Novel Drug-Delivery Technologies for Localized Control of Adrenal Corticosteroid Concentrations

My research seeks to develop novel drug delivery techniques for manipulating local tissue concentrations of adrenal corticosteroids. Using these novel delivery techniques, we explore the therapeutic benefit of localized control of corticosteroid concentrations. 

The adrenal glucocorticoid, cortisol, plays a wide range of roles in health and disease.  Bone, the cardiovascular and renal systems, feeding behavior and metabolic homeostasis, immune system function, and mood and cognition are all under the control of the adrenal glucocorticoids. 

Natural and synthetic glucocorticoids, such as hydrocortisone and dexamethasone, are among the most widely utilized drugs on the market.  The glucocorticoids are particularly effective at suppressing inflammation and relieving inflammatory pain, yet one of the primary detrimental effects of long-term glucocorticoid use is bone loss and the development of osteoporosis. 

While the glucocorticoids make extremely effective drugs, their ubiquitous organ system effects increase the likelihood of developing undesirable side effects when these compounds are administered systemically.  Therefore, my laboratory is interested in the technologies that allow for localized manipulation of corticosteroid hormone concentrations so that the benefit of the change in the local concentration of the corticosteroid can be realized without the widespread deleterious systemic effects.

When corticosteroids are secreted from the adrenal gland, they regulate their effects on target cells by binding and activating their receptors, which are intracellular transcription factors called the mineralocorticoid (MR) and glucocorticoid (GR) receptors.  Importantly, the concentrations of various corticosteroids in target tissues and their ability to activate MR and GR are controlled by the local expression of enzymes such as the 11β-hydroxysteroid dehydrogenase enzymes (11β-HSD, Type 1 and Type 2).

The 11β-HSDs are present in many corticosteroid target tissues, including bone, and in the intra-articular synovial fluid.  Therefore, local regulation of corticosteroid concentrations plays an important role in healing processes such as bone regeneration and pathological processes such as arthritic joint inflammation. 

Our goal is to utilize novel drug delivery technologies such as injectable scaffolds and implantable release devices to manipulate the local concentrations of corticosteroids through the localized delivery of enzymes such as the 11β-HSDs.  It could be therapeutically beneficial to elevate cortisol levels in an inflamed arthritic joint or to decrease cortisol levels at the site of a fracture, for example.  Therefore, through various approaches, our work explores the utility of localized control of corticosteroid levels and develops novel drug delivery technologies and strategies for the realization of the local control of corticosteroid concentration.

Research Funding

Completed

NIH/NICHD, HD047890 (PI); 07/04-06/08
Effects of in utero exposure to anti-epileptic drugs on fetal neuronal structural and functional damage

NIH/NIA, R03, AG022624 (PI); 05/04-04/06
Ovarian senescence and adrenal hormone responses

Georgetown Intramural Research Grant (PI); 07/04-06/05
Estrogen, estrogen receptors, and body weight homeostasis

The Center for Biological Modulators, Korea Research Institute of Chemical Technology (PI); 01/03-09/05
Development of selective estrogen receptor modulators for the prevention of postmenopausal obesity and cardiovascular disease

National Kidney Foundation of the National Capital Area, Inc. (PI); 08/03-07/04
Ovarian steroid modulation of aldosterone secretion

NIH/NHLBI, F32, National Research Service Award (PI); 08/00-07/03
Effect of estradiol on aldosterone responses and actions