Small molecule hydrophobic drugs can self-assemble to colloidal drug aggregates in aqueous media, interfering with conventional drug screening strategies, such as enzyme inhibition and cellular toxicity assays. For example, when colloidal drug aggregates form during enzyme inhibition assays, adsorption of enzymes to the colloidal surface leads to inhibition, falsely indicating that the drug is efficacious. Colloidal drug aggregates also form in high protein milieus such as cell culture media and can be problematic in cell toxicity assays. We found that the inability of colloidal aggregates to cross the cell membranes leads to cells remaining viable, falsely indicating that the drug is ineffective. As opposed to the typical sigmoidal dose-response curves, colloidal drug aggregates can lead to bell-shaped curves. Thus colloidal drug aggregation is problematic in drug screening.<br/><br/>With the goal of turning these lemons into lemonade, we sought to stabilize colloidal drug aggregates. To this end, we examined a series of different strategies, including co-aggregation with dyes, such as Congo Red and Evans Blue, and co-formulation with proteins and polymeric surfactants. We found that different strategies are effective with different colloidal drug aggregates. For example, fulvestrant is more effectively stabilized with BSA than with IgG; and the surfactant, UP80, is more effective than the proteins. Interestingly, a doxorubicin prodrug, PPD, is more effectively stabilized with a custom-synthesized amphiphilic polymer than with UP80, reflecting the individual properties of each colloid-forming compound. These drug colloid formulations remain stable in serum containing media and can then be assayed for cell toxicity.

Self-assembly of chemotherapeutic colloidal drug aggregates

253rd National Meeting (2017)

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