We have performed two sets of all atom molecular dynamics (MD) simulations of poly(acrylic acid) (PAA) oligomers, considered as a model pH-responsive drug carrier. In the first set, multiple oligomers of PAA are simulated in model gastric and intestinal fluids, where the degree of deprotonation of PAA oligomers is varied with the medium pH. Since the gastric fluid has a pH substantially lower than that of intestinal fluid, PAA is relatively lesser ionized in gastric fluid and forms aggregates. In the second set, we simulated multiple oligomers of PAA with multiple molecules of a cationic anticancer drug, doxorubicin (DOX), for a range of pH values representative of various physiological conditions. The diffusion coefficient of DOX decreases with an increase in pH due to an increase in the ionic complexation of PAA with DOX, despite a decrease in PAA aggregation. Our findings are in agreement with recent experimental reports on pH-triggered targeting of tumor cells by the PAA-DOX system. Results of these two sets of studies establish that both carrier aggregation and carrier-drug interactions are competing influences that together determine the drug release from pH-responsive polymers.
Keywords: cancer; controlled release; diffusion; macromolecular drug delivery; molecular dynamics; pH; pharmacokinetics; polyelectrolytes; polymeric drug carrier; simulations.