PMID- 35563462
OWN - NLM
STAT- MEDLINE
DCOM- 20220517
LR  - 20220716
IS  - 1422-0067 (Electronic)
IS  - 1422-0067 (Linking)
VI  - 23
IP  - 9
DP  - 2022 May 3
TI  - Development and Biochemical Characterization of Self-Immolative Linker Containing 
      GnRH-III-Drug Conjugates.
LID - 10.3390/ijms23095071 [doi]
LID - 5071
AB  - 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).
FAU - Schuster, Sabine
AU  - Schuster S
AUID- ORCID: 0000-0001-9888-4446
AD  - Faculty of Science, Institute of Chemistry, Eotvos Lorand University, 1117 
      Budapest, Hungary.
AD  - ELKH-ELTE Research Group of Peptide Chemistry, Faculty of Science, Eotvos Lorand 
      University, 1117 Budapest, Hungary.
FAU - Juhasz, Eva
AU  - Juhasz E
AD  - Department of Pediatrics, Faculty of Medicine, University of Debrecen, 4032 
      Debrecen, Hungary.
FAU - Halmos, Gabor
AU  - Halmos G
AD  - Department of Biopharmacy, Faculty of Pharmacy, University of Debrecen, 4032 
      Debrecen, Hungary.
FAU - Neundorf, Ines
AU  - Neundorf I
AUID- ORCID: 0000-0001-6450-3991
AD  - Department of Chemistry, Institute of Biochemistry, University of Cologne, 50674 
      Cologne, Germany.
FAU - Gennari, Cesare
AU  - Gennari C
AUID- ORCID: 0000-0002-7635-4900
AD  - Dipartimento di Chimica, Universita degli Studi di Milano, 20133 Milano, Italy.
FAU - Mezo, Gabor
AU  - Mezo G
AD  - Faculty of Science, Institute of Chemistry, Eotvos Lorand University, 1117 
      Budapest, Hungary.
AD  - ELKH-ELTE Research Group of Peptide Chemistry, Faculty of Science, Eotvos Lorand 
      University, 1117 Budapest, Hungary.
LA  - eng
PT  - Journal Article
DEP - 20220503
PL  - Switzerland
TA  - Int J Mol Sci
JT  - International journal of molecular sciences
JID - 101092791
RN  - 0 (Receptors, LHRH)
RN  - 0 (gonadotropin-releasing hormone-III)
RN  - 33515-09-2 (Gonadotropin-Releasing Hormone)
RN  - EC 3.4.22.1 (Cathepsin B)
RN  - P88XT4IS4D (Paclitaxel)
RN  - SZB83O1W42 (Pyrrolidonecarboxylic Acid)
RN  - ZS7284E0ZP (Daunorubicin)
SB  - IM
MH  - Animals
MH  - Antineoplastic Combined Chemotherapy Protocols/chemistry/therapeutic use
MH  - Cathepsin B/chemistry/therapeutic use
MH  - Cell Line, Tumor
MH  - Daunorubicin/chemistry/therapeutic use
MH  - Female
MH  - *Gonadotropin-Releasing Hormone/therapeutic use
MH  - Humans
MH  - *Molecular Targeted Therapy/methods
MH  - *Ovarian Neoplasms
MH  - Paclitaxel/chemistry/therapeutic use
MH  - Petromyzon
MH  - Pyrrolidonecarboxylic Acid/analogs & derivatives/therapeutic use
MH  - *Receptors, LHRH/therapeutic use
PMC - PMC9105102
OTO - NOTNLM
OT  - SMDC
OT  - antitumor activity
OT  - cathepsin B
OT  - daunorubicin
OT  - drug delivery system
OT  - gonadotropin releasing hormone
OT  - paclitaxel
OT  - peptide-drug conjugates
OT  - targeted cancer therapy
COIS- The authors declare no conflict of interest.
EDAT- 2022/05/15 06:00
MHDA- 2022/05/18 06:00
PMCR- 2022/05/03
CRDT- 2022/05/14 01:06
PHST- 2022/04/06 00:00 [received]
PHST- 2022/04/26 00:00 [revised]
PHST- 2022/04/29 00:00 [accepted]
PHST- 2022/05/14 01:06 [entrez]
PHST- 2022/05/15 06:00 [pubmed]
PHST- 2022/05/18 06:00 [medline]
PHST- 2022/05/03 00:00 [pmc-release]
AID - ijms23095071 [pii]
AID - ijms-23-05071 [pii]
AID - 10.3390/ijms23095071 [doi]
PST - epublish
SO  - Int J Mol Sci. 2022 May 3;23(9):5071. doi: 10.3390/ijms23095071.