Photosubstitution in a trisheteroleptic ruthenium complex inhibits conjunctival melanoma growth in a zebrafish orthotopic xenograft model.

Autor: Chen Q; Division of Spine Surgery, Department of Orthopedic Surgery, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School Nanjing China.; Institute of Biology, Leiden University Leiden The Netherlands b.e.snaar-jagalska@biology.leidenuniv.nl +31-71-527-4980., Cuello-Garibo JA; Leiden Institute of Chemistry, Leiden University P. O. Box 9502 2300 RA Leiden The Netherlands bonnet@chem.leidenuniv.nl +31-71-527-4260., Bretin L; Leiden Institute of Chemistry, Leiden University P. O. Box 9502 2300 RA Leiden The Netherlands bonnet@chem.leidenuniv.nl +31-71-527-4260., Zhang L; Leiden Institute of Chemistry, Leiden University P. O. Box 9502 2300 RA Leiden The Netherlands bonnet@chem.leidenuniv.nl +31-71-527-4260., Ramu V; Leiden Institute of Chemistry, Leiden University P. O. Box 9502 2300 RA Leiden The Netherlands bonnet@chem.leidenuniv.nl +31-71-527-4260., Aydar Y; Institute of Biology, Leiden University Leiden The Netherlands b.e.snaar-jagalska@biology.leidenuniv.nl +31-71-527-4980., Batsiun Y; Leiden Institute of Chemistry, Leiden University P. O. Box 9502 2300 RA Leiden The Netherlands bonnet@chem.leidenuniv.nl +31-71-527-4260., Bronkhorst S; Leiden Institute of Chemistry, Leiden University P. O. Box 9502 2300 RA Leiden The Netherlands bonnet@chem.leidenuniv.nl +31-71-527-4260., Husiev Y; Leiden Institute of Chemistry, Leiden University P. O. Box 9502 2300 RA Leiden The Netherlands bonnet@chem.leidenuniv.nl +31-71-527-4260., Beztsinna N; Leiden Institute of Chemistry, Leiden University P. O. Box 9502 2300 RA Leiden The Netherlands bonnet@chem.leidenuniv.nl +31-71-527-4260., Chen L; Institute of Biology, Leiden University Leiden The Netherlands b.e.snaar-jagalska@biology.leidenuniv.nl +31-71-527-4980., Zhou XQ; Leiden Institute of Chemistry, Leiden University P. O. Box 9502 2300 RA Leiden The Netherlands bonnet@chem.leidenuniv.nl +31-71-527-4260., Schmidt C; Institute of Medicinal and Pharmaceutical Chemistry, Technische Universität Braunschweig Beethovenstrasse 55 D-38106 Braunschweig Germany., Ott I; Institute of Medicinal and Pharmaceutical Chemistry, Technische Universität Braunschweig Beethovenstrasse 55 D-38106 Braunschweig Germany., Jager MJ; Department of Ophthalmology, Leiden University Medical Center Leiden The Netherlands m.j.jager@lumc.nl., Brouwer AM; Van't Hoff Institute for Molecular Sciences, University of Amsterdam Science Park 904 1098 XH Amsterdam The Netherlands., Snaar-Jagalska BE; Institute of Biology, Leiden University Leiden The Netherlands b.e.snaar-jagalska@biology.leidenuniv.nl +31-71-527-4980., Bonnet S; Leiden Institute of Chemistry, Leiden University P. O. Box 9502 2300 RA Leiden The Netherlands bonnet@chem.leidenuniv.nl +31-71-527-4260.
Jazyk: angličtina
Zdroj: Chemical science [Chem Sci] 2022 May 16; Vol. 13 (23), pp. 6899-6919. Date of Electronic Publication: 2022 May 16 (Print Publication: 2022).
DOI: 10.1039/d2sc01646j
Abstrakt: In vivo data are rare but essential for establishing the clinical potential of ruthenium-based photoactivated chemotherapy (PACT) compounds, a new family of phototherapeutic drugs that are activated via ligand photosubstitution. Here a novel trisheteroleptic ruthenium complex [Ru(dpp)(bpy)(mtmp)](PF 6 ) 2 ([2](PF 6 ) 2 , dpp = 4,7-diphenyl-1,10-phenanthroline, bpy = 2,2'-bipyridine, mtmp = 2-methylthiomethylpyridine) was synthesized and its light-activated anticancer properties were validated in cancer cell monolayers, 3D tumor spheroids, and in embryonic zebrafish cancer models. Upon green light irradiation, the non-toxic mtmp ligand is selectively cleaved off, thereby releasing a phototoxic ruthenium-based photoproduct capable notably of binding to nuclear DNA and triggering DNA damage and apoptosis within 24-48 h. In vitro , fifteen minutes of green light irradiation (21 mW cm -2 , 19 J cm -2 , 520 nm) were sufficient to generate high phototherapeutic indexes (PI) for this compound in a range of cancer cell lines including lung (A549), prostate (PC3Pro4), conjunctival melanoma (CRMM1, CRMM2, CM2005.1) and uveal melanoma (OMM1, OMM2.5, Mel270) cancer cell lines. The therapeutic potential of [2](PF 6 ) 2 was further evaluated in zebrafish embryo ectopic (PC3Pro4) or orthotopic (CRMM1, CRMM2) tumour models. The ectopic model consisted of red fluorescent PC3Pro4-mCherry cells injected intravenously (IV) into zebrafish, that formed perivascular metastatic lesions at the posterior ventral end of caudal hematopoietic tissue (CHT). By contrast, in the orthotopic model, CRMM1- and CRMM2-mCherry cells were injected behind the eye where they developed primary lesions. The maximally-tolerated dose (MTD) of [2](PF 6 ) 2 was first determined for three different modes of compound administration: (i) incubating the fish in prodrug-containing water (WA); (ii) injecting the prodrug intravenously (IV) into the fish; or (iii) injecting the prodrug retro-orbitally (RO) into the fish. To test the anticancer efficiency of [2](PF 6 ) 2 , the embryos were treated 24 h after engraftment at the MTD. Optimally, four consecutive PACT treatments were performed on engrafted embryos using 60 min drug-to-light intervals and 90 min green light irradiation (21 mW cm -2 , 114 J cm -2 , 520 nm). Most importantly, this PACT protocol was not toxic to the zebrafish. In the ectopic prostate tumour models, where [2](PF 6 ) 2 showed the highest photoindex in vitro (PI > 31), the PACT treatment did not significantly diminish the growth of primary lesions, while in both conjunctival melanoma orthotopic tumour models, where [2](PF 6 ) 2 showed more modest photoindexes (PI ∼ 9), retro-orbitally administered PACT treatment significantly inhibited growth of the engrafted tumors. Overall, this study represents the first demonstration in zebrafish cancer models of the clinical potential of ruthenium-based PACT, here against conjunctival melanoma.
Competing Interests: There are no conflicts of interest to declare.
(This journal is © The Royal Society of Chemistry.)
Databáze: MEDLINE
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