Novel Crizotinib–GnRH conjugates revealed the significance of lysosomal trapping in GnRH-based drug delivery systems

Murányi, József and Varga, Attila and Gyulavári, Pál and Pénzes, Kinga and Németh, Csilla E. and Csala, Miklós and Pethő, Lilla and Csámpai, Antal and Halmos, Gábor and Peták, István and Vályi-Nagy, István (2019) Novel Crizotinib–GnRH conjugates revealed the significance of lysosomal trapping in GnRH-based drug delivery systems. INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES, 20 (22). pp. 1-23. ISSN 1661-6596 (print); 1422-0067 (online)

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Abstract

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.

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