Cell-penetrating compounds (CPCs) are commonly used to enhance drug internalization, but their cell uptake mechanism is poorly understood. We hypothesize that glycosaminoglycans (GAGs) play an integral role in the recognition and subsequent internalization of CPCs and their attached cargo. Here, the interactions of TAT peptide, G5 polyamidoamine dendrimer and polyethyleneimine with four GAGs were studied through microcalorimetry to determine binding thermodynamics. Significant differences in affinity and stoichiometry were seen, likely reflecting charge density and hydroxyl stereochemistry variations in GAG structure, which have been characterized by colorimetric assay and NMR. Competitive displacement assays were used to quantify the concentration of each GAG needed to disrupt DNA complexes of the CPCs, to model premature release of cargo at the cell surface. CPCs showed lower affinity to lipid vesicle model cell membranes than to GAGs, revealing the potential importance of their GAG interaction for cell surface recognition. These results lead to understanding the role these GAGs play in the cellular internalization of biomaterials, which will contribute to the design of systems with enhanced uptake ability and have implications in targeted delivery to a variety of cell types with different expression levels of these GAG receptors.

Structure affects the interactions of cell-penetrating compounds with cell-surface glycosaminoglycans and lipid vesicle model membranes

247th National Meeting (2014)

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