Selective drug delivery system to bone: 3GLA-conjugation

Abstract

Abstract

Background The concept of drug delivery system is to deliver drug directly to certain organ without distributing to other tissues causing adverse effect. Based on this system, we developed a novel osteotropic prodrug of estradiol (E2) conjugated with gamma-caboxyglutamic acid (Gla), the main specific amino acid in osteocalcin for using as drug delivery system.

Objectives To determine whether Gla-estradiol conjugation can serve as target-specific drug carrier.

Study design Experimental study

Setting Tokyo Medical and Dental University, Tokyo, Japan

Results Hydroxyapatite binding assay showed this molecule could bind to hydroxyapatite. After being conjugated with dansyl chloride, fluorescent for labeling amino acid, this molecule specifically distributed to bone. In vivo study, ovariectomized mice injected subcutaneously with Gla3-estradiol revealed that this compound could prevent bone loss without estrogen-like adverse effect. According to estrogen receptor a binding assay, this molecule itself could not bind to estrogen receptor, resulting from changing its hydrophobicity but it could release and permit estradiol to enter the cell.

Conclusion These findings indicate that Gla3-estradiol can be used as an osteotropic drug delivery agent. Its metabolism, however, is still to be thoroughly investigated. Thus, after optimal modification, we may use this molecule for efficient and effective treatment of bone disease in clinical situation in the near future.

Key words: 17a-estradiol, gamma-carboxyglutamic acid, MCF-7 cell, Osteotropic drug delivery system, ovariectomized mice