Coacervation in polyzwitterion-polyelectrolyte systems and their potential applications for gastrointestinal drug delivery platforms

Abstract

Traditionally, complex coacervation is regarded as a process whereby two oppositely charged polyelectrolytes self-assemble into spherical droplets. Here, we introduce the polyzwitterionic complex, “pZC”, formed by the liquid-liquid phase separation of a polyzwitterion and a polyelectrolyte, and elucidate a mechanism by which such complexes can assemble using theory and experimental evidence. This system exhibits orthogonal phase behavior-it remains intact in acidic conditions, but disassembles as the pH increases, a process governed by the acid-base equilibria of the constituent chains. We relate the observed phase behavior to physiological conditions within the gastrointestinal tract with a simulation of the gastroduodenal junction, and demonstrate using video microscopy the viability of polyzwitterionic coacervates as technologies for the pH-triggered release of cargo. Such a system is envisaged to tackle imminent problems of drug transport via the oral route and serve as a packaging solution to increase uptake efficiency.

Theory of self-coacervation in semi-dilute and concentrated zwitterionic polymer solutions

“…Note that the latter approximation was adopted in recent works. 31,32 As is seen, the theory based on the Keesom approximation coincides with the present RPA-based theory only within a narrow region of the electrostatic strength (where the polymer volume fraction in the coacervate is close to zero). However, at a rather high value of the electrostatic strength, the Keesom approximation considerably overestimates the polymer volume fraction in the coacervate phase relative to the RPA-based theory.…”

“…Using a mean-field theory accounting for the entropy of all dissociated ions in the system, electrostatic interactions between the dipolar and charged segments of the complexes and separated polyelectrolytes, and polymer-solvent hydrophobicity, the authors predicted closed liquid-liquid phase diagrams with lower and upper critical points of such a system in terms of the polyelectrolyte composition, added salt concentration, and temperature. In paper 32 using similar mean-field theory, the authors described the complex coacervation formed by the liquid-liquid phase separation of a polyzwitterion and a polyelectrolyte. The authors demonstrated the potential of polyzwitterionic coacervates as a tool for pH-triggered release of pharmaceutically active compounds inside the gastrointestinal tract.…”

Dipole-driven interlude of mesomorphism in polyelectrolyte solutions

“…An understanding of the role of dipolar interactions in these systems of intermolecular complexation is only at its infancy. Even in the simplest case of uniformly dipolar polymers such as polyzwitterions, where the focus has been on the effects arising from hydrophobic effects, the role of dipolar interactions in the formation of their intrinsic structures and their complexes with polyelectrolytes remains unexplored ( 23 – 30 ).…”

Effects of Control Factors on Protein–Polyelectrolyte Complex Coacervation

“…For example, there has been increasing evidence of the involvement of coacervation in neurodegenerative diseases, such as amyotrophic lateral sclerosis (ALS), , frontotemporal dementia, and Alzheimer’s disease . Moreover, the formation principles and functionalities (solute condensation and surface and responsive properties) of the coacervates are inspirational for developing soft materials for biomedical applications, − e.g., the vehicles for intracellular drug delivery as discovered recently. , …”

“…12 Moreover, the formation principles and functionalities (solute condensation and surface and responsive properties) of the coacervates are inspirational for developing soft materials for biomedical applications, 13−17 e.g., the vehicles for intracellular drug delivery as discovered recently. 18,19 Among the diverse coacervation systems, protein-involved complex coacervation, typically with oppositely charged polymers, demonstrates an essential yet challenging process arising from the protein structure and charge features. 20,21 First of all, proteins are made up of different amino acids, so there is always a corresponding isoelectric point (pI) under which the proteins are supposed to have equal numbers of positive and negative charges.…”