Many small molecule drug candidates form colloidal aggregates governed by a critical aggregation concentration, below which the compound exists as free drug monomers. A number of approved drugs form colloidal aggregates at micromolar and sub-micromolar concentrations. Non-specific enzyme inhibition, through protein sequestration to the colloid surface, often leads to false-positives in high-throughput screening. Furthermore, colloids also lead to false-negative results in cell-based assay where the inability of colloids to diffuse across cell membranes leads to an apparent loss in cytotoxic activity of a number of chemotherapeutics.<br/><br/>Though colloids have typically been seen as nuisance compounds, their drug-rich composition and ability to release the monomeric form upon disruption has interesting potential applications. Unfortunately, these aggregates are only transiently stable and often precipitate over the course of a day. In an effort to determine if colloid formation can be exploited, here we investigate the impact of surfactants on colloid stability and interactions with biomolecules. Specifically, we investigate the role of surfactants on the formation and stability of colloid-forming chemotherapeutics. We find that surfactants can stabilize colloids in buffered solutions and biologically relevant media with high protein concentrations, preserving their spherical morphology. Furthermore, the incorporation of surfactants reduces adsorption of proteins to the colloid surface preventing non-specific enzyme inhibition. The results of this work provides further understanding of how the properties of colloidal drug aggregates impact their fate in biological environments.

Controlling colloidal drug aggregate stability and protein adsorption

253rd National Meeting (2017)

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