Special delivery. With the help of a tridentate chelating ligand, the estrogenic steroid 17-ethynylestradiol (to the left of the squiggly line) affords effective intracellular delivery of a range of transition metals.

For targets such as breast cancer malignancies, one set of attractive delivery vectors for transition metals consists of estrogen-derived steroid conjugates containing chelating ligands. Like parental estrogenic steroids, these compounds should be readily transported through the blood, then across the cell membrane, and finally into the cell nucleus via estrogen receptor (ER)-binding in the cytoplasm. Furthermore, many types of breast cancer cells are known to be rich in ERs.

Using palladium-catalyzed cross-coupling reactions and a range of transition metals (zinc, nickel, platinum, palladium, and rhenium), a joint group of British researchers at the University of Warwick (Coventry, U.K.) and Amersham Laboratories (Buckinghamshire, U.K.) prepared a group of neutral and monocationic metallo-estrogen complexes based on 17-ethynylestradiol and some metal-chelating moieties (Inorg. Chem. 2001, 40, 3964–3973). Employing competitive binding assays in the presence of isolated ERs and whole cancerous cells (ER-positive human breast cancer cell line MCF-7), the researchers found that all of the estrogen-derived steroidal metal complexes exhibit effective binding to ERs and are delivered across the cell membrane into MCF-7 cells.

Surprisingly, the monocationic palladium and platinum complexes show similar–actually somewhat enhanced—receptor-binding affinities compared with their corresponding metal-free neutral ligands. This finding is unusual because cationic complexes normally have been observed to lower ER binding affinity, and it highlights the importance of hydrophobic and steric interactions over charge effects in designing these vectors.

The researchers are convinced that they have developed a generic synthetic approach for mediated transport of a variety of metal ions with luminescent and radioisotopic imaging potential or chemo- and radiotherapeutic capacities into desired cells. They also believe that this approach can be used for targeted intracellular delivery of chemical species that may bind to a given metal center within metallo-estrogen conjugates.