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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