1. Synthesis, in vitro stability, and antiproliferative effect of d-cysteine modified GnRH-doxorubicin conjugates.
- Author
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Li S, Zhao H, Chang X, Wang J, Zhao E, Yin Z, Mao X, Deng S, Hao T, Wang H, and Yang Y
- Subjects
- Animals, Antibiotics, Antineoplastic chemistry, Antibiotics, Antineoplastic metabolism, Cell Proliferation drug effects, Cell Survival drug effects, Cross-Linking Reagents chemistry, Cytotoxins chemistry, Cytotoxins metabolism, Doxorubicin analogs & derivatives, Doxorubicin metabolism, Drug Stability, Gene Expression, Gonadotropin-Releasing Hormone analogs & derivatives, Gonadotropin-Releasing Hormone chemical synthesis, Gonadotropin-Releasing Hormone metabolism, Humans, MCF-7 Cells, Maleimides chemistry, Mice, NIH 3T3 Cells, Oligopeptides chemical synthesis, Oligopeptides metabolism, Protein Binding, Receptors, LHRH genetics, Receptors, LHRH metabolism, Succinimides chemistry, Antibiotics, Antineoplastic pharmacology, Cytotoxins pharmacology, Doxorubicin pharmacology, Drug Carriers, Gonadotropin-Releasing Hormone pharmacology, Oligopeptides pharmacology
- Abstract
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-Cys
6 , 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 conjugates 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 cytotoxicity of conjugate II against GnRH receptor-negative 3T3 mouse embryo fibroblast cells was decreased in comparison with free Dox. GnRH receptor inhibition test suggested that the antiproliferative activity of conjugate II might be due to the cellular uptake mediated by the targeting binding of [d-Cys6 -des-Gly10 -Pro9 -NHEt]-GnRH to GnRH receptors. Our study indicates that targeting delivery of conjugate II mediated by [d-Cys6 -des-Gly10 -Pro9 -NHEt]-GnRH is a promising strategy for chemotherapy of tumors that overexpress GnRH receptors., (© 2018 European Peptide Society and John Wiley & Sons, Ltd.)- Published
- 2019
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