Photosensitization of albumin: a potential approach to modulate drug delivery into abnormal cells.

分子交换，包括全身给药，在组织和组织之间的交换 血管形成依赖于穿过毛细血管管腔的内皮细胞层的血清白蛋白。 人血清白蛋白(HSA)的摄取可以通过蛋白质与特定的天然受体的对接而发生。 (Gp60)在内皮细胞表面。然而，另一类受体(gp18和gp30)已经被 被发现了。这类受体与结构修饰的人血清白蛋白结合。据信，这些 受体作为清道夫清除未正确折叠的HSA。它们被发现在其他星球的表面 细胞类型，如成纤维细胞，但已发现它们在某些癌细胞中过度表达，如 三重阴性乳腺癌。假设人血清白蛋白与其受体对接的基本范式 依赖于结构的互补性，这两类受体的存在为 通过调节HSA的结构靶向两种不同的细胞类型。该项目建议调查 光敏化作为一种调节人血清白蛋白结构和诱导gp18优先结合的途径 或GP30受体，从而提供了一种将白蛋白定向到三阴性乳腺癌细胞的方法。自.以来 人血清白蛋白携带化疗药物等，建议的方法可以应用于改进 抗癌治疗的选择性。基于PI的群与球状的结果 蛋白质，所提出的活性的工作假说是HSA的光敏化，由一种 卟啉配体，导致HSA结构的局部改变，并通过这样做，抑制与天然的对接 同时促进与gp18和gp30受体的结合。将诱导人血清白蛋白的光敏化 在体外，在体内测试之前，从而将对细胞的不良影响降至最低。拟议的项目包括 使用体外和体内实验方法结合计算模拟来表征 人血清白蛋白的结构变化，并研究这些变化如何影响其与内皮AS受体的对接 癌细胞也是如此。与受体的对接也将使用模型蛋白(骨联素)进行研究。 据推测，它与天然的gp60受体有一个共同的对接HSA的基序。总的来说， 证明人血清白蛋白与膜受体的对接可以通过光学方法进行修饰， 对药物输送的管理产生潜在的重要影响。

The exchange of molecules, including systemically-administered pharmaceuticals, between tissues and the vasculature depends on serum albumin crossing the endothelial cell layer that lines the lumen of the capillaries. Uptake of human serum albumin (HSA) can occur through the docking of the protein to specific native receptors (gp60) at the surface of the endothelial cells. However, another class of receptors (gp18 and gp30) has been discovered. This class of receptors binds HSA that has been structurally modified. It is believed that these receptor act as scavenger to eliminate HSA that is not properly folded. They are found at the surface of other cell types such as fibroblasts but it has been discovered that they are overexpressed in some cancer cells such as triple negative breast cancer. Assuming the fundamental paradigm that docking of HSA to its receptors depends on structure complementarity, the existence of the two classes of receptors opens the possibility of targeting two different cell types by modulating the structure of HSA. The project proposes to investigate photosensitization as an approach to modulate the structure of HSA and induce the preferential binding to gp18 or gp30 receptor thus providing a method to direct albumin to target triple negative breast cancer cells. Since HSA carries, among others, chemotherapeutic medications, the proposed approach could apply to an improve selectivity of anticancer treatments. Based on results that the group of the PI has obtained with globular proteins, the working hypothesis of the proposed activity is that photosensitization of HSA, mediated by a porphyrin ligand, causes local alteration of the structure of HSA and by doing so, suppress docking to the native gp60 receptor while promoting binding to the gp18 and gp30 receptors. Photosensitization of HSA will be induced in vitro, prior to the testing in vivo, thus minimizing adverse effects on cells. The proposed project includes the use of experimental in vitro and in vivo methods combined with computational simulations to characterize the structural changes of HSA and investigate how these changes affect its docking to receptors on endothelial as well as cancer cells. The docking to the receptor will be also investigated using a model protein (osteonectin) which is postulated to share with the native gp60 receptor a common motif for the docking of HSA. Overall, demonstrating that the docking of HSA to membrane receptors can be modified through optical methods, would provide potentially important repercussion in the management of drug delivery.