T. Sekido et al., Novel drug delivery system to bone using acidic oligopeptide: Pharmacokinetic characteristics and pharmacological potential, J DRUG TAR, 9(2), 2001, pp. 111-121
We synthesized fifteen oligopeptides consisting of Asp or Glu conjugated wi
th a fluorescent probe, 9- fluorenylinethylchloroformate (Fmoc). In the in
vitro binding assay to putative hydroxyapatite (HA), the affinities of thes
e conjugates depended only on the number of amino acid residues, not on the
ir optical characters (L or D) or their species (Asp or Glu). In an in vivo
experiment involving a single i.v. injection of Fmoc-D-Asp oligopeptides i
nto mice, peptides consisting of over six Asp residues were selectively dis
tributed to the bone. Then, we synthesized estradiol-17 beta -succinate-(L-
Asp)(6) [E-2-(L-Asp)(6)] and studied its pharmacokinetic characteristics an
d its antiosteoporotic effects on ovariectomized (OVX) mice. Although the d
istribution volume of E-2-(L-Asp)(6) was significantly smaller than that of
E-2, E-2-(L-Asp)(6) was selectively distributed in the bone after i.v. inj
ection and gradually decreased during 7 days. E-2-(L-Asp)(6) effectively pr
evented OVX-induced bone loss, without altering the uterine weight, in the
dosage range of 0.11 to 1.1 mu mol/kg once a week, while E-2 increased both
the bone mineral density and uterine weight at 0.37 mu mol/kg every third
day. The results suggest that acidic oligopeptide may be useful for drug de
livery to bone and E-2-(L-Asp)(6) is a good candidate as an anti-osteoporos
is drug without the adverse side effects of E-2.