Molecular Design of a Nanoparticle-Polymer Conjugated Drug Delivery System for PD-166793 in Cardiovascular Repair

Overexpression of matrix metalloproteinases (MMPs) following myocardial infarction (MI) is linked to deleterious left ventricle remodeling and heart failure. Current research has focused on introducing a therapeutically relevant concentration of effective MMP inhibitor to the MI site to mitigate the harmful tissue remodeling. Theoretical molecular level studies provide an effective platform for designing novel delivery systems for MMP inhibition that can provide valuable insights for experimental researchers. This study focuses on developing a drug delivery pathway using PD-166793 that has shown great promise as a broad spectrum MMP inhibitor in recent years. In this system, PD-166793 is bound to poly methyl acrylic acid (PMAA) polymer and one end of the polymer is tethered to a spherical silica nanoparticle surface to carry the drug to the desired site. A molecular model using single chain mean field theory (SCMFT) is used to scan the wide range of possible design parameters. The molecular theory properly accounts for the highly non-additive coupling of molecular interactions among all the species. The size, shape, electrical properties and physical conformations of the polymer, drug and solvent are taken into account. The binding of PD-166793 with polymer is modeled by a ligand-receptor binding mechanism. The model is used to study the variation of this binding with changing pH, salt concentration, grafting density and length of the polymer. Experimental studies have shown that this system is capable of retaining PD-166793 at more than 100 times the inhibitory concentration against MMP-2 with a particle concentration of 2.5mg/mL. The model is used as a tool for continual improvements in binding of PD-166793 by providing valuable feedback on how the variations of system parameters affect the binding efficiency.