Macromolecular Dimensions of a Synthetic Polyelectrolyte as a Factor in its Interactions with Protein and Cells -Longer Chains are Favoured

Abstract

Understanding the mechanism of interactions between synthetic polyelectrolytes and ionic matter ubiquitous in living systems, such as proteins and cells, is a fundamental challenge and an important requirement for their clinical development as biomaterials and drug delivery systems. In contrast with small molecules or proteins, in which an active center or epitope largely defines the binding pattern, ionic polymers utilize a plurality of repeat units, which, individually, capable of only weak interactions with the target. Although, it can be expected that the effects of chain length and cooperativity play an important role in such interactions, this essential factor is often overlooked in practical research. Nevertheless, preclinical experience demonstrates the existence of activity -molar mass relationship for polyelectrolytes. Here, we focus on studying in vitro interactions of a clinical grade macromolecule -poly[di(carboxylatophenoxy)phosphazene] (PCPP), for which such relationship was already established in vivo. We found that polymers of various molar masses show different in vitro avidity to a model antigenic protein -lysozyme, with longer PCPP chains displaying lower dissociation constants and reduced entropic penalties. Higher molar mass polymers result in less compact complex morphologies, in which the protein was easier accessed by the antibody. The trend of greater in vitro activation of engineered immune cells with longer polymer chains was also observed. The results suggest that morphological and entropic benefits provided by higher molar mass polymers are critical in explaining previously observed in vivo trends, and such aspects should be prioritized in designing next generation macromolecular immunoadjuvants.