Analyzing the Release Kinetics of "Sticky" Peptides From PLGA (Poly(lactic-co-glycolic) Acid) Microspheres

Controlled release formulations can dramatically increase the safety and efficacy of peptide therapeutics by increasing the drug’s therapeutic index and improving patient compliance. This technology often takes the form of biodegradable polymers that encapsulate a therapeutic agent and slowly release it as they breakdown over weeks or months. However, controlled release formulations often release macromolecules in a counterintuitive manner; possibly due to the fact that polymers and macromolecules both possess charged functional groups whose potential for interaction remains poorly characterized. To determine the impact of peptide charge on release kinetics, peptides of specific, varying charge were encapsulated in microparticles fabricated with PLGA polymers. These controlled release formulations encompass the impact of the therapeutic peptide, initial polymer charge, and polymer degradation, whose products are anionic.  Release studies were performed for peptide-loaded microparticles. These studies revealed that positive charge on a peptide dramatically impedes its rate of release. To further complicate matters, peptide charge is a function of pH, which changes with time inside of a degrading microparticle as the microenvironment becomes more acidic. Thus, a first-principles diffusion-reaction model was built to predict the generation of the acidic microclimate and subsequently, the peptide charge.  Importantly, a quantitative relationship between the released macromolecule, polymeric delivery device (geometry, dimension, and biomaterial) and the extent of drug retainment could be established, allowing for the prediction of systems where drug-polymer interactions will be maximized or negligible.