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MSE PhD Prospectus Defense: Madeline Loffredo
TITLE: Regioselective Sulfated Polyamidosaccharides for the Prevention of Metastasis
ADVISOR: Mark Grinstaff, MSE
COMMITTEE:
Joe DeRosa, Chemistry; Michael Albro, MSE; Elliot Chaikof, ChemE
ABSTRACT:
Cancer is one of the leading causes of death worldwide, with metastasis being a prime culprit. Cancers of the breast and lung are the two most common cancers today, and the most fatal cancers for women. While breast cancer has become increasingly treatable with a five-year survival rate of 99% (early stage), this drops down to 20-28% after metastasis. Likewise, the 5-year survival rate for lung cancer patients drops from 65% to 7% after the cancer metastasizes. P-selectin (CD62P) is a protein upregulated on many tumor types, including breast and lung. It plays a crucial role in the dissemination of those cells around the body due to its function mediating the rolling of cells and facilitating adhesion of blood cells to the endothelium of other organs. In healthy cells, the expression level of CD62P is constitutively low, while in tumor microenvironments such as kidney, lung, and breast cancers, the protein is highly expressed and can be further induced via radiation treatment. Fucoidan exhibits nanomolar affinity for CD62P and is actively investigated as a targeting moiety for drug delivery platforms. Unfortunately, given that fucoidan is isolated from the cell-wall matrix of seaweed, there is high dispersity and structural irregularity within batches, along with large batch-to-batch variability based on the environmental conditions the polysaccharide is isolated from. Thus, changes in the sulfation and methylation pattern of the monosaccharide units leads to inconsistent binding affinity for CD62P. Here, I describe the synthesis of a 3,6-disulfated polyamidosaccharide (disulPAS), as well as ongoing studies to elucidate its efficacy as a much-needed synthetic fucoidan mimetic, retaining the biocompatibility of natural polysaccharides but with a tunable sulfation density, molecular weight, and narrow dispersity. Additionally, the ongoing binding studies on a library of disulPAS varying in molecular weight and sulfation density will give insight into the currently unclear mechanisms of CD62P binding, and paclitaxel loaded nanoparticles decorated with disulPAS will target CD62P expressing cancer cells, preventing metastasis.
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