UC San Diego

Poly(glutamyl-glutamate) paclitaxel (PGG-PTX) is a potential anticancer therapeutic in preclinical development. There has been increasing attention on how structural and functional properties of therapeutic nanoparticles, such as size, shape, flexibility, surface hydrophilicity, and aggregation, influence efficacy. This thesis demonstrates the application of computer simulations to elucidate these properties of PGG-PTX candidates, which would otherwise be tedious or inaccessible to achieve experimentally. Computer simulations were carried out by running molecular dynamics (MD) simulations on eighteen coarse-grained (CG) PGG-PTX models, varying in the PTX loading fraction (f/PTX = 0.18, 0.24, and 0.37) and spatial PTX arrangement (uniform : 'even' and 'random', clustered : 'clusters' and 'ends', concentrated : 'middle' and 'side') on the PGG backbone. The results show that PGG-PTX molecules with concentrated spatial PTX arrangements produce filamentous shapes and are more flexible, while PGG-PTX molecules with uniform PTX arrangements generate globular morphologies and are less flexible. The PTX loading fraction and spatial PTX arrangement have a minimal effect on the size of a PGG-PTX molecule. Intermolecular aggregation increases with increasing PTX loading fraction, while surface hydrophilicity decreases with increasing PTX loading fraction. The PGG-PTX molecules at f/PTX = 0.24 with concentrated spatial PTX distributions exhibit nonspherical shape, high flexibility, low aggregation, and high surface hydrophilicity. Since these properties have been shown to be clinically advantageous, we recommend the PGG-PTX molecules at f/PTX = 0.24 with concentrated spatial PTX distributions for experimental testing. The shape, flexibility, and surface hydrophilicity of nonpeptide RGD-targeted PGG-PTX systems varying in poly(ethylene glycol) (PEG) spacer length (500 Da, 1000 Da, and 2000 Da) and npRGD ligand density (4, 8, 12, and 16 per PGG-PTX-PEG-npRGD molecule) were also examined. Results from CG MD simulations show that the PGG-PTX- PEG1000-npRGD₈ and PGG-PTX-PEG1000-npRGD₁₂ molecules were the most promising candidates, given their filamentous shape, high flexibility, and high surface hydrophilicity. Overall, we introduce computer simulations as a tool for facilitating the preclinical development of polymeric drug delivery systems