剂。 治疗基底膜的纳米粒(TNPs)，不会对正常大脑造成毒性。这个 该方法依赖于基质金属蛋白酶-14在基底膜中的高流行率，这是一种已被证实的可激活基质金属蛋白酶-14的前药策略，以及 一种基于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TNPs将是 仅在表达基质金属蛋白酶-14的肿瘤内转化为活性治疗剂，释放治疗药物 氮杂甲基秋水仙碱，具有显著的抗肿瘤作用。此外，我们假设氧化铁 纳米粒子部分将允许实时监测药物在肿瘤中的蓄积和定位 磁共振成像(MRI)。在目标1中，我们将评估TNP剂量和VDA有效载荷是否影响VDA介导 血管破裂、血脑屏障(BBB)破坏和癌症特异性毒性。在目标2中，我们将调查 VDA介导的肿瘤微血管破坏、微血管内皮细胞死亡与GIC的关系 死亡。TNPs有可能在显著提高治疗效果的同时减少 剂量限制毒性。实现我们的目标将为成功的GBM治疗发现新的靶点和机制， 消除或大幅减少非目标毒性，为患有脑癌的儿童提供急需的 新的治疗方案。

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.