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

MRI 生物传感器和补充药物纳米载体，用于有效的图像引导药物输送和儿科髓母细胞瘤的早期肿瘤反应评估

• 批准号: 10005400
• 负责人: Ethel Joso Ngen
• 金额: $ 20.42万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-09-01 至 2023-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10005400
• 关键词: Acids; Active Sites; Advanced Development; Aftercare; Alkylating Agents; Amides; Amines; Antibodies; Bacteriophage T4; Biological; Biosensor; Blood - brain barrier anatomy; Brain Neoplasms; Cell Death; Cell Line; Cells; Chemicals; Childhood Medulloblastomas; Contrast Media; DNA; DNA Alkylation; Desmoplastic; Dose; Drug Delivery Systems; Drug Monitoring; Drug Targeting; Drug usage; Generations; Histology; Human; Hydroxyl Radical; Image; Imaging Device; Imaging Techniques; Immunohistochemistry; In Vitro; Intervention; Intravenous; Magnetic Resonance; Magnetic Resonance Imaging; Melphalan; Metals; Molecular; Monitor; Patients; Pediatric Neoplasm; Penetration; Pharmaceutical Preparations; Physiologic pulse; Positron-Emission Tomography; Procedures; Process; Protons; Regimen; Reporting; Signal Transduction; Techniques; Time; Tumor Markers; Water; base; bioluminescence imaging; cellular imaging; chemotherapeutic agent; chemotherapy; contrast imaging; early detection biomarkers; effective therapy; fluorodeoxyglucose; image-guided drug delivery; imaging approach; imaging biomarker; improved; in vivo; interest; medulloblastoma cell line; nanocarrier; nanoparticle; neoplastic cell; non-invasive imaging; personalized therapeutic; prognostic; radio frequency; response; screening; theranostics; therapy resistant; treatment planning; tumor; tumor microenvironment

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.

化学疗法是所有小儿髓母细胞瘤治疗计划的主要组成部分。但是，报告 表明只有不到1％的药物静脉注射到脑肿瘤。挑战之一 血液脑屏障（BBB）将药物输送到脑肿瘤，这限制了药物渗透到脑中 肿瘤。有针对性的药物输送系统和能够穿越BBB的目标介入程序 可以改善进入脑肿瘤的药物。这些有针对性的药物输送系统将极大地受益 从无创成像方法监测药物输送过程。同样至关重要的是需要 无创的预后成像标记物，能够预测早期肿瘤反应或肿瘤对 药物输送后的治疗。这些成像工具对于验证药物的效率至关重要 交付过程，将通过允许快速选择的患者管理 最有效的治疗选择和剂量升级量表。这些努力将带来个性化的治疗 方案更接近实现。该项目的总体目的是开发分子磁 共振成像（MRI）生物传感器能够直接和非侵入性成像在BBB上输送药物 并进入脑肿瘤，也能够对与肿瘤反应相关的早期分子变化或 抑制肿瘤治疗。化学交换满意度转移MRI（CEST MRI）是相对新的MRI 通过饱和特定的可交换质子饱和，显示出对有机分子进行成像有望的技术 （例如胺，酰胺和羟基质子）在感兴趣的分子上，具有定义的射频脉冲。 虽然CEST MRI基于磁共振光谱（MRS）技术，但它是几个顺序 幅度比MRS更敏感。我们假设某些DNA烷基化剂的不稳定质子 产生pH依赖性的CEST MRI对比信号，可用于监测其向脑肿瘤的递送， 并报告针对治疗的早期分子肿瘤变化。这个项目将通过 两个具体的目标。在AIM 1中，我们将筛选六种DNA烷基化剂，并评估每种药物的作用潜力 作为CEST MRI生物传感器。从这个目的，我们将获得每种药物的签名CEST MRI概况，这将 使我们能够在药物输送后检测到肿瘤中的药物。在Aims 2中，我们将评估使用 签名的CEST MRI对比度的相关生物传感器以检测有针对性的药物输送 介入程序，也来自靶向药物纳米载体。我们还将评估使用的可行性 生物传感器的pH依赖性CEST信号对早期肿瘤反应或对治疗的耐肿瘤耐药性， 体内。所有CEST MRI结果将通过使用药物的生物发光成像，免疫组织化学来验证 使用[18F] 2-氟-2-- 脱氧-D-葡萄糖。该项目将大大提高更有效和毒性较小的发展 小儿髓母细胞瘤患者的治疗计划。