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

白蛋白光敏化：调节药物输送到异常细胞的潜在方法。

• 批准号: 9552214
• 负责人: LORENZO BRANCALEON
• 金额: $ 14.7万
• 依托单位: UNIVERSITY OF TEXAS SAN ANTONIO
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-09-01 至 2020-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9552214
• 关键词: Abnormal Cell; Address; Adopted; Adverse effects; Affect; Affinity; Albumins; Binding; Binding Proteins; Blood capillaries; Breast Cancer Cell; Cell membrane; Cells; Complex; Computer Simulation; Computing Methodologies; Data; Development; Docking; Drug Delivery Systems; Drug Targeting; Endothelial Cells; Engineering; Fatty Acids; Fibroblasts; Fluorescence Microscopy; Future; Genetic Materials; Goals; Human; In Vitro; Investigation; Lasers; Ligands; Malignant Neoplasms; Mass Spectrum Analysis; Mediating; Membrane; Membrane Glycoproteins; Methodology; Methods; Microtubules; Modeling; Molecular; Molecular Conformation; NMR Spectroscopy; Optical Methods; Optics; Osteonectin; Outcome; Pharmaceutical Preparations; Pharmacologic Substance; Photosensitization; Photosensitizing Agents; Porphyrins; Proteins; Receptor Cell; Research; Resolution; Retinal; Rhodopsin; Serum; Serum Albumin; Signal Transduction; Specificity; Spectrum Analysis; Structure; Surface; Techniques; Testing; Tissues; Tubulin; Ultracentrifugation; X ray diffraction analysis; analog; anticancer treatment; base; cancer cell; cell type; experience; experimental study; globular protein; improved; in vivo; in vivo evaluation; irradiation; man; neonatal Fc receptor; novel; novel strategies; optogenetics; overexpression; photonics; polypeptide; porphyrin a; prevent; receptor; receptor binding; simulation; triple-negative invasive breast carcinoma; tumor; uptake

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.

组织和组织之间的分子交换，包括全身给药的药物 脉管系统依赖于穿过毛细血管腔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天然受体的对接来实现 (gp60)在内皮细胞表面。然而，另一类受体（gp18 和 gp30）已被 发现了。这类受体结合结构经过修饰的 HSA。据信，这些 受体充当清道夫来消除未正确折叠的HSA。它们存在于其他物体的表面 成纤维细胞等细胞类型，但已发现它们在某些癌细胞中过度表达，例如 如三阴性乳腺癌。假设 HSA 与其受体对接的基本范式 取决于结构互补性，两类受体的存在开启了可能性 通过调节 HSA 的结构来靶向两种不同的细胞类型。本项目建议调查 光敏化作为调节 HSA 结构并诱导与 gp18 优先结合的方法 或 gp30 受体，从而提供了一种引导白蛋白靶向三阴性乳腺癌细胞的方法。自从 HSA 携带化疗药物等，所提出的方法可用于改善 抗癌治疗的选择性。基于 PI 小组用球状获得的结果 蛋白质，所提出的活性的工作假设是HSA的光敏化，由a介导 卟啉配体，引起 HSA 结构的局部改变，并通过这样做，抑制与天然的对接 gp60 受体，同时促进与 gp18 和 gp30 受体的结合。会诱导HSA光敏化 在体内测试之前进行体外测试，从而最大限度地减少对细胞的不利影响。拟议的项目包括 使用体外和体内实验方法与计算模拟相结合来表征 HSA 的结构变化并研究这些变化如何影响其与内皮细胞受体的对接 以及癌细胞。还将使用模型蛋白（骨连接素）研究与受体的对接 假定其与天然 gp60 受体共享 HSA 对接的共同基序。全面的， 证明 HSA 与膜受体的对接可以通过光学方法进行修改， 对药物输送的管理产生潜在的重要影响。