Formulation of pH-Responsive Methacrylate-Based Polyelectrolyte-Stabilized Nanoparticles for Applications in Drug Delivery

Abstract

pH-responsive polyelectrolytes, including methacrylate-based anionic copolymers (MACs), are widely used as enteric coatings and matrices in oral drug delivery. Despite their widespread use in these macroscopic applications, the molecular understanding of their use as stabilizers for nanoparticles (NPs) is lacking. Here, we investigate how MACs can be used to create NPs for therapeutic drug delivery and the role of MAC molecular properties on the assembly of NPs via flash nanoprecipitation. The NP size is tuned from 59 to 454 nm by changing the degree of neutralization, ionic strength, total mass concentration, and the core-to-MAC ratio. The NP size is determined by the volume of hydrophilic domains on the surface relative to the volume of hydrophobic domains in the core. We calculate the dimensions of the hydrophobic NP core relative to the thickness of the polyelectrolyte layer over a range of ionizations. Importantly, the results are shown to apply to both high-molecular-weight polymers as core materials and small-molecule drugs. The pH responsiveness of MAC-stabilized NPs is also demonstrated. Future development of polyelectrolyte copolymer-stabilized nanomedicines will benefit from the guiding principles established in this study.

The use of supramolecular systems in biomedical applications for antimicrobial properties, biocompatibility, and drug delivery

“…Being sensitive to the change of pH is not necessarily a drawback, some researchers use this property to control the drug release profile of the system. For example, Kim et al [73] studied pH-sensitive polymer coating by supramolecular complexation for therapeutic drug delivery. The research team focused on the influence of methacrylate-based anionic copolymers on the stability of nanoparticles.…”

Nanoscale Ion-Exchange Materials: From Analytical Chemistry to Industrial and Biomedical Applications

“…Reisch et al [ 26 ] proposed a simple and flexible protocol for the preparation of ultrasmall NIEs based on charge-controlled nanoprecipitation that basically only requires dissolving a charged polymer in a water-miscible solvent and adding this solution to water. In some cases, the assembly of NIEs needs virtually no polymerization, such as for particles that consist of a hydrophobic polymeric core and an anionic methacrylate-based layer, and nanoization can be attained using flash nanoprecipitation [ 42 ]. In this kinetically controlled process, an organic stream containing core and amphiphilic polymer materials is mixed under turbulent flow conditions with an aqueous stream, promoting uniform nucleation and particle growth.…”

“…In another recent study, an anionic PMMA-based polymer approved by the FDA was applied to poly(lactic acid) nanoparticles, and, simultaneously, a small-molecule therapeutic drug was incorporated into the structure, thereby creating an effective oral nanoformulation [ 42 ]. The drug release from the nanoparticle core largely depends on the pH responsiveness of the polymer coating provided by the presence of carboxyl groups.…”

“…On the other hand, the charge density measurements can be carried out instrumentally by a particle charge detector [41]. Another parameter indicative of the number of ionizable groups is the degree of neutralization (or percent of neutralization), which is reliably quantified by 13 C NMR spectroscopy [42]. For PS-based NIEs, the surface charge, surface-to-volume ratio, and electric potential have been estimated by calculation but without experimental verification [31].…”