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：
10197928
负责人：
Huang Chiao Huang
金额：
$ 22.83万
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/10197928
关键词：
ABCB1 gene 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 Penetration Pharmaceutical Preparations Photochemistry Photosensitizing Agents Primary Brain Neoplasms Procedures Prognosis 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 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 pancreatic cancer model patient derived xenograft model pharmacokinetic model physiologically based pharmacokinetics real time monitoring relating to nervous system tool treatment effect tumor

ABCB1 gene 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 Penetration Pharmaceutical Preparations Photochemistry Photosensitizing Agents Primary Brain Neoplasms Procedures Prognosis 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 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 pancreatic cancer model patient derived xenograft model pharmacokinetic model physiologically based pharmacokinetics real time monitoring relating to nervous system tool treatment effect tumor

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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.

项目摘要大多数原发性脑肿瘤是通过最大安全切除来管理的，然后进行化学疗法和放射线治疗残留和潜在的浸润性肿瘤细胞。但是，这些辅助方法无法有效由于限制有效药物的完整血脑屏障（BBB），治疗肿瘤摄取的大脑区域穿透或对附近神经结构的毒性高风险。越来越多的临床证据表明 BBB在保护脑肿瘤免于暴露于循环药物中的强度不仅可以维持内皮细胞之间完整的紧密连接，但也有广泛的ATP结合盒（ABC）药物外排内皮和癌细胞的转运蛋白。我们的中心假设是亚周毒性光动力启动（PDP）调节紧密连接蛋白和ABC转运蛋白，可以提供更具体的和有效地将药物传递到脑肿瘤的策略较小。利用尖端纳米技术，光学成像和计算建模，三个特定目标将使用我们的假设来检验我们的假设胶质母细胞瘤的原始患者衍生的异种移植大鼠模型。 AIM 1将揭示纳米技术辅助PDP在紧密连接蛋白上和ABC外排外皮转运蛋白上细胞和癌细胞。 AIM 2将采用荧光成像来监测纳米医学的递送并建立基于生理的药代动力学模型。 AIM 3将将基于图像的药代动力学建模应用于指导PDP开始体内药物转运的双向调节。创建这样的管道将基本发现转化为潜在的治疗药，以极大地加速范式从标准的细胞毒性程序转变为一种将彻底改变的光化学方法胶质母细胞瘤治疗。这里开发的原理和纳米技术将适合理解并治疗广泛的中枢神经系统疾病，例如神经变性和脊髓疾病。