Targeting the estrogen receptor using steroid-therapeutic drug conjugates (hybrids).

The estrogen receptor (ER) is a potentially useful biological target for diagnosis and therapy in hormonally responsive human breast cancer. This protein is often overexpressed both on the membrane and on the nuclear compartment of breast cancer cells and therefore provides a mechanism for targeted drug delivery. Over the past 30 years, many research groups have attempted to exploit the high affinity and receptor selectivity of steroidal estrogens to deliver cytotoxic agents that by themselves lack selectivity.

Design, synthesis, and initial biological evaluation of a steroidal anti-estrogen-doxorubicin bioconjugate for targeting estrogen receptor-positive breast cancer cells.

As part of our program to develop breast cancer specific therapeutic agents, we have synthesized a conjugate agent that is a conjugate of the steroidal anti-estrogen and the potent cytotoxin doxorubicin. In this effort, we employed a modular assembly approach to prepare a novel 11β-substituted steroidal anti-estrogen functionalized with an azido-tetraethylene glycol moiety, which could be coupled to a complementary doxorubicin benzoyl hydrazone functionalized with a propargyl tetraethylene glycol moiety. Huisgen [3 + 2] cycloaddition chemistry gave the final hybrid that was evaluated for selective uptake and cytotoxicity in ER(+)-MCF-7 and ER(-)-MDA-MB-231 breast cancer cell lines.