title: Gonadotropin-releasing hormone receptor-targeted paclitaxel-degarelix conjugate: synthesis and in vitro evaluation.
abstract: To increase the selectivity of chemotherapeutic agents, receptor-mediated tumor-targeting approaches have been developed. Here, degarelix [Ac-D-Nal-D-Cpa-D-Pal-Ser-Aph(L-Hor)-D-Aph(Cbm)-Leu-ILys-Pro-D-Ala-NH2], a gonadotropin-releasing hormone antagonist, was employed as a targeting moiety for paclitaxel (PTX). Five PTX-degarelix conjugates were synthesized, in which PTX was attached via disulfide bond to the different position in the degarelix sequence. All of the PTX-degarelix conjugates exhibited a half-life greater than 10 h determined in human serum. A fluorometric imaging plate reader assay showed that the conjugates LK-MY-9 and LK-MY-10 had an antagonism efficacy similar to that of degarelix. The in vitro cytostatic effects of the conjugates were determined by a (3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium) (MTS) assay, and the 50% inhibitory concentration value of the conjugates on 3T3 mouse embryonic fibroblast cells were one order of magnitude higher than the 50% inhibitory concentration values of the conjugates on MCF-7 human breast cancer cells and HT-29 human colon cancer cells. Receptor saturation tests further demonstrated that pre-incubation of the cells with degarelix reduced the efficacy of LK-MY-10 in a concentration-dependent manner. In conclusion, degarelix is a valid and stable moiety that has great potential for targeting chemotherapy drugs.
authors: State Key Laboratory of Toxicology and Medical Countermeasures, Beijing Institute of Pharmacology and Toxicology, Beijing, 100850, China.
authors: Chenhong
authors: C
authors: Wang
authors: State Key Laboratory of Toxicology and Medical Countermeasures, Beijing Institute of Pharmacology and Toxicology, Beijing, 100850, China.
authors: Yongtao
authors: Y
authors: Ma
authors: State Key Laboratory of Toxicology and Medical Countermeasures, Beijing Institute of Pharmacology and Toxicology, Beijing, 100850, China.
authors: Siliang
authors: S
authors: Feng
authors: State Key Laboratory of Toxicology and Medical Countermeasures, Beijing Institute of Pharmacology and Toxicology, Beijing, 100850, China.
authors: Keliang
authors: K
authors: Liu
authors: State Key Laboratory of Toxicology and Medical Countermeasures, Beijing Institute of Pharmacology and Toxicology, Beijing, 100850, China.
authors: Ning
authors: N
authors: Zhou
mesh_terms: D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000737:chemistry* / Q000494:pharmacology; D002470:Cell Survival / Q000187:drug effects; D004220:Disulfides / Q000737:chemistry; D006001:Glycoconjugates / Q000138:chemical synthesis* / Q000494:pharmacology; D019073:HT29 Cells; D006727:Hormone Antagonists / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology; D006801:Humans; D020128:Inhibitory Concentration 50; D061986:MCF-7 Cells; D051379:Mice; D058990:Molecular Targeted Therapy; D041681:NIH 3T3 Cells; D009842:Oligopeptides / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology; D017239:Paclitaxel / Q000737:chemistry* / Q000494:pharmacology; D011485:Protein Binding; D011966:Receptors, LHRH / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism
chemical_list: D000972:Antineoplastic Agents, Phytogenic; D004220:Disulfides; D006001:Glycoconjugates; D006727:Hormone Antagonists; D009842:Oligopeptides; D011966:Receptors, LHRH; C431566:acetyl-2-naphthylalanyl-3-chlorophenylalanyl-1-oxohexadecyl-seryl-4-aminophenylalanyl(hydroorotyl)-4-aminophenylalanyl(carbamoyl)-leucyl-ILys-prolyl-alaninamide; D017239:Paclitaxel
keywords: gonadotropin-releasing hormone antagonist; in vitro stability; paclitaxel-degarelix conjugates; targeted drug delivery