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Photodynamic Priming for Bidirectional Modulation of Drug Transport Across the Blood-Brain Tumor Barrier

光动力引发双向调节药物跨血脑肿瘤屏障转运

基本信息

批准号：
10057075
负责人：
Huang Chiao Huang
金额：
$ 20.35万
依托单位：
UNIV OF MARYLAND, COLLEGE PARK
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：
2020-07-01 至 2023-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10057075
关键词：
ABCG2 gene ATP-Binding Cassette Transporters Adjuvant Adult Animals Antibodies Binding Biodistribution Biomedical Engineering Biometry Blood - brain barrier anatomy Brain Brain Neoplasms Brain region Cancer Biology Cells Central Nervous System Diseases Chemotherapy and/or radiation Clinic Clinical Computer Models Coupled Custom Diffuse Drug Delivery Systems Drug Efflux Drug Kinetics Drug Modulation Drug Monitoring Drug Targeting Drug Transport Endothelial Cells Engineering Ensure Evans blue stain Excision Exposure to Extravasation Glioblastoma Glioma Goals Image In Vitro Invaded Lesion Light Malignant Neoplasms Malignant neoplasm of brain Malignant neoplasm of pancreas Mediating Modeling Molecular Monitor Movement Multi-Drug Resistance Nanotechnology Nerve Degeneration Operative Surgical Procedures Outcome P-Glycoprotein Patients Penetration Pharmaceutical Preparations Photochemistry Photosensitization Photosensitizing Agents Primary Brain Neoplasms Procedures Proteins Pump Rattus Recurrence Residual state Role Spinal Cord Diseases Structure Surface Surgical margins System Techniques Technology Testing Therapeutic Tight Junctions Time Tissues Toxic effect Translating Treatment outcome Tumor Burden Xenograft procedure base blood-brain barrier permeabilization blood-brain tumor barrier brain endothelial cell brain tissue cancer cell cerebral capillary chemotherapy cytotoxic density dosimetry effective therapy fluorescein isothiocyanate dextran fluorescence imaging high risk image guided image-guided drug delivery imaging approach imaging study improved in vivo interest irinotecan light dosimetry mouse model multidisciplinary nanomedicine nanoparticle nanotechnology platform neoplastic cell neurosurgery occludin optical imaging outcome forecast pancreatic cancer model pharmacokinetic model physiologically based pharmacokinetics real time monitoring relating to nervous system tool treatment effect tumor

项目摘要

PROJECT SUMMARY Most primary brain tumors are managed by maximal safe resection followed by chemotherapy and radiation to treat residual and potentially infiltrative tumor cells. However, these adjuvant approaches do not effectively treat the tumor-invaded brain regions due to an intact blood-brain barrier (BBB) that restricts efficient drug penetration or a high risk of toxicity to nearby neural structures. Increasing clinical evidence indicates that the strength of the BBB in protecting brain tumors from exposure to circulating drugs is maintained by not only the intact tight junctions between endothelial cells, but also a broad range of ATP-binding cassette (ABC) drug efflux transporters on endothelial and cancer cells. Our central hypothesis is that sub-cytotoxic photodynamic priming (PDP), which modulates both the tight junction proteins and ABC transporters, can offer a more specific and less disruptive strategy to deliver drugs into the brain tumor effectively. Leveraging cutting-edge nanotechnology, optical imaging and computational modeling, three specific aims will test our hypothesis using orthotopic patient-derived xenograft rat models of glioblastoma. Aim 1 will unravel the molecular impact of nanotechnology-assisted PDP on the tight junction proteins and ABC efflux transporters of brain endothelial cells and cancer cells. Aim 2 will employ fluorescence imaging to monitor nanomedicine delivery and establish a physiologically based pharmacokinetic model. Aim 3 will apply image-based pharmacokinetic modeling to guide the initiation of PDP for bidirectional modulation of drug transport in vivo. Creation of such a pipeline to translate fundamental discoveries into potential therapeutics stands to dramatically accelerate the paradigm shift from standard cytotoxic procedures to a gentler photochemical approach that will revolutionize glioblastoma treatment. The principles and nanotechnology developed here will be adaptable to understanding and treating a broad range of central nervous system disorders, such as neuro-degenerative malignancies and spinal cord disease.

项目总结大多数原发性脑肿瘤的治疗方法是最大限度地安全切除，然后进行化疗和放射治疗治疗残留的和潜在的浸润性肿瘤细胞。然而，这些辅助方法并不有效。由于血脑屏障(BBB)的完整限制了有效药物的使用，治疗肿瘤侵袭的脑区穿透或对附近神经结构有很高的毒性风险。越来越多的临床证据表明，血脑屏障在保护脑瘤免受循环药物暴露方面的力量不仅由内皮细胞之间完整的紧密连接，但也有广泛的ATP结合盒(ABC)药物外流内皮细胞和癌细胞上的转运蛋白。我们的中心假设是亚细胞毒性光动力启动 (PDP)同时调节紧密连接蛋白和ABC转运蛋白，可以提供更特异和破坏性较小的策略，将药物有效地输送到脑瘤中。利用尖端技术纳米技术、光学成像和计算建模，三个特定的目标将使用大鼠胶质母细胞瘤原位移植模型的建立。目标1将揭开分子的影响纳米技术辅助PDP对脑内皮细胞紧密连接蛋白和ABC外排转运蛋白的影响细胞和癌细胞。AIM 2将使用荧光成像来监测纳米药物的传递并建立一个基于生理的药代动力学模型。AIM 3将应用基于图像的药代动力学建模引导PDP的启动，实现体内药物转运的双向调控。创建这样一条管道，以将基础发现转化为潜在的治疗方法将极大地加速这一范式从标准的细胞毒性程序转向更温和的光化学方法，这将带来革命性的变化胶质母细胞瘤的治疗。这里开发的原理和纳米技术将适用于理解并治疗广泛的中枢神经系统疾病，如神经退行性恶性肿瘤和脊髓疾病。