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

项目摘要 大多数原发性脑肿瘤通过最大限度的安全切除，然后进行化疗和放疗， 治疗残留和潜在浸润性肿瘤细胞。然而，这些辅助方法不能有效地 由于血脑屏障（BBB）完好，限制了有效的药物治疗， 渗透或对附近神经结构的高毒性风险。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通过 内皮细胞之间完整的紧密连接，而且还有广泛的ATP结合盒（ABC）药物外排 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)调节紧密连接蛋白和ABC转运蛋白，可以提供更特异， 更少的破坏性策略，以有效地将药物输送到脑肿瘤中。利用尖端技术 纳米技术，光学成像和计算建模，三个具体的目标将测试我们的假设，使用 原位患者来源的胶质母细胞瘤异种移植大鼠模型。Aim 1将揭示 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。AIM2将利用荧光成像来监测纳米药物的输送， 基于生理学的药代动力学模型。Aim 3将应用基于图像的药代动力学建模， 引导PDP的启动，用于体内药物转运的双向调节。建立这样一条管道， 将基础发现转化为潜在的治疗方法， 从标准的细胞毒性程序转变为温和的光化学方法， 胶质母细胞瘤治疗。这里开发的原理和纳米技术将适用于理解 和治疗广泛的中枢神经系统疾病，例如神经变性恶性肿瘤， 脊髓疾病

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.