PD98059 is a reversible MEK inhibitor that we are investigating as a potential 
treatment for neurochemical changes in the brain that drive neurohumoral 
excitation in heart failure. In a rat model that closely resembles human heart 
failure, we found that central administration of PD98059 inhibits 
phosphorylation of ERK1/2 in the paraventricular nucleus of the hypothalamus, 
ultimately reducing sympathetic excitation which is a major contributor to 
clinical deterioration. Studies revealed that the pharmacokinetics and 
biodistribution of PD98059 match a two-compartment model, with drug found in 
brain as well as other body tissues, but with a short elimination half-life in 
plasma (approximately 73 min) that would severely limit its potential clinical 
usefulness in heart failure. To increase its availability to tissues, we 
prepared a sustained release PD98059-loaded PLGA microparticle formulation, 
using an emulsion solvent evaporation technique. The average particle size, 
yield percent, and encapsulation percent were found to be 16.73 μm, 76.6%, and 
43%, respectively. In vitro drug release occurred over 4 weeks, with no 
noticeable burst release. Following subcutaneous injection of the microparticles 
in rats, steady plasma levels of PD98059 were detected by HPLC for up to 
2 weeks. Furthermore, plasma and brain levels of PD98059 in rats with heart 
failure were detectable by LC/MS, despite expected erratic absorption. These 
findings suggest that PD98059-loaded microparticles hold promise as a novel 
therapeutic intervention countering sympathetic excitation in heart failure, and 
perhaps in other disease processes, including cancers, in which activated MAPK 
signaling is a significant contributing factor. Graphical abstract.