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.

项目概要大多数原发性脑肿瘤的治疗方法是最大程度安全切除，然后进行化疗和放疗治疗残留和潜在浸润的肿瘤细胞。然而，这些辅助方法并不能有效地由于完整的血脑屏障（BBB）限制了有效药物，因此可以治疗肿瘤侵袭的大脑区域渗透或对附近神经结构具有高毒性风险。越来越多的临床证据表明 BBB 保护脑肿瘤免于接触循环药物的强度不仅由以下因素维持：内皮细胞之间完整的紧密连接，以及广泛的 ATP 结合盒 (ABC) 药物流出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引发 (PDP) 可调节紧密连接蛋白和 ABC 转运蛋白，可以提供更特异和有效地将药物输送到脑肿瘤中的破坏性较小的策略。充分利用尖端技术纳米技术、光学成像和计算建模，三个具体目标将使用以下方法检验我们的假设原位患者来源的胶质母细胞瘤异种移植大鼠模型。目标 1 将揭示分子影响纳米技术辅助 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。目标 2 将采用荧光成像来监测纳米药物的输送并建立基于生理学的药代动力学模型。目标 3 将应用基于图像的药代动力学模型指导 PDP 的启动，以实现体内药物转运的双向调节。创建这样一个管道将基本发现转化为潜在的治疗方法将极大地加速这一范例从标准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治疗。这里开发的原理和纳米技术将适用于理解治疗广泛的中枢神经系统疾病，例如神经退行性恶性肿瘤和脊髓疾病。