Characterization of a clinical polymer‐drug conjugate using multiscale modeling

The molecular conformation of certain therapeutic agents has been shown to affect the ability to gain access to target cells, suggesting potential value in defining conformation of candidate molecules. This study explores how the shape and size of poly‐γ‐glutamyl‐glutamate paclitaxel (PGG‐PTX), an amphiphilic polymer‐drug with potential chemotherapeutic applications, can be systematically controlled by varying hydrophobic and hydrophilic entities. Eighteen different formulations of PGG‐PTX varying in three PTX loading fractions (f_PTX) of 0.18, 0.24, and 0.37 and six spatial arrangements of PTX (‘clusters’, ‘ends’, ‘even’, ‘middle’, ‘random’, and ‘side’) were explored. Molecular dynamics (MD) simulations of all‐atom (AA) models of PGG‐PTX were run until a statistical equilibrium was reached at 100 ns and then continued as coarse‐grained (CG) models until a statistical equilibrium was reached at an effective time of 800 ns. Circular dichroism spectroscopy was used to suggest initial modeling configurations. Results show that a PGG‐PTX molecule has a strong tendency to form coil shapes, regardless of the PTX loading fraction and spatial PTX arrangement, although globular shapes exist at f_PTX = 0.24. Also, less uniform PTX arrangements such as ‘ends’, ‘middle’, and ‘side’ produce coil geometries with more curvature. The prominence of coil shapes over globules suggests that PGG‐PTX may confer a long circulation half‐life and high propensity for accumulation to tumor endothelia. This multiscale modeling approach may be advantageous for the design of cancer therapeutic delivery systems. © 2010 Wiley Periodicals, Inc. Biopolymers 93: 936–951, 2010.