A Theoretical Study of Polymer-Based Drug Delivery Systems

Abstract

A variety of interactions between drug delivery devices and local cells and tissues impact clinical outcomes in terms of both therapeutic action and biological response. Understanding the competition of interactions in highly inhomogeneous environments such as those relevant in tissue engineering, nanotechnology, and those responsible for biological cell function is critical to the further development of design platforms for delivery systems. We use a three dimensional mean-field theory to study the competition between electrostatic, van der Waals and steric interactions in determining the molecular organization of micelles made of ampliphilic diblock polybases designed to carry doxorubicin to cancer cells. The micelles are assumed to target cancer cells primarily through electrostatic binding as several cancers are known to flip negatively charged lipids to the outer-leaflet. The polyelectrolyte micelles spontaneously form self-assembled aggregates whose physical properties are manipulated by the composition of the solution in contact with the polymer system. These theoretical calculations show that chemical equilibrium and the relevant physical interactions present in responsive polymer micelless couple in such a highly non-additive manner that the qualitative physics can only be accurately determined through a highly detailed molecular theory.We find that charge regulation stabilizes micellar domains over a wide range of pH by reducing the local charge in the aggregate at the cost of chemical free energy and gaining in the van der Waals attractive interactions. The balance of interactions in this highly inhomogeneous environment determines the boundaries between different carrier and release morphologies. We predict the formation of polymer micelle phases based on the proper choice of solution pH and salt concentration, and one can use these predictions to provide design guidelines for the creation of responsive polymer delivery systems presenting self-organized patterns with the desired functional properties.