Complexation of Polyelectrolytes with Hydrophobic Drug Molecules in Salt-Free Solution: Theory and Simulations

Abstract

The delivery and dissolution of poorly soluble drugs is challenging in the pharmaceutical industry. One way to significantly improve the delivery efficiency is to incorporate these hydrophobic small molecules into a colloidal polyelectrolyes(PE)-drug complex in their ionized states. Despite its huge application value, the general mechanism of PE collapse and complex formation in this system has not been well understood. In this work, by combining a mean-field theory with extensive molecular simulations, we unveil the phase behaviors of the system under dilute and salt-free conditions. We find that the complexation is a first-order-like phase transition triggered by the hydrophobic attraction between the drug molecules. Importantly, the valence ratio between the drug molecule and PE monomer plays a crucial role in determining the stability and morphology of the complex. Moreover, the sign of the zeta potential and the net charge of the complex are found to be inverted as the hydrophobicity of the drug molecules increases. Both theory and simulation indicate that the complexation point and complex morphology and the electrostatic properties of the complex have a weak dependence on chain length. Finally, the dynamics aspect of PE-drug complexation is also explored, and it is found that the complex can be trapped into a nonequilibrium glasslike state when the hydropobicity of the drug molecule is too strong. Our work gives a clear physical picture behind the PE-drug complexation phenomenon and provides guidelines to fabricate the colloidal PE-drug complex with the desired physical characteristics.

Nano-Assembly of Quisinostat and Biodegradable Macromolecular Carrier Results in Supramolecular Complexes with Slow-Release Capabilities

“…Therefore, it was largely assumed that such constructs may be physiologically unstable [42][43][44]. However, hydrophobic organic counterions are expected to minimize unfavorable contacts with water molecules, which can lead to a desirable counterion "condensation" and physiologically stable drug-carrier complexes [43,45,46]. Unfortunately, this phenomenon can also cause potential collapse of polymer chain and undesirable phase separation [31,32,40,47].…”

Dynamic Coupling in Unentangled Liquid Coacervates Formed by Oppositely Charged Polyelectrolytes

“…The phase with high polymer concentration is called a coacervate and is frequently used in the food and consumer product industries. Research interest in such materials is, in part, driven by emerging technological applications such as protein encapsulation for drug delivery, − model protocells for the study of synthetic cell-like entities, , and the design of functional coatings, , fibers, and self-healing materials. , Coacervates are also observed in a variety of biological systems, e.g., sandcastle worms secrete oppositely charged polyelectrolytes to create underwater bioadhesives, and coacervation of intrinsically disordered proteins is important for cellular function. , Such applications have motivated numerous studies ,− of their thermodynamic properties. However, despite their importance for the design and processing of coacervates, the dynamic and flow properties of coacervates and their connection to microscopic structure remain poorly understood …”

Tuning the collapse transition of weakly charged polymers by ion-specific screening and adsorption

“…This would allow to build a predictive model, which may be applied for determination of protein stability, but also for designing biomaterials of desired properties in their native environments. Computer simulations have already illuminated the action of varying solvents and cosolutes in coarse-grained simulations 26,[28][29][30][31][32][33][34] or all-atom simulations 21,[35][36][37] . Typically the results are interpreted by theories for chain structure and swelling, 38 e.g., due to a counterion condensation at highly charged polymers [39][40][41][42][43] or specific steric interactions.…”