Augmentation of all-trans-retinoic acid concentration in plasma by preventing inflammation responses induced by atRA-loaded microspheres with concurrent treatment of dexamethasone

Abstract

All-trans retinoic acid (atRA)-loaded microspheres severely induce inflammatory responses after microsphere implantation. Fibroblasts and a thick band of fibrous capsule resulting from the inflammatory responses could hamper drug permeation to the bloodstream because fibroblasts actively metabolize atRA into polar metabolites and the thick fibrous capsule acts as a diffusion barrier. In the present study, we investigated whether the fibroblast proliferation and collagen deposition induced by atRA released from microspheres might affect the atRA concentration in plasma and atRA metabolism with or without treatment of dexamethasone as an anti-inflammatory drug. After subcutaneous injection of atRA-loaded microspheres in rats, it was observed that atRA-loaded microspheres induced severe inflammatory responses and stimulated fibroblast proliferation and collagen deposition in fibrous capsules. On the other hand, the orally treated dexamethasone effectively prevented inflammatory responses in a dose-dependent manner and suppressed about 49% of the number of fibroblasts and collagen deposition in fibrous capsules at 14 days. In addition, after the treatment of dexamethasone, the atRA concentration in plasma was increased, and its metabolism was decreased approximately by 40% at 7 days, compared to the group treated alone with atRA-loaded microspheres. In conclusion, the concurrent treatment of dexmethasone with atRA-loaded microspheres could prevent inflammatory responses and metabolism of atRA, thereby maintaining the atRA concentration in plasma for longer periods in the therapeutic range.