The combination of photodynamic therapy and radiotherapy has given rise to a modality called radiodynamic therapy (RDT), based on reactive oxygen species-producing radiosensitizers. The production of singlet oxygen, O2(1Δg), by octahedral molybdenum (Mo6) clusters upon X-ray irradiation allows for simplification of the architecture of radiosensitizing systems. In this context, we prepared a radiosensitizing system using copper-free click chemistry between a Mo6 cluster bearing azido ligands and the homo-bifunctional linker bis-dPEG11-DBCO. The resulting compound formed nanoparticles, which featured production of O2(1Δg) and efficient cellular uptake, leading to remarkable photo- and radiotoxic effects against the prostatic adenocarcinoma TRAMP-C2 cell line. Spheroids of TRAMP-C2 cells were also used for evaluation of toxicity and phototoxicity. In vivo experiments on a mouse model demonstrated that subcutaneous injection of the nanoparticles is a safe administration mode at a dose of up to 0.08 g kg-1. The reported results confirm the relevancy of Mo6-based radiosensitizing nanosystems for RDT.

Department of Analytical Chemistry University of Chemistry and Technology Prague 166 28 Praha Czech Republic

Department of Biochemistry and Microbiology University of Chemistry and Technology Prague 166 28 Praha 6 Czech Republic

Department of Biotechnology University of Chemistry and Technology Prague 166 28 Praha Czech Republic

Institute of Inorganic Chemistry of the Czech Academy of Sciences Řež 1001 250 68 Husinec Řež Czech Republic

Institute of Molecular Genetics of the Czech Academy of Sciences Vídeňská 1084 142 20 Praha Czech Republic

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Algorri J. F.; Ochoa M.; Roldán-Varona P.; Rodríguez-Cobo L.; López-Higuera J. M. Photodynamic Therapy: A Compendium of Latest Reviews. Cancers 2021, 13, 4447.10.3390/cancers13174447. PubMed DOI PMC

Gunaydin G.; Gedik M. E.; Ayan S. Photodynamic Therapy-Current Limitations and Novel Approaches. Front. Chem. 2021, 9 (9), 691–697. 10.3389/fchem.2021.691697. PubMed DOI PMC

Brown S. Two photons are better than one. Nat. Photonics 2008, 2, 394–395. 10.1038/nphoton.2008.112. DOI

Fan N.; Li P.; Wu C.; Wang X.; Zhou Y.; Tang B. ALP-Activated Chemiluminescence PDT Nano-Platform for Liver Cancer-Specific Theranostics. ACS Appl. Bio Mater. 2021, 4, 1740–1748. 10.1021/acsabm.0c01504. PubMed DOI

Wang G. D.; Nguyen H. T.; Chen H.; Cox P. B.; Wang L.; Nagata K.; Hao Z.; Wang A.; Li Z.; Xie J. X-Ray Induced Photodynamic Therapy: A Combination of Radiotherapy and Photodynamic Therapy. Theranostics 2016, 6 (13), 2295–2305. 10.7150/thno.16141. PubMed DOI PMC

Chen W.; Zhang J. Using Nanoparticles to Enable Simultaneous Radiation and Photodynamic Therapies for Cancer Treatment. J. Nanosci. Nanotechnol. 2006, 6, 1159–1166. 10.1166/jnn.2006.327. PubMed DOI

Zhang G.; Guo M.; Ma H.; Wang J.; Zhang X.-D. Catalytic Nanotechnology of X-Ray Photodynamics for Cancer Treatments. Biomater. Sci. 2023, 11, 1153–1181. 10.1039/D2BM01698B. PubMed DOI

Sun W.; Zhou Z.; Pratx G.; Chen X.; Chen H. Nanoscintillator-Mediated X-Ray Induced Photodynamic Therapy for Deep-Seated Tumors: From Concept to Biomedical Applications. Theranostics 2020, 10, 1296–1318. 10.7150/thno.41578. PubMed DOI PMC

Kirakci K.; Kubát P.; Fejfarová K.; Martinčík J.; Nikl M.; Lang K. X-Ray Inducible Luminescence and Singlet Oxygen Sensitization by an Octahedral Molybdenum Cluster Compound: A New Class of Nanoscintillators. Inorg. Chem. 2016, 55, 803–809. 10.1021/acs.inorgchem.5b02282. PubMed DOI

Maverick A. W.; Najdzionek J. S.; MacKenzie D.; Nocera D. G.; Gray H. B. Spectroscopic, Electrochemical, and Photochemical Properties of Molybdenum(II) and Tungsten(II) Halide Clusters. J. Am. Chem. Soc. 1983, 105, 1878–1882. 10.1021/ja00345a034. DOI

