Effects of solution concentration on the physicochemical properties of a polymeric anticancer therapeutic

Poly(γ-glutamyl-glutamate) paclitaxel (PGG-PTX) is a series of eighteen semiflexible polymer-drug constructs varying in PTX loading fraction (f(PTX) of 0.18, 0.24, and 0.37) and spatial PTX arrangement (uniform, "even" and "random"; clustered, "clusters" and "ends"; concentrated, "ends" and "side"). Structural properties of PGG-PTX in dilute and concentrated conditions are determined from coarse-grained molecular dynamics (MD) simulations. Since PGG-PTX does not have a specific conformation, MD simulations were run until minimal structural deviations persisted. Root-mean-square deviation (RMSD) clustering was then used to determine the significant, unique characteristic conformations. Results show that dilute PGG-PTX undergoes a globule-to-filament transition with respect to increasingly denser PTX arrangements. While a similar transition is apparent in concentrated conditions, PGG-PTX tends to be more filamentous on the whole. PGG-PTX is also more rigid in concentrated conditions, and a higher PTX loading fraction leads to decreased flexibility. In general, the dilute "ends", "middle", and "side" PGG-PTX molecules at f(PTX) = 0.18 and 0.24 prove to be the most efficaciously promising and are recommended for future biological testing. This study demonstrates the practicality of molecular modeling toward understanding structural behavior of an anticancer therapeutic in different solution concentrations.