, Volume 31, Issue 4, pp 517–525 | Cite as

The cluster [Re6Se8I6]3− penetrates biological membranes: drug-like properties for CNS tumor treatment and diagnosis

  • Lisbell D. Estrada
  • Elizabeth Duran
  • Matias Cisterna
  • Cesar Echeverria
  • Zhiping Zheng
  • Vincenzo Borgna
  • Nicolas Arancibia-Miranda
  • Rodrigo Ramírez-Tagle


Tumorigenic cell lines are more susceptible to [Re6Se8I6]3− cluster-induced death than normal cells, becoming a novel candidate for cancer treatment. Still, the feasibility of using this type of molecules in human patients remains unclear and further pharmacokinetics analysis is needed. Using coupled plasma optical emission spectroscopy, we determined the Re-cluster tissue content in injected mice, as a biodistribution measurement. Our results show that the Re-cluster successfully reaches different tissues, accumulating mainly in heart and liver. In order to dissect the mechanism underlying cluster biodistribution, we used three different experimental approaches. First, we evaluate the degree of lipophilicity by determining the octanol/water partition coefficient. The cluster mostly remained in the octanol fraction, with a coefficient of 1.86 ± 0.02, which indicates it could potentially cross cell membranes. Then, we measured the biological membrane penetration through a parallel artificial membrane permeability assays (PAMPA) assay. The Re-cluster crosses the artificial membrane, with a coefficient of 122 nm/s that is considered highly permeable. To evaluate a potential application of the Re-cluster in central nervous system (CNS) tumors, we analyzed the cluster’s brain penetration by exposing cultured blood–brain-barrier (BBB) cells to increasing concentrations of the cluster. The Re-cluster effectively penetrates the BBB, reaching nearly 30% of the brain side after 24 h. Thus, our results indicate that the Re-cluster penetrates biological membranes reaching different target organs—most probably due to its lipophilic properties—becoming a promising anti-cancer drug with high potential for CNS cancer’s diagnosis and treatment.


Cluster Blood–brain barrier (BBB) Brain Tumors Cancer 



This work was supported by Fondecyt 11130007 to RR-T and Fondecyt 11130561 to LDE.

Compliance with ethical standards

Conflicts of interest

The authors declare no conflict of interest.


