End group chemistry modulates physical properties and biomolecule release from biodegradable polyesters

Abstract

Long-acting injectable protein therapeutics are a rapidly advancing arm of pharmaceuticals. A promising and versatile class of such formulations involves encapsulation of therapeutic protein within poly(lactic-co-glycolic acid) (PLGA) degradable microparticles (MP) to shield the protein from enzymatic degradation and control the release rate. However, models based on degradation and erosion of PLGA polymer matrices do not always fully capture release behavior, due in part to electrostatic interactions between the polymer terminal group and encapsulated compound. The repertoire of functionalized PLGA polymers commercially available has now expanded to include terminal group chemistries that may significantly alter polymer characteristics including charge, hydrophobicity, and erosion. This work aims to explore how PLGA terminal group chemistry affects polymer physical properties and charged biomolecule release kinetics. PLGA with hydroxyl (PLGA–OH), amine (PLGA–NH₂), or carboxylic acid (PLGA–COOH) terminal groups that have neutral, positive, or negative charge, respectively, were evaluated. Experiments assessing the physical properties of the polymers indicate PLGA–NH₂ has reduced hydrophobicity, degrades faster, exhibits emulsion stabilizing behavior, and has reduced phagocytic clearance by bone marrow derived macrophages. Charged biomolecule release rates are increased from PLGA–NH₂ MPs and slightly accelerated from PLGA–OH MPs, compared to PLGA–COOH MPs. These studies provide further insight into the interactions between charged biomolecules and the encapsulating polymer and could provide additional tools to tune release for various protein therapeutics that experience such interactions.