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. [Figure not available: see fulltext.].
|Number of pages||10|
|Journal||Drug Delivery and Translational Research|
|State||Published - Feb 2021|
Bibliographical noteFunding Information:
This work was supported by the National Institute of Health grants R01-HL-136149 to R.B.F. and S10-OD-019941 to R.M.W., and by the Lyle and Sharon Bighley Professorship (A.K.S.). B.E.G. was supported by the National GEM Consortium, the Alfred P. Sloan Minority Ph.D. Scholarship and the University of Iowa Graduate College Dean’s Fellowship.
© 2020, Controlled Release Society.
- Heart failure
- MEK1/2 inhibitor
- Sustained release
ASJC Scopus subject areas
- Pharmaceutical Science