  1. Aguirre JD, Angeles-Boza AM, Chouai A, Turro C, Pellois JP, Dunbar KR (2009) Anticancer activity of heteroleptic diimine complexes of dirhodium: a study of intercalating properties, hydrophobicity and in cellulo activity. Dalton Trans. Google Scholar
  2. Alvarado-Soto L, Ramirez-Tagle R (2015) A theoretical study of the binding of [Re6Se8(OH)2(H2O)4] rhenium clusters to DNA purine base guanine. Materials (Basel) 8:3938–3944. CrossRefGoogle Scholar
  3. Aubert T, Ledneva AY, Grasset F et al (2010) Synthesis and characterization of A4[Re6Q8L6]@SiO2 red-emitting silica nanoparticles based on Re6 metal atom clusters (A = Cs or K, Q = S or Se, and L = OH or CN). Langmuir 26:18512–18518. CrossRefPubMedGoogle Scholar
  4. Bain RL, Shriver DF, Ellis DE (2001) Extended materials based on the [Mo6Cl8]4+ building block bridged by 4,4′-bipyridine. Inorg Chim Acta 325:171–174CrossRefGoogle Scholar
  5. Brylev K, Shestopalov M (2013) Biodistribution of rhenium cluster complex K4 in the body of laboratory rats. Bull Exp 155:741–744Google Scholar
  6. Choi S-J, Brylev KA, Xu J-Z et al (2008) Cellular uptake and cytotoxicity of octahedral rhenium cluster complexes. J Inorg Biochem 102:1991–1996. CrossRefPubMedGoogle Scholar
  7. Dubey S, Jain V, Preethi G (2009) Evaluation of lipophilicity, antimicrobial activity and mutagenicity of some novel ester prodrugs of metronidazole. Indian J Chem Sect 48:1571–1576Google Scholar
  8. Echeverría C, Becerra A, Nuñez-Villena F et al (2012) The paramagnetic and luminescent [Re6Se8I6]3− cluster. Its potential use as an antitumoral and biomarker agent. New J Chem 36:927. CrossRefGoogle Scholar
  9. Gavrilovic IT, Posner JB (2005a) Brain metastases: epidemiology and pathophysiology. J Neurooncol 75:5–14. CrossRefPubMedGoogle Scholar
  10. Gavrilovic IT, Posner JB (2005b) Brain metastases: epidemiology and pathophysiology. J Neurooncol 75:5–14. CrossRefPubMedGoogle Scholar
  11. Horky LL, Hsiao EM, Weiss SE et al (2011) Dual phase FDG-PET imaging of brain metastases provides superior assessment of recurrence versus post-treatment necrosis. J Neurooncol 103:137–146. CrossRefPubMedGoogle Scholar
  12. Kansy M, Avdeef A, Fischer H (2004) Advances in screening for membrane permeability: high-resolution PAMPA for medicinal chemists. Drug Discov Today Technol 1:349–355CrossRefPubMedGoogle Scholar
  13. Kirakci K, Kubát P, Dušek M et al (2012) A highly luminescent hexanuclear molybdenum cluster—a promising candidate toward photoactive materials. Eur J Inorg Chem 2012:3107–3111. CrossRefGoogle Scholar
  14. Krasilnikova AA, Shestopalov MA, Brylev KA et al (2015) Prospects of molybdenum and rhenium octahedral cluster complexes as X-ray contrast agents. J Inorg Biochem 144:13–17. CrossRefPubMedGoogle Scholar
  15. Liu X, Testa B, Fahr A (2011) Lipophilicity and its relationship with passive drug permeation. Pharm Res 28:962–977. CrossRefPubMedGoogle Scholar
  16. Ljubimova JY, Sun T, Mashouf L et al (2017) Covalent nano delivery systems for selective imaging and treatment of brain tumors. Adv Drug Deliv Rev 113:177–200CrossRefPubMedPubMedCentralGoogle Scholar
  17. Orto PJ, Nichol GS, Okumura N et al (2008) Cluster carbonyls of the [Re(6)(mu(3)-Se)(8)](2+) core: synthesis, structural characterization, and computational analysis. Dalton Trans 6:4247–4253. CrossRefGoogle Scholar
  18. Ramirez-Tagle R, Arratia-Pérez R (2008a) Electronic structure and molecular properties of the [Mo6X8L6]2−; X = Cl, Br, I; L = F, Cl, Br, I clusters. Chem Phys Lett 460:438–441. CrossRefGoogle Scholar
  19. Ramirez-Tagle R, Arratia-Pérez R (2008b) The luminescent [Mo6X8(NCS)6]2− (X = Cl, Br, I) clusters?: a computational study based on time-dependent density functional theory including spin-orbit and solvent-polarity effects. Chem Phys Lett 455:38–41. CrossRefGoogle Scholar
  20. Ramirez-tagle R, Arratia-pérez R (2009) Pyridine as axial ligand on the [Mo6Cl8]4+ core switches off luminescence. Chem Phys Lett 475:232–234. CrossRefGoogle Scholar
  21. Ramírez-Tagle R, Arratia-Pérez R (2008) Electronic structure and molecular properties of the mixed rhenium-molybdenum [Re6−xMoxS8(CN)6]q−, (x = 0 to 6) clusters. J Clust Sci 20:159–164. CrossRefGoogle Scholar
  22. Rojas-Mancilla E, Oyarce A, Verdugo V et al (2015) The cluster [Re6Se8I6]3− induces low hemolysis of human erythrocytes in vitro: protective effect of albumin. Int J Mol Sci 16:1728–1735. CrossRefPubMedPubMedCentralGoogle Scholar
  23. Rojas-Mancilla E, Oyarce A, Verdugo V et al (2017) The [Mo6Cl14]2− cluster is biologically secure and has anti-rotavirus activity in vitro. Molecules. PubMedGoogle Scholar
  24. Rutkowska E, Pająk K, Jóźwiak K (2013) Lipophilicity—methods of determination and its role in medicinal chemistry. Acta Pol Pharm Drug Res 70:3–18Google Scholar
  25. Shestopalov MA, Zubareva KE, Khripko OP et al (2014) The first water-soluble hexarhenium cluster complexes with a heterocyclic ligand environment: synthesis, luminescence, and biological properties. Inorg Chem 53:9006–9013. CrossRefPubMedGoogle Scholar
  26. Solovieva AO, Vorotnikov YA, Trifonova KE et al (2016) Cellular internalisation, bioimaging and dark and photodynamic cytotoxicity of silica nanoparticles doped by Mo6I84+ metal clusters. J Mater Chem B 4:4839–4846. CrossRefGoogle Scholar
  27. Solovieva AO, Kirakci K, Ivanov AA et al (2017) Singlet oxygen production and biological activity of hexanuclear chalcocyanide rhenium cluster complexes [Re6Q8(CN)6]4− (Q = SSe, Te). Inorg Chem. PubMedGoogle Scholar
  28. Sperduto PW, Kased N, Roberge D et al (2012) Effect of tumor subtype on survival and the graded prognostic assessment for patients with breast cancer and brain metastases. Int J Radiat Oncol Biol Phys 82:2111–2117. CrossRefPubMedGoogle Scholar
  29. Szczepura LF, Edwards JA, Cedeño DL (2008) Luminescent properties of hexanuclear molybdenum(II) chloride clusters containing thiolate ligands. J Clust Sci 20:105–112. CrossRefGoogle Scholar
  30. Vraka C, Nics L, Wagner KH et al (2017) LogP, a yesterday’s value? Nucl Med Biol 50:1–10. CrossRefPubMedGoogle Scholar
  31. Waterhouse RN (2003) Determination of lipophilicity and its use as a predictor of blood-brain barrier penetration of molecular imaging agents. Mol Imaging Biol 5:376–389. CrossRefPubMedGoogle Scholar

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© Springer Science+Business Media, LLC, part of Springer Nature 2018

Authors and Affiliations

  • Lisbell D. Estrada
    • 1
  • Elizabeth Duran
    • 1
  • Matias Cisterna
    • 1
  • Cesar Echeverria
    • 1
  • Zhiping Zheng
    • 2
  • Vincenzo Borgna
    • 3
    • 4
  • Nicolas Arancibia-Miranda
    • 5
    • 6
  • Rodrigo Ramírez-Tagle
    • 7
  1. 1.Centro de Biología y Química Aplicada (CIBQA)Universidad Bernardo O HigginsSantiagoChile
  2. 2.Department of ChemistryThe University of ArizonaTucsonUSA
  3. 3.Urology DepartmentHospital Barros Luco TrudeauSantiagoChile
  4. 4.Andes Biotechnologies SA and Fundación Ciencia para la VidaSantiagoChile
  5. 5.Facultad de Química y BiologiaUniversidad de Santiago de ChileSantiagoChile
  6. 6.Center of Development of Nanoscience and Nanotechnology CEDENNASantiagoChile
  7. 7.Facultad de Ingeniería Ciencia y TecnologíaUniversidad Bernardo O HigginsSantiagoChile

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