Universität zu Köln

Schuster, Sabine ORCID: 0000-0001-9888-4446, Juhasz, Eva, Halmos, Gabor, Neundorf, Ines ORCID: 0000-0001-6450-3991, Gennari, Cesare ORCID: 0000-0002-7635-4900 and Mezo, Gabor (2022). Development and Biochemical Characterization of Self-Immolative Linker Containing GnRH-III-Drug Conjugates. Int. J. Mol. Sci., 23 (9). BASEL: MDPI. ISSN 1422-0067

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Abstract

The human gonadotropin releasing hormone (GnRH-I) and its sea lamprey analogue GnRH-III specifically bind to GnRH receptors on cancer cells and can be used as targeting moieties for targeted tumor therapy. Considering that the selective release of drugs in cancer cells is of high relevance, we were encouraged to develop cleavable, self-immolative GnRH-III-drug conjugates which consist of a p-aminobenzyloxycarbonlyl (PABC) spacer between a cathepsin B-cleavable dipeptide (Val-Ala, Val-Cit) and the classical anticancer drugs daunorubicin (Dau) and paclitaxel (PTX). Alongside these compounds, non-cleavable GnRH-III-drug conjugates were also synthesized, and all compounds were analyzed for their antiproliferative activity. The cleavable GnRH-III bioconjugates revealed a growth inhibitory effect on GnRH receptor-expressing A2780 ovarian cancer cells, while their activity was reduced on Panc-1 pancreatic cancer cells exhibiting a lower GnRH receptor level. Moreover, the antiproliferative activity of the non-cleavable counterparts was strongly reduced. Additionally, the efficient cleavage of the Val-Ala linker and the subsequent release of the drugs could be verified by lysosomal degradation studies, while radioligand binding studies ensured that the GnRH-III-drug conjugates bound to the GnRH receptor with high affinity. Our results underline the high value of GnRH-III-based homing devices and the application of cathepsin B-cleavable linker systems for the development of small molecule drug conjugates (SMDCs).

Item Type:	Journal Article
Creators:	Creators Email ORCID ORCID Put Code Schuster, Sabine UNSPECIFIED orcid.org/0000-0001-9888-4446 UNSPECIFIED Juhasz, Eva UNSPECIFIED UNSPECIFIED UNSPECIFIED Halmos, Gabor UNSPECIFIED UNSPECIFIED UNSPECIFIED Neundorf, Ines UNSPECIFIED orcid.org/0000-0001-6450-3991 UNSPECIFIED Gennari, Cesare UNSPECIFIED orcid.org/0000-0002-7635-4900 UNSPECIFIED Mezo, Gabor UNSPECIFIED UNSPECIFIED UNSPECIFIED
URN:	urn:nbn:de:hbz:38-686421
DOI:	10.3390/ijms23095071
Journal or Publication Title:	Int. J. Mol. Sci.
Volume:	23
Number:	9
Date:	2022
Publisher:	MDPI
Place of Publication:	BASEL
ISSN:	1422-0067
Language:	English
Faculty:	Unspecified
Divisions:	Unspecified
Subjects:	no entry
Uncontrolled Keywords:	Keywords Language GONADOTROPIN-RELEASING-HORMONE; VITRO ANTITUMOR-ACTIVITY; IN-VITRO; BIOLOGICAL EVALUATION; MOLECULAR-STRUCTURE; DAUNORUBICIN; CANCER; PRODRUGS; DNA; BREAST Multiple languages Biochemistry & Molecular Biology; Chemistry, Multidisciplinary Multiple languages
URI:	http://kups.ub.uni-koeln.de/id/eprint/68642