Positive charge of “sticky” peptides and proteins impedes release from negatively charged PLGA matrices

Abstract

The influence of electrostatic interactions and/or acylation on release of charged (“sticky”) agents from biodegradable polymer matrices was systematically characterized. We hypothesized that release of peptides with positive charge would be hindered from negatively charged poly(lactic-co-glycolic acid) (PLGA) microparticles. Thus, we investigated release of peptides with different degrees of positive charge from several PLGA microparticle formulations, with different molecular weights and/or end groups (acid- or ester-terminated). Indeed, release studies revealed distinct inverse correlations between the amount of positive charge on peptides and their release rates from each PLGA microparticle formulation. Furthermore, we examined the case of peptides with net charge that changes from negative to positive within the pH range observed in degrading microparticles. These charge changing peptides displayed counterintuitive release kinetics, initially releasing faster from slower degrading (less acidic) microparticles, and releasing slower from the faster degrading (more acidic) microparticles. Importantly, trends between agent charge and release rates for model peptides also translated to larger, therapeutically relevant proteins and oligonucleotides. The results of these studies may improve future design of controlled release systems for numerous therapeutic biomolecules exhibiting positive charge, ultimately reducing time-consuming and costly trial and error iterations of such formulations.

TRI Microspheres prevent key signs of dry eye disease in a murine, inflammatory model

“…TGF-β microspheres (MS) were reformulated from what was previously described [refs 28 – 31 ] to eliminate the 20-day initial lag phase of release in the prior formulation. The new formulation of TGF-β MS contains a PEG-PLGA diblock copolymer (4 wt%, Mn ~5 kDa), which accelerated release by increasing matrix swelling, and the ester-terminated PLGA helped to minimize the electrostatic interactions between the PLGA polymer and the positively charged protein 32 . After measuring the release of TGF-β, the surface morphology of the microspheres was characterized using scanning electron microscopy (SEM).…”

Fabrication and characterization of PLGA nanoparticles encapsulating large CRISPR–Cas9 plasmid

“…The formation of acid groups due to hydrolysis is probably why lower DNA release was measured for the lower pH cases. Hydrolysis of PLGA is catalyzed by acidic conditions and, as the PLGA breaks down to form more acid groups, the local pH inside the core decreases [19]. This positive feedback loop accelerates the further breakdown of PLGA [20].…”

“…If the DNA is exposed to these highly acidic conditions for a long period of time, it could degrade quickly and fall below the detection limit of the assay. Balmert et al [19] estimated the intraparticle pH of ester endcapped PLGA microparticles (MW = 15 kDa) as ~ 3-4 within 1-3 days in neutral pH media conditions. This may account for the relatively rapid release of the DNA.…”

Effect of Stabilizers on Encapsulation Efficiency and Release Behavior of Exenatide-Loaded PLGA Microsphere Prepared by the W/O/W Solvent Evaporation Method

“…At pH 7.4, even though the incubation was short, ionization of carboxylic acid groups could occur by hydration because used PLGA503H is uncapped PLGA. A negative or neutral net charge of the peptide could mask the fact that positively charged residues can still exist and may interact electrostatically with negatively charged carboxylic acid end-groups of PLGA [54]. Nevertheless, it is natural that non-specific interactions are reduced.…”