MRI biosensors and complementary drug nanocarriers for effective image-guided drug delivery and early tumor response assessment of pediatric medulloblastomas

化疗是所有儿童髓母细胞瘤治疗计划的主要组成部分。然而，有报道称 这表明，静脉注射的药物中，只有不到1%能到达脑瘤。其中一个挑战是 向脑肿瘤输送药物是血脑屏障(Bbb)，它限制药物进入大脑。 肿瘤。靶向给药系统和能够穿越血脑屏障的靶向介入程序 可以改善对脑瘤的药物输送。这些靶向给药系统将极大地受益 从非侵入性成像方法到监测药物输送过程。同样重要的是需要 非侵入性预后成像标记物，能够预测早期肿瘤反应或肿瘤对 治疗，在药物输送之后。这些成像工具对于验证药物的有效性是必不可少的 交付流程，并将通过允许快速选择 最有效的治疗选择和剂量递增标准。这些努力将带来个性化的治疗 养生计划离实现又近了一步。这个项目的总体目标是发展分子磁学 磁共振成像(MRI)生物传感器能够直接和非侵入性地成像跨血脑屏障的药物输送 也能够成像与肿瘤反应相关的早期分子变化或 肿瘤对治疗的抗药性。化学交换饱和转移磁共振成像(CEST MRI)是一种较新的磁共振成像技术 通过饱和特定的可交换质子来成像有机分子的技术 (例如胺、酰胺和羟基质子)在感兴趣的分子上，使用定义的射频脉冲。 尽管CEST MRI基于磁共振波谱(MRS)技术，但它是几个数量级的 比夫人灵敏得多我们假设某些DNA烷化剂的不稳定质子 产生依赖于pH的CEST MRI对比信号，可以用来监测它们对脑肿瘤的输送， 并报告早期分子肿瘤对治疗的反应变化。该项目将通过以下方式实现 有两个明确的目标。在目标1中，我们将筛选六种DNA烷基化试剂，并评估每种药物的作用潜力 作为CEST核磁共振生物传感器。从这个目标，我们将获得每种药物的签名CEST MRI简档，这将 使我们能够在给药后在肿瘤中检测到药物。在AIMS 2中，我们将评估使用 用于检测靶向给药过程中各个生物传感器的标志性CEST MRI对比度曲线 介入手术和靶向药物纳米载体也是如此。我们还将评估使用 依赖于pH的生物传感器的CEST信号以成像早期的肿瘤反应或肿瘤对治疗的抵抗， 在活体内。所有CEST MRI结果将通过生物发光成像、免疫组织化学和药物- 特异性抗体，组织学，多参数磁共振成像和正电子发射断层扫描，使用[18F]2-氟-2- 脱氧D-葡萄糖。该项目将大大推进更有效、更低毒的开发 儿童髓母细胞瘤患者的治疗计划。

Chemotherapy is a major component of all pediatric medulloblastoma treatment plans. However, reports suggest that less than 1% of drugs administered intravenously reach brain tumors. One of the challenges of delivering drugs to brain tumors is the blood brain barrier (BBB), which restricts drug penetration into brain tumors. Targeted drug delivery systems and targeted interventional procedures capable of traversing the BBB could improve drug delivery into brain tumors. These targeted drug delivery systems will tremendously benefit from noninvasive imaging approaches to monitor the drug delivery process. Also critical is the need for noninvasive prognostic imaging markers, capable of predicting early tumor response or tumor resistance to therapy, following drug delivery. These imaging tools will be essential in validating the efficiency of the drug delivery process and will enable more effective patient management, by permitting the rapid selection of the most effective treatment option and dose escalation scale. These efforts will bring personalized therapeutic regimens one step closer to realization. The overall objective of this project is to develop molecular magnetic resonance imaging (MRI) biosensors capable of directly and noninvasively imaging drug delivery across the BBB and into brain tumors, and also capable of imaging early molecular changes associated with tumor response or tumor resistance to therapy. Chemical exchange saturation transfer MRI (CEST MRI), is a relatively new MRI technique which shows promise for imaging organic molecules by saturating specific exchangeable protons (such as amine, amide and hydroxyl protons) on the molecules of interest, with defined radiofrequency pulses. Although, CEST MRI is based on a magnetic resonance spectroscopic (MRS) technique, it is several orders of magnitude more sensitive than MRS. We postulate that the labile protons of some DNA alkylating agents generate a pH-dependent CEST MRI contrast signal that can be used to monitor their delivery to brain tumors, and also to report on early molecular tumor changes in response to therapy. This project will be achieved through two specific aims. In aim 1, we will screen six DNA alkylating agents and evaluate each drug’s potential to act as a CEST MRI biosensor. From this aim we will obtain a signature CEST MRI profile for each drug, which will enable us to detect the drug in tumors after drug delivery. In aims 2, we will evaluate the feasibility of using the signature CEST MRI contrast profiles of the respective biosensors to detect drug delivery during a targeted interventional procedure and also from targeted drug nanocarriers. We will also evaluate the feasibility of using the pH-dependent CEST signal of the biosensors to image early tumor response or tumor resistance to therapy, in vivo. All CEST MRI results will be validated with bioluminescence imaging, immunohistochemistry using drug- specific antibodies, histology, multi-parametric MRI and positron emission tomography, using [18F] 2-fluoro-2- deoxy-D-glucose. This project will significantly advance the development of more effective and less toxic treatment plans for pediatric medulloblastoma patients.