Magnetofluorescent nanoplatform for glioblastoma therapy

用于胶质母细胞瘤治疗的磁荧光纳米平台

基本信息

批准号：
10060454
负责人：
John S Yu
金额：
$ 62.35万
依托单位：
CEDARS-SINAI MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-09-11 至 2025-08-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10060454
关键词：
Anemia Antineoplastic Agents Area Autopsy Biodistribution Blood - brain barrier anatomy Brain Brain Neoplasms Canis familiaris Carrier Proteins Cells Chemotherapy and/or radiation Cisplatin Combination Drug Therapy Contrast Media Disease remission Drug Delivery Systems Drug resistance Encapsulated Endothelium Epithelial Epithelium Euthanasia Excision FDA approved Future Glioblastoma Glioma Human Intracranial Neoplasms Label Ligands Magnetic Resonance Imaging Magnetism Malignant - descriptor Malignant Neoplasms Mediating Modeling Mus Nature Nude Mice Operative Surgical Procedures Organic Anion Transporters Paclitaxel Pathologic Patients Pharmaceutical Preparations Property Radiation therapy Recurrence Residual Tumors Role Sampling Schedule Serum Survival Rate Technology Testing TimeLine Tissues Tumor Tissue blood-brain barrier crossing brain tissue cancer cell cyanine drug development ferumoxytol image guided image-guided drug delivery imaging agent in vivo iron oxide nanoparticle mouse model multimodality nanodrug nanoparticle nanoprobe nanotechnology platform neoplastic cell off-label use overexpression polypeptide preclinical study preservation prevent recruit small molecule inhibitor standard of care stem cells superparamagnetism temozolomide tumor uptake

项目摘要

ABSTRACT: Glioblastoma multiforme (GBM) is among the most lethal and aggressive cancers. Standard of care starts with surgery, to eliminate most of the tumor mass, followed by a combination of chemotherapy and radiation therapy to eradicate residual tumor tissue. However, the infiltrating nature of these tumors renders it almost impossible to resect all of the tumor mass, while preserving eloquent brain tissue. A major challenge with current chemotherapeutic drugs to treat GBM are their lack of efficient crossing across the brain blood barrier (BBB), preventing enough drug to reach the tumor area, which often results in recurrence of the tumor. Herein, we propose to develop a BBB-crossing, glioma cell targeting magnetofluorescent nanoprobe for the image-guided delivery of drugs across the BBB and into GBM tumors. At the core of our platform technology is Feraheme (FH), an FDA-approved superparamagnetic iron oxide nanoparticle (SPION). To FH, we conjugate hepthamethine cyanine (HMC), a unique near infrared fluorescent ligand that specifically targets the organic anion transporter protein (OATP) overexpressed in various tumors, including GBM microvasculature. HMC’s ability to cross the BBB and internalize into GBM cancer cells is mediated by the OATP subtypes OATP1A2 and OATP2B. Upon conjugation of HMC to FH, the resulting HMC-FH nanoprobe has a unique combination of the following properties: (1) dual magnetic (MRI) and near infrared fluorescent properties, (2) BBB-crossing and specific glioma targeting ability, with no accumulation in heathy brain, and (3) delivery of drugs across BBB with specific accumulation in brain tumors, acting as a glioma-specific image-guided delivery nanodrug. Our preliminary studies show that HMC-FH selectively accumulates in intracranial human GBM tumor xenographs in nude mice, particularly in in infiltrating areas within the brain. In addition, studies show that HMC-FH crosses the BBB in the tumor area and associates with the GBM cells within the tumor, facilitating drug delivery and reducing tumor size in mice when paclitaxel is encapsulated within the HMC-FH. Therefore, we hypothesize that HMC-FH can facilitate the delivery of drugs across the BBB and into glioma tumor cells, causing tumor remission and increasing survival in mice with orthotopic intracranial GBM. In addition, biodistribution and tumor uptake studies will be done in a spontaneous high-grade glioma canine model. To test our hypothesis, the following specific aims will be pursued: 1) Optimization of drug loading into HMC-FH, 2) Study the mechanism of BBB crossing and GBM cancer cell internalization of HMC-FH, 3) Investigate HMC-FH biodistribution, tumor uptake, retention and ability to deliver drugs in an intracranial tumor mouse models using human and canine derived GBM cells, 4) Investigate the biodistribution, tumor uptake and retention of HMC-FH in a canine GBM model

抽象的：胶质母细胞瘤多形（GBM）是最致命和侵略性的癌症之一。护理标准始于手术，以消除大多数肿瘤肿块，然后进行化学疗法和放射治疗的组合放射性残留肿瘤组织。但是，这些肿瘤的浸润性几乎是不可能的为了分辨所有肿瘤质量，同时保留雄辩的脑组织。当前的主要挑战治疗GBM的化学治疗药物缺乏在脑血屏障（BBB）中缺乏有效的交叉防止足够的药物到达肿瘤区域，这通常会导致肿瘤复发。这里，我们为图像引导的靶向磁荧光纳米探针开发BBB跨BBB的胶质瘤细胞的提议在BBB和GBM肿瘤中递送药物。我们平台技术的核心是Feraheme（FH），由FDA批准的超顺磁性氧化铁纳米颗粒（SPION）。对于FH，我们偶联的肝甲烷氰胺（HMC），一种独特的近感染荧光配体，专门针对有机阴离子转运蛋白蛋白质（OATP）在各种肿瘤中过表达，包括GBM微脉管系统。 HMC越过 BBB并内化为GBM癌细胞由OATP亚型OATP1A2和OATP2B介导。之上 HMC与FH的结合，由此产生的HMC-FH纳米探针具有以下独特的组合特性：（1）双磁性（MRI）和近红外荧光性能，（2）BBB交叉和特定神经胶质瘤的靶向能力，没有在希思大脑中积累，（3）特定于BBB的药物递送在脑肿瘤中积聚，充当胶质瘤特异性图像引导的纳米果。我们的初步研究表明，HMC-FH选择性地积累了裸鼠内颅内GBM肿瘤Xenographts，特别是在大脑内部浸润区域。此外，研究表明，HMC-FH在肿瘤区域并与肿瘤内的GBM细胞相关联，支持药物输送并减少肿瘤的大小在HMC-FH中封装紫杉醇时，小鼠在小鼠中。因此，我们假设HMC-FH可以促进药物在BBB和神经胶质瘤肿瘤细胞中的递送，导致肿瘤的缓解和与原位颅内GBM相比，在小鼠中增加生存率。此外，生物分布和肿瘤摄取研究将在赞助高级神经胶质瘤犬模型中完成。为了检验我们的假设，以下具体将追求目的：1）将药物负载优化到HMC-FH中，2）研究BBB交叉的机制 HMC-FH的GBM癌细胞内在化，3）研究HMC-FH生物分布，肿瘤摄取，保留率以及使用人和犬类衍生的GBM细胞在颅内肿瘤小鼠模型中输送药物的能力， 4）研究HMC-FH在犬GBM模型中的生物分布，肿瘤摄取和保留