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Biological evaluation of complexes of cyclopentadienyl M(CO)3+ (M = Re, 99mTc) with high blood–brain barrier penetration potential as brain cancer agents

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Summary

To address the major medical need for effective chemotherapeutics/diagnostics for brain cancer, in this work three cyclopentadienyl M(CO)3+ (M = Re, 99mTc) complexes, which cross the blood-brain barrier (BBB) in high % and are designed to mimic the anticancer agent 2-phenylbenzothiazole, are in vitro and in vivo evaluated for anticancer action. The study includes cytotoxicity and uptake studies in cancer and healthy neuronal cell lines, mechanistic investigation of potential anticancer pathways, and biodistribution studies in mice bearing glioblastoma xenografts. The stable Re complexes exhibit selective uptake and significant antiproliferative effect, particularly against U-251 MG glioblastoma cells, with no significant toxicity in healthy neurons, demonstrating the suitability of this type of complexes to serve as selective therapeutic/imaging agents for brain cancer. Furthermore, they result in the generation of elevated Reactive Oxygen Species (ROS) levels, and lead to significant G2/M arrest followed by apoptosis. Biodistribution studies in U-251 MG xenograft bearing mice with the radioactive 99mTc complex that exhibits the highest BBB penetration, show retention at the tumor-site offering a diagnostic prospect and, in addition, indicating the capability of the Re analogue to accumulate at the tumor site for therapeutic action. Overall, the complexes demonstrate significant anticancer properties that, combined with their high BBB penetration potential, render them strong candidates for further evaluation as brain cancer agents.

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Acknowledgements

B. Mavroidi gratefully acknowledges the financial support by the State Scholarships Foundation (ΙΚΥ) through the implementation of the Operational Programme «Human Resources Development, Education and Lifelong Learning» in the context of the project “Reinforcement of Postdoctoral Researchers -2nd Cycle” (MIS-5033021), co-financed by Greece and the European Union (European Social Fund-ESF).

Funding

This research is co-financed by Greece and the European Union (European Social Fund-ESF) through the Operational Programme «Human Resources Development, Education and Lifelong Learning» in the context of the project “Reinforcement of Postdoctoral Researchers 2nd Cycle” (MIS-5033021), implemented by the State Scholarships Foundation (ΙΚΥ).

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Authors and Affiliations

  1. Institute of Biosciences & Applications, National Centre for Scientific Research “Demokritos”, 15310, Athens, Greece

    B. Mavroidi, A. Kaminari, M. Sagnou & M. Pelecanou

  2. Institute of Nuclear & Radiological Sciences & Technology, Energy & Safety, National Centre for Scientific Research “Demokritos”, 15310, Athens, Greece

    K. Makrypidi, A. Shegani, P. Bouziotis, I. Pirmettis & M. Papadopoulos

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  1. B. Mavroidi
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All authors contributed to the present study and all read and approved the final manuscript.

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Correspondence to B. Mavroidi.

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This study was conducted in accordance with the Presidential Decree 56/2013 (published in the Official Government Gazette of Greece 106 A/30–4-2013) that has transposed the EU Directive 2010/63 on the protection of animals used for scientific purposes.

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All procedures performed in studies involving animals were in accordance with the Presidential Decree 56/2013 (published in the Official Government Gazette of Greece 106 A/30–4-2013) that has transposed the EU Directive 2010/63 on the protection of animals used for scientific purposes.

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Mavroidi, B., Kaminari, A., Makrypidi, K. et al. Biological evaluation of complexes of cyclopentadienyl M(CO)3+ (M = Re, 99mTc) with high blood–brain barrier penetration potential as brain cancer agents. Invest New Drugs 40, 497–505 (2022). https://doi.org/10.1007/s10637-022-01211-z

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