The interaction between SBA-15 derivative loaded with Ph3Sn(CH2)6OH and human melanoma A375 cell line: uptake and stem phenotype loss

  • Danijela Maksimović-Ivanić
  • Mirna Bulatović
  • David Edeler
  • Christian Bensing
  • Igor Golić
  • Aleksandra Korać
  • Goran N. KaluđerovićEmail author
  • Sanja MijatovićEmail author
Original Paper


Extraordinary progress in medicinal inorganic chemistry in the past few years led to the rational design of novel platinum compounds, as well as nonplatinum metal-based antitumor agents, including organotin compounds, whose activity is not based on unrepairable interaction with DNA. To overcome poor solubility and toxicity problems that limited the application of these compounds numerous delivering systems were used (Lila et al. in Biol Pharm Bull 37:206–211, 2014; Yue and Cao in Curr Cancer Drug Targets 16:480–488, 2016; Duan et al. in WIREs Nanomed Nanobiotechnol 8:776–791, 2016). Regarding high drug loading capacity, mesoporous silica nanoparticles like SBA-15 became more important for targeted drug delivery. In this study, cellular uptake and biological activities responsible for organotin(IV) compound Ph3Sn(CH2)6OH (Sn6) grafted into (3-chloropropyl)triethoxysilane functionalized SBA-15 (SBA-15p → SBA-15p|Sn6) were evaluated in human melanoma A375 cell line. Moreover, the influence of SBA-15p grafted with organotin(IV) compound on the stemness of A375 cell was tested. Given the fact that SBA-15p|Sn6 nanoparticles are nonspherical and relatively large, their internalization efficiently started even after 15 min with stable adhesion to the cell membrane. After only 2 h of incubation of A375 cells with SBA-15p|Sn6 passive fluid-phase uptake and macropinocytosis were observed. Inside of the cell, treatment with SBA-15p loaded with Sn6 promoted caspase-dependent apoptosis in parallel with senescence development. The subpopulation of cells expressing Schwann-like phenotype arose upon the treatment, while the signaling pathway responsible for maintenance of pluripotency and invasiveness, Wnt, Notch1, and Oct3/4 were modulated towards less aggressive signature. In summary, SBA-15p enhances the efficacy of free Sn6 compound through efficient uptake and well profