Comparative evaluation of Estredox, a brain-targeted estradiol delivery system versus traditional estrogen replacement therapy.

Estredox is a novel brain-targeted delivery system for estradiol (E2). The mechanism of this estradiol-chemical delivery system (E2-CDS) is based on an interconvertible dihydropiridine <--> pyridinium salt carrier (targetor) attached to E2. After administration of the E2-CDS, the targetor moiety is oxidized to a quaternary pyridinium salt (E2-Q+). Here we demonstrate that a single i.v. injection with E2-CDS (3 mg/kg) resulted in sustained presence of E2-Q+ in three various brain regions. The sustained and gradual release of estradiol from E2-Q+ is reflected by the time-course of plasma estrogen level. At the end of repeated administration of E2-CDS (daily once 0.3 mg/kg i.v. for 10 consecutive days) we found a sharp decrease in the levels of plasma estradiol followed by a gradual decrease. The levels of E2-Q+ in the investigated brain regions decreased gradually from the first post-treatment day, however, a detectable amount of E2-Q+ was still present in the hypothalamus, striatum, and cortex even on the 24th post-treatment day. Strikingly different plasma estradiol levels were found in the groups of orchidectomized rats that received daily i.v. injections of estradiol benzoate (E2-BZ). The plasma estradiol levels in these animals were much higher compared to E2-CDS-treated animals throughout the treatment period but the level sharply dropped immediately after the treatments. In contrast to the E2-CDS-treated animals there was no estradiol in any of the brain regions of E2-BZ-treated rats on the 1st and 2nd post-treatment day. All of these data are in line with the long-lasting pharmacological effects of E2-CDS-treatment on estrogen-mediated functions in castrated rats and give further experimental support for brain-targeting estrogen-treatment approach as opposed to the traditional estrogen replacement therapy.