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Open AccessArticle

Novel Crizotinib–GnRH Conjugates Revealed the Significance of Lysosomal Trapping in GnRH-Based Drug Delivery Systems

1
MTA-SE Pathobiochemistry Research Group, Tűzoltó St. 37-47, H1094 Budapest, Hungary
2
Department of Medical Chemistry, Molecular Biology and Pathobiochemistry, Semmelweis University, H1094 Budapest, Hungary
3
MTA-ELTE Research Group of Peptide Chemistry, Eötvös Loránd University, H1117 Budapest, Hungary
4
Institute of Chemistry, Eötvös Loránd University, H1117 Budapest, Hungary
5
Department of Biopharmacy, Faculty of Pharmacy, University of Debrecen, H4032 Debrecen, Hungary
6
Oncompass Medicine Hungary Ltd., H1024 Budapest, Hungary
7
Central Hospital of Southern Pest National Institute of Hematology and Infectious Diseases, H1097 Budapest, Hungary
*
Author to whom correspondence should be addressed.
Int. J. Mol. Sci. 2019, 20(22), 5590; https://doi.org/10.3390/ijms20225590
Received: 30 September 2019 / Accepted: 6 November 2019 / Published: 8 November 2019
(This article belongs to the Special Issue The Role of Gonadotropin-Releasing Hormone Receptor in Human Diseases)
Several promising anti-cancer drug–GnRH (gonadotropin-releasing hormone) conjugates have been developed in the last two decades, although none of them have been approved for clinical use yet. Crizotinib is an effective multi-target kinase inhibitor, approved against anaplastic lymphoma kinase (ALK)- or ROS proto-oncogene 1 (ROS-1)-positive non-small cell lung carcinoma (NSCLC); however, its application is accompanied by serious side effects. In order to deliver crizotinib selectively into the tumor cells, we synthesized novel crizotinib analogues and conjugated them to a [d-Lys6]–GnRH-I targeting peptide. Our most prominent crizotinib–GnRH conjugates, the amide-bond-containing [d-Lys6(crizotinib*)]–GnRH-I and the ester-bond-containing [d-Lys6(MJ55*)]–GnRH-I, were able to bind to GnRH-receptor (GnRHR) and exert a potent c-Met kinase inhibitory effect. The efficacy of compounds was tested on the MET-amplified and GnRHR-expressing EBC-1 NSCLC cells. In vitro pharmacological profiling led to the conclusion that that crizotinib–GnRH conjugates are transported directly into lysosomes, where the membrane permeability of crizotinib is diminished. As a consequence of GnRHR-mediated endocytosis, GnRH-conjugated crizotinib bypasses its molecular targets—the ATP-binding site of RTKs— and is sequestered in the lysosomes. These results explained the lower efficacy of crizotinib–GnRH conjugates in EBC-1 cells, and led to the conclusion that drug escape from the lysosomes is a major challenge in the development of clinically relevant anti-cancer drug–GnRH conjugates. View Full-Text
Keywords: targeted drug delivery 1; GnRH 2; GnRHR 3; lysosome 3; permeability 4; crizotinib 5; conjugate 6; NSCLC 7; c-Met 8; endocytosis 9; galectin 10 targeted drug delivery 1; GnRH 2; GnRHR 3; lysosome 3; permeability 4; crizotinib 5; conjugate 6; NSCLC 7; c-Met 8; endocytosis 9; galectin 10
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MDPI and ACS Style

Murányi, J.; Varga, A.; Gyulavári, P.; Pénzes, K.; Németh, C.E.; Csala, M.; Pethő, L.; Csámpai, A.; Halmos, G.; Peták, I.; Vályi-Nagy, I. Novel Crizotinib–GnRH Conjugates Revealed the Significance of Lysosomal Trapping in GnRH-Based Drug Delivery Systems. Int. J. Mol. Sci. 2019, 20, 5590.

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