Colloidal drug formulations can explain "bell-shaped" concentration-response curves

Area of Science:

• Pharmacology
• Physical Chemistry
• Biophysics

Background:

• Drug efficacy often shows sigmoidal concentration-response curves.
• Bell-shaped curves, indicating complex biological effects, have puzzled researchers for decades.
• A physical property-based mechanism for bell-shaped curves is investigated.

Purpose of the Study:

• To investigate a physical property-based mechanism for bell-shaped drug concentration-response curves.
• To determine if colloidal aggregation of drugs causes bell-shaped curves.
• To explore the mechanism of activity loss at high drug concentrations.

Main Methods:

• Determined concentration-response curves for three aggregating anticancer drugs formulated as colloids and monomers.
• Assessed 12 literature-reported bell-shaped curve molecules for colloidal aggregation.
• Investigated colloidal species' cell permeability using Evans blue dye.

Main Results:

• Colloidal drug formulations exhibited bell-shaped curves, losing activity at higher concentrations.
• Monomeric formulations showed typical sigmoidal curves with sustained activity.
• Five out of 12 tested molecules with bell-shaped curves formed colloidal aggregates.
• Colloidal species were excluded from cells, unlike monomers.

Conclusions:

• Colloidal aggregation is a key mechanism driving bell-shaped drug concentration-response curves.
• Drug aggregation leads to reduced efficacy at higher concentrations due to cellular exclusion.
• This finding has implications for drug formulation, efficacy, and toxicological screening methods.