Photosensitizing Nanoconstructs for Regulation of ATP-Binding Cassette Transporters in the Brain

三磷酸腺苷(ATP)分子是细胞内能量传递的核苷酸。三磷酸腺苷能够在细胞内储存和运输化学能。能量通过第三个磷酸基团的水解释放，这些能量被蛋白质捕获以驱动细胞过程。三磷酸腺苷结合盒(ABC)转运蛋白是在我们的细胞中发现的蛋白质，它从细胞内部吸收有毒化学物质，并将它们推到细胞外部。大脑中的血管细胞采用这种保护机制将各种药物泵出大脑，从而使治疗无效。目前还没有有效的策略来选择性地抑制疾病组织中的ABC转运蛋白，同时保留健康组织。该项目通过研究光、化学和纳米材料可以用来调节脑微血管内皮细胞ABC转运蛋白的基本机制，填补了一个主要的空白。这项工作将量化光化学和纳米材料对ABC转运蛋白活性和完整性的影响。光敏剂在纳米级物体中的区隔和空间组织将被研究，以改变甚至增强ABC转运蛋白的光化学效应。细胞器的光化学调节和ABC转运蛋白的功能之间的关系也将被建立。该项目的第三个目标涉及了解光如何调节药物通过血脑屏障的运输。该项目的结果可能会使新型纳米结构的开发成为可能，这将使脑癌和其他类型癌症的治疗发生转变。拟议的研究将与教育、指导和推广活动无缝结合，以促进生物光子学和神经科学领域的跨学科计划。研究成果将通过期刊出版物、会议和在UMD举办的研讨会广泛传播。这项工作将在有关光化学、光生物学和生物医学光学的国际会议上公布。该奖项反映了NSF的法定使命，并通过使用基金会的智力优势和更广泛的影响审查标准进行评估，被认为值得支持。

The adenosine triphosphate (ATP) molecule is the nucleotide of intracellular energy transfer. ATP is able to store and transport chemical energy within cells. Energy is released by hydrolysis of the third phosphate group, and this energy is captured by proteins to drive cellular processes. ATP-binding cassette (ABC) transporters are proteins found within our cells that take toxic chemicals from the inside of a cell and push them to the outside of a cell. Blood vessel cells in the brain adopt this protective mechanism to pump a variety of drugs out of the brain, thereby making treatment ineffective. There are currently no effective strategies for selective inhibition of ABC transporters in diseased tissues while sparing healthy tissues. This project fills a major gap by studying the fundamental mechanisms by which light, chemistry, and nanomaterials can be exploited to modulate ABC transporters in brain microvascular endothelial cells. This work will quantify the impact of photochemistry and nanomaterials on the activity and integrity of ABC transporters. Compartmentalization and spatial organization of photosensitizers in nanoscale objects will be investigated to alter or even enhance the photochemical effects on ABC transporters. A correlation between the photochemical modulation of organelles and the function of ABC transporters will also be established. The third objective of the project involves understanding how light modulates drug transport across the blood-brain barrier. The results of this project may enable the development of new types of nanoconstructs, which will enable a transformation in the treatment of brain cancer and other types of cancer. The proposed research will be seamlessly integrated with educational, mentoring, and outreach activities to advance the cross-disciplinary program in the field of Biophotonics and Neuroscience. The research results will be disseminated broadly through journal publications, conferences, and workshops held at UMD. This work will be presented at international conferences on photochemistry, photobiology, and biomedical optics.This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.