Osteotropic Drug Delivery System (ODDS) Based on Bisphosphonic Prodrug. V. Biological Disposition and Targeting Characteristics of Osteotropic Estradiol.

Abstract

An osteotropic drug delivery system (ODDS) based on a bisphosphonic prodrug has been developed for 17 beta-estradiol (E2) to improve patient compliance in estrogen replacement therapy of postmenopausal osteoporosis. The biological disposition and the targeting efficiency of a bisphosphonic prodrug of E2, disodium [17 beta-(3'-hydroxy-1',3',5'-estratrienyloxy)carbonylpropyl carboxamidomethylene]bisphosphonate (E2-BP), was investigated in ovariectomized rats. After intravenous injection, E2-BP was rapidly taken up into the bone and subsequently cleared from the bone at a half-life of 13.5 d. The bone concentration of regenerated E2 was maintained throughout 28 d. In contrast, E2 injected intravenously showed extremely low bone distribution and rapid clearance from the bone, and E2 administered orally showed even lower bone distribution. Therapeutic availability (TA) and drug targeting index (DTI), which were calculated on the basis of the AUCs for E2 in the bone and plasma after injection of E2-BP and E2, were 64.6 and 451, respectively. These results suggest that ODDS has a potential to improve not only the apparent potency but also the therapeutic index of E2. As compared with the conventional estrogenic products, E2-BP should improve patient compliance with lower adverse effects and less frequent medication in long-term estrogen replacement therapy.

Targeting Systemically Administered Proteins to Bone by Bisphosphonate Conjugation

“…BSA (lot 107H7600), chicken egg LYZ (lot 90K1922), 2-iminothiolane (2-IT), N-ethylmaleimide (NEM), and all buffer salts were from Sigma (St. Louis, MO). 125 I-labeled proteins were obtained by using 1,3,4,6-tetrachloro-3,6-diphenylglycoluril (iodination reagent; SIGMA) as described elsewhere (6). Free 125 I after iodination was removed by a NAP column (Amersham) and, if necessary, extensive dialysis.…”

Statins and osteoporosis: new role for old drugs

“…Site-specific drug delivery via a pro-drug approach has generated considerable interest for enhancing the potency or diminishing the side effects of a drug. Recently, there have been many reports of targeting drugs to osseous tissue by conjugating them with osteotropic moieties, like bisphopshonates (Fujisaki et al 1995(Fujisaki et al , 1996(Fujisaki et al , 1997(Fujisaki et al , 1998Hirabayashi et al 2001). The drug is linked to a bisphosphonic moiety via bioreversible bonds.…”

Synthesis, characterization and in vitro evaluation of a bone targeting delivery system for salmon Calcitonin

“…In response, investigators have attempted to increase the duration of sCT circulation by conjugation to linear polyethylene glycol (PEG). Compared to native sCT, the PEGylated conjugates showed reduced systemic clearance due to altered tissue distribution, with enhanced in vivo hypocalcaemic efficacy versus native sCT for both the intra-intestinal and pulmonary delivery routes (Lee et al, 2003;Shin et al, 2004;Youn et al, 2006;Fujisaki et al, 1997;Cenni et al, 2008;Cheng et al, 2007). However, increasing the circulation time of non-targeting formulations of sCT would not necessarily translate into optimal bone-based therapeutic effects, as the competitive uptake of sCT by non-bone tissue resident CTRs would still remain despite PEGylation.…”

“…Accordingly, the competitive uptake of available sCT amongst such CTRs likely further reduces sCT availability to bone osteoclast cells, particularly if the drug is administered systemically, and not specifically targeted to bone. Thus, we attempted to develop a delivery system capable of improving sCT targeting, localization and retention to bone with the potential to positively impact sCT therapy, whilst reducing the drug concentration in non-bone loci containing the CTR (Pierce and Waite, 1987;Kasugai et al, 2000;Yokogawa et al, 2001;Orme and Labroo, 1994;Fujisaki et al, 1997;Cenni et al, 2008).…”