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Novel Drug Delivery System to Bone Using Acidic Oligopeptide: Pharmacokinetic Characteristics and Pharmacological Potential

2001; Taylor & Francis; Volume: 9; Issue: 2 Linguagem: Inglês

10.3109/10611860108997922

1061-186X

Tohru Sekido, Naoki Sakura, Yasuhiko Higashi, Kazuhiro Miya, Youko Nitta, Masaaki Nomura, Hiroyuki Sawanishi, Keiko Morito, Yukito Masamune, Shohei Kasugai, Koiçhi Yokogawa, Ken-Ich Miyamoto,

Estrogen and related hormone effects

We synthesized fifteen oligopeptides consisting of Asp or Glu conjugated with a fluorescent probe, 9- fluorenylmethylchloroformate (Fmoc). In the in vitro binding assay to putative hydroxy apatite (HA), the affinities of these conjugates depended only on the number of amino acid residues, not on their 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 into mice, peptides consisting of over six Asp residues were selectively distributed to the bone. Then, we synthesized estradiol-17β-succinate-(L-Asp)6 [E2-(L-Asp)6] and studied its pharmacokinetic characteristics and its antiosteoporotic effects on ovariectomized (OVX) mice. Although the distribution volume of E2-(L-Asp)6 was significantly smaller than that of E2, E2-(L-Asp)6 was selectively distributed in the bone after i.v. injection and gradually decreased during 7 days. E2-(L-Asp)6 effectively prevented OVX-induced bone loss, without altering the uterine weight, in the dosage range of 0.11 to 1.1 μmol/kg once a week, while E2 increased both the bone mineral density and uterine weight at 0.37 μmol/kg every third day. The results suggest that acidic oligopeptide may be useful for drug delivery to bone and E2-(L-Asp)6is a good candidate as an anti-osteoporosis drug without the adverse side effects of E2.