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:
  • 金额:
    $ 20.35万
  • 依托单位:
  • 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

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。

项目成果

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Huang Chiao Huang其他文献

Huang Chiao Huang的其他文献

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{{ truncateString('Huang Chiao Huang', 18)}}的其他基金

Targeting Fluid Stress-induced Chemoresistance in a 3D Carcinomatosis Perfusion Model Using Mechanism-based Photo-immunoconjugate Nanoparticles
使用基于机制的光免疫缀合物纳米颗粒在 3D 癌病灌注模型中靶向流体应激诱导的化疗耐药性
  • 批准号:
    10587481
  • 财政年份:
    2023
  • 资助金额:
    $ 20.35万
  • 项目类别:
Nanotherapeutic enhancement of interstitial thermal therapy for glioblastoma
胶质母细胞瘤间质热疗法的纳米治疗增强
  • 批准号:
    10583661
  • 财政年份:
    2022
  • 资助金额:
    $ 20.35万
  • 项目类别:
Addressing Chemoresistance in Pancreatic and Ovarian Cancers: Photodynamic Priming and Repurposing of Tetracyclines using Targeted Photo-Activable Multi-Inhibitor Liposome
解决胰腺癌和卵巢癌的化疗耐药性:使用靶向光激活多抑制剂脂质体进行四环素的光动力启动和再利用
  • 批准号:
    10197327
  • 财政年份:
    2021
  • 资助金额:
    $ 20.35万
  • 项目类别:
Addressing Chemoresistance in Pancreatic and Ovarian Cancers: Photodynamic Priming and Repurposing of Tetracyclines using Targeted Photo-Activable Multi-Inhibitor Liposome
解决胰腺癌和卵巢癌的化疗耐药性:使用靶向光激活多抑制剂脂质体进行四环素的光动力启动和再利用
  • 批准号:
    10373082
  • 财政年份:
    2021
  • 资助金额:
    $ 20.35万
  • 项目类别:
Addressing Chemoresistance in Pancreatic and Ovarian Cancers: Photodynamic Priming and Repurposing of Tetracyclines using Targeted Photo-Activable Multi-Inhibitor Liposome
解决胰腺癌和卵巢癌的化疗耐药性:使用靶向光激活多抑制剂脂质体进行四环素的光动力启动和再利用
  • 批准号:
    10594035
  • 财政年份:
    2021
  • 资助金额:
    $ 20.35万
  • 项目类别:
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
  • 批准号:
    10197928
  • 财政年份:
    2020
  • 资助金额:
    $ 20.35万
  • 项目类别:
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
  • 批准号:
    10381605
  • 财政年份:
    2020
  • 资助金额:
    $ 20.35万
  • 项目类别:
Multifunctional, GBM-activatable nanocarriers for image-guided photochemotherapy
用于图像引导光化疗的多功能、GBM 可激活纳米载体
  • 批准号:
    9260692
  • 财政年份:
    2016
  • 资助金额:
    $ 20.35万
  • 项目类别:

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