Kirakci K.; Kubát P.; Dušek M.; Fejfarová K.; Šícha V.; Mosinger J.; Lang K. A Highly Luminescent Hexanuclear Molybdenum Cluster – A Promising Candidate toward Photoactive Materials. Eur. J. Inorg. Chem. 2012, 2012 (19), 3107–3111. 10.1002/ejic.201200402. DOI

Kirakci K.; Kubát P.; Langmaier J.; Polívka T.; Fuciman M.; Fejfarová K.; Lang K. A Comparative Study of the Redox and Excited State Properties of (nBu4N)2[Mo6X14] and (nBu4N)2[Mo6X8(CF3COO)6] (X = Cl, Br, or I). Dalton Trans. 2013, 42 (19), 7224.10.1039/c3dt32863e. PubMed DOI

Kirakci K.; Zelenka J.; Rumlová M.; Cvačka J.; Ruml T.; Lang K. Cationic Octahedral Molybdenum Cluster Complexes Functionalized with Mitochondria-Targeting Ligands: Photodynamic Anticancer and Antibacterial Activities. Biomater. Sci. 2019, 7 (4), 1386–1392. 10.1039/C8BM01564C. PubMed DOI

Kirakci K.; Demel J.; Hynek J.; Zelenka J.; Rumlová M.; Ruml T.; Lang K. Phosphinate Apical Ligands: A Route to a Water-Stable Octahedral Molybdenum Cluster Complex. Inorg. Chem. 2019, 58 (24), 16546–16552. 10.1021/acs.inorgchem.9b02569. PubMed DOI

Kirakci K.; Zelenka J.; Křížová I.; Ruml T.; Lang K. Octahedral Molybdenum Cluster Complexes with Optimized Properties for Photodynamic Applications. Inorg. Chem. 2020, 59 (13), 9287–9293. 10.1021/acs.inorgchem.0c01173. PubMed DOI

Kirakci K.; Kubáňová M.; Přibyl T.; Rumlová M.; Zelenka J.; Ruml T.; Lang K. A Cell Membrane Targeting Molybdenum-Iodine Nanocluster: Rational Ligand Design toward Enhanced Photodynamic Activity. Inorg. Chem. 2022, 61 (12), 5076–5083. 10.1021/acs.inorgchem.2c00040. PubMed DOI

Brandhonneur N.; Hatahet T.; Amela-Cortes M.; Molard Y.; Cordier S.; Dollo G. Molybdenum cluster loaded PLGA nanoparticles: An innovative theranostic approach for the treatment of ovarian cancer. Eur. J. Pharm. Biopharm. 2018, 125, 95–105. 10.1016/j.ejpb.2018.01.007. PubMed DOI

Brandhonneur N.; Boucaud Y.; Verger A.; Dumait N.; Molard Y.; Cordier S.; Dollo G. Molybdenum cluster loaded PLGA nanoparticles as efficient tools against epithelial ovarian cancer. Int. J. Pharm. 2021, 592, 120079.10.1016/j.ijpharm.2020.120079. PubMed DOI

Verger A.; Dollo G.; Martinais S.; Molard Y.; Cordier S.; Amela-Cortes M.; Brandhonneur N. Molybdenum-Iodine Cluster Loaded Polymeric Nanoparticles Allowing a Coupled Therapeutic Action with Low Side Toxicity for Treatment of Ovarian Cancer. J. Pharm. Sci. 2022, 111, 3377–3383. 10.1016/j.xphs.2022.09.010. PubMed DOI

Solovieva A. O.; Vorotnikov Y. A.; Trifonova K. E.; Efremova O. A.; Krasilnikova A. A.; Brylev K. A.; Vorontsova E. V.; Avrorov P. A.; Shestopalova L. V.; Poveshchenko A. F.; Mironov Y. V.; Shestopalov M. A. Cellular internalisation, bioimaging and dark and photodynamic cytotoxicity of silica nanoparticles doped by {Mo6I8}4+ metal clusters. J. Mater. Chem. B 2016, 4 (28), 4839–4846. 10.1039/C6TB00723F. PubMed DOI

Beltrán A.; Mikhailov M.; Sokolov M. N.; Pérez-Laguna V.; Rezusta A.; Revillo M. J.; Galindo F. A photobleaching resistant polymer supported hexanuclear molybdenum iodide cluster for photocatalytic oxygenations and photodynamic inactivation of Staphylococcus aureus. J. Mater. Chem. B 2016, 4 (36), 5975–5979. 10.1039/C6TB01966H. PubMed DOI

Vorotnikova N. A.; Alekseev A. Y.; Vorotnikov Y. A.; Evtushok D. V.; Molard Y.; Amela-Cortes M.; Cordier S.; Smolentsev A. I.; Burton C. G.; Kozhin P. M.; Zhu P.; Topham P. D.; Mironov Y. V.; Bradley M.; Efremova O. A.; Shestopalov M. A. Octahedral molybdenum cluster as a photoactive antimicrobial additive to a fluoroplastic. Mater. Sci. Eng. C 2019, 105, 110150.10.1016/j.msec.2019.110150. PubMed DOI

Felip-León C.; Arnau del Valle C.; Pérez-Laguna V.; Isabel Millán-Lou M.; Miravet J. F.; Mikhailov M.; Sokolov M. N.; Rezusta-López A.; Galindo F. Superior performance of macroporous over gel type polystyrene as a support for the development of photo-bactericidal materials. J. Mater. Chem. B 2017, 5 (30), 6058–6064. 10.1039/C7TB01478C. PubMed DOI

Kirakci K.; Nguyen T. K. N.; Grasset F.; Uchikoshi T.; Zelenka J.; Kubát P.; Ruml T.; Lang K. Electrophoretically Deposited Layers of Octahedral Molybdenum Cluster Complexes: A Promising Coating for Mitigation of Pathogenic Bacterial Biofilms under Blue Light. ACS Appl. Mater. Interfaces 2020, 12 (47), 52492–52499. 10.1021/acsami.0c19036. PubMed DOI

Kirakci K.; Zelenka J.; Rumlová M.; Martinčík J.; Nikl M.; Ruml T.; Lang K. Octahedral molybdenum clusters as radiosensitizers for X-ray induced photodynamic therapy. J. Mater. Chem. B 2018, 6 (26), 4301–4307. 10.1039/C8TB00893K. PubMed DOI

Kirakci K.; Pozmogova T. N.; Protasevich A. Y.; Vavilov G. D.; Stass D. V.; Shestopalov M. A.; Lang K. A water-soluble octahedral molybdenum cluster complex as a potential agent for X-ray induced photodynamic therapy. Biomater. Sci. 2021, 9 (8), 2893–2902. 10.1039/D0BM02005B. PubMed DOI

Koncošová M.; Rumlová M.; Mikyšková R.; Reiniš M.; Zelenka J.; Ruml T.; Kirakci K.; Lang K. Avenue to X-ray-induced photodynamic therapy of prostatic carcinoma with octahedral molybdenum cluster nanoparticles. J. Mater. Chem. B 2022, 10 (17), 3303–3310. 10.1039/D2TB00141A. PubMed DOI

Pozmogova T. N.; Sitnikova N. A.; Pronina E. V.; Miroshnichenko S. M.; Kushnarenko A. O.; Solovieva A. O.; Bogachev S. S.; Vavilov G. D.; Efremova O. A.; Vorotnikov Y. A.; Shestopalov M. A. Hybrid system {W6I8}-cluster/dsDNA as an agent for targeted X-ray induced photodynamic therapy of cancer stem cells. Mater. Chem. Front. 2021, 5 (20), 7499–7507. 10.1039/D1QM00956G. DOI

Jokerst J. V.; Lobovkina T.; Zare R. N.; Gambhir S. S. Nanoparticle PEGylation for imaging and therapy. Nanomedicine 2011, 6 (4), 715–728. 10.2217/nnm.11.19. PubMed DOI PMC

Mironova A. D.; Mikhailov M. A.; Brylev K. A.; Gushchin A. L.; Sukhikh T. S.; Sokolov M. N. Phosphorescent complexes of {Mo6I8}4+ with triazolates: [2 + 3] cycloaddition of alkynes to [Mo6I8(N3)6]2–. New J. Chem. 2020, 44, 20620–20625. 10.1039/D0NJ04259E. DOI

Kirakci K.; Kubát P.; Kučeráková M.; Šícha V.; Gbelcová H.; Lovecká P.; Grznárová P.; Ruml T.; Lang K. Water-soluble octahedral molybdenum cluster compounds Na2[Mo6I8(N3)6] and Na2[Mo6I8(NCS)6]: Syntheses, luminescence, and in vitro studies. Inorg. Chim. Acta 2016, 441, 42–49. 10.1016/j.ica.2015.10.043. DOI

Wang L.; Yang H.; Li B. Photodynamic Therapy for Prostate Cancer: A Systematic Review and Meta-Analysis. Prostate Int. 2019, 7, 83–90. 10.1016/j.prnil.2018.12.002. PubMed DOI PMC

Wilkins A.; Parker C. Treating Prostate Cancer with Radiotherapy. Nat. Rev. Clin. Oncol. 2010, 7, 583–589. 10.1038/nrclinonc.2010.135. PubMed DOI

Kessel D.; Reiners J. J. Photodynamic Therapy: Autophagy and Mitophagy, Apoptosis and Paraptosis. Autophagy 2020, 16, 2098–2101. 10.1080/15548627.2020.1783823. PubMed DOI PMC

Petri A.; Yova D.; Alexandratou E.; Kyriazi M.; Rallis M. Comparative characterization of the cellular uptake and photodynamic efficiency of Foscan® and Fospeg in a human prostate cancer cell line. Photodiagn. Photodyn. Ther. 2012, 9, 344–354. 10.1016/j.pdpdt.2012.03.008. PubMed DOI

Dhar S.; Gu F. X.; Langer R.; Farokhzad O. C.; Lippard S. J. Targeted Delivery of Cisplatin to Prostate Cancer Cells by Aptamer Functionalized Pt(IV) Prodrug-PLGA–PEG Nanoparticles. Proc. Natl. Acad. Sci. U.S.A. 2008, 105, 17356–17361. 10.1073/pnas.0809154105. PubMed DOI PMC

Verger A.; Dollo G.; Brandhonneur N.; Martinais S.; Cordier S.; Lang K.; Amela-Cortes M.; Kirakci K. PEGylated Poly(Lactic-Co-Glycolic Acid) Nanoparticles Doped with Molybdenum-Iodide Nanoclusters as a Promising Photodynamic Therapy Agent against Ovarian Cancer. Mater. Adv. 2023, 4, 3207–3214. 10.1039/D3MA00206C. DOI

Mishchenko T.; Balalaeva I.; Gorokhova A.; Vedunova M.; Krysko D. V. Which Cell Death Modality Wins the Contest for Photodynamic Therapy of Cancer?. Cell Death Dis. 2022, 13, 455.10.1038/s41419-022-04851-4. PubMed DOI PMC

Zelenka J.; Koncošová M.; Ruml T. Targeting of Stress Response Pathways in the Prevention and Treatment of Cancer. Biotechnol. Adv. 2018, 36, 583–602. 10.1016/j.biotechadv.2018.01.007. PubMed DOI

Riegman M.; Sagie L.; Galed C.; Levin T.; Steinberg N.; Dixon S. J.; Wiesner U.; Bradbury M. S.; Niethammer P.; Zaritsky A.; Overholtzer M. Ferroptosis Occurs through an Osmotic Mechanism and Propagates Independently of Cell Rupture. Nat. Cell Biol. 2020, 22, 1042–1048. 10.1038/s41556-020-0565-1. PubMed DOI PMC

Wu C.; Zhao W.; Yu J.; Li S.; Lin L.; Chen X. Induction of Ferroptosis and Mitochondrial Dysfunction by Oxidative Stress in PC12 Cells. Sci. Rep. 2018, 8, 574.10.1038/s41598-017-18935-1. PubMed DOI PMC

Hamilton G.; Rath B. Applicability of Tumor Spheroids for In Vitro Chemosensitivity Assays. Expert Opin. Drug Metab. Toxicol 2019, 15, 15–23. 10.1080/17425255.2019.1554055. PubMed DOI

Lener J.; Bíbr B. Effects of molybdenum on the organism (a review). J. Hyg., Epidemiol., Microbiol., Immunol. 1984, 28 (4), 405–419. PubMed

Krasilnikova A. A.; Solovieva A. O.; Ivanov A. A.; Trifonova K. E.; Pozmogova T. N.; Tsygankova A. R.; Smolentsev A. I.; Kretov E. I.; Sergeevichev D. S.; Shestopalov M. A.; Mironov Y. V.; Shestopalov A. M.; Poveshchenko A. F.; Shestopalova L. V. Comprehensive Study of Hexarhenium Cluster Complex Na4[{Re6Te8}(CN)6] – In Terms of a New Promising Luminescent and X-Ray Contrast Agent. Nanomed. Nanotechnol. Biol. Med. 2017, 13, 755–763. 10.1016/j.nano.2016.10.016. PubMed DOI