Synthesis, in vitro stability, and antiproliferative effect of d ‐cysteine modified GnRH‐doxorubicin conjugates

A novel [d‐Cys6, des ‐Gly10, Pro9‐NHEt]‐GnRH‐Doxorubicin conjugate was designed and synthesized. It showed improved human serum stability and targeting antiproliferative effect on GnRH receptor positive MCF‐7 human breast cancer cells. Overexpression of gonadotropin ‐releasing hormone (GnRH) receptor in many tumors but not in normal tissues makes it possible to use GnRH analogs as targeting peptides for selective delivery of cytotoxic agents, which may help to enhance the uptake of anticancer drugs by cancer cells and reduce toxicity to normal cells. The GnRH analogs [d‐Cys6, desGly10, Pro9‐NH2] ‐GnRH, [d‐Cys6, desGly10, Pro9‐NHEt]‐GnRH, and [d‐Cys6, α‐aza‐Gly10‐NH2] ‐GnRH were conjugated with doxorubicin (Dox), respectively, through N‐succinimidyl‐3‐maleimidopropionate as a linker to afford three new GnRH‐Dox conjugates. The metabolic stability of these conjugates in human serum was determined by RP‐HPLC. The antiproliferative activity of the conjug ates was examined in GnRH receptor‐positive MCF‐7 human breast cancer cell line by MTT assay. The three GnRH‐Dox conjugates showed improved metabolic stability in human serum in comparison with AN‐152. The antiproliferative effect of conjugate II ([d‐Cys6, desGly10, Pro9‐NHEt]‐GnRH‐Dox) on MCF‐7 cells was higher than that of conjugate I ([d‐Cys6, desGly10, Pro9‐NH2] ‐GnRH‐Dox) and conjugate III ([d‐Cys6, α‐aza‐Gly10‐NH2] ‐GnRH‐Dox), and the cyto...
Source: Journal of Peptide Science - Category: Biochemistry Authors: Tags: RESEARCH ARTICLE Source Type: research