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.
The proposed research investigates how laser-induced alterations of human serum albumin can be adopted to increase the specificity of the protein for receptors on triple negative breast cancer cells. Since albumin is the most common carrier of systemically-administered drugs in the body, the successful completion of the proposed research will provide novel strategies to target certain cancers (e.g., triple negative breast cancer cells) that may specifically internalize laser-modified albumin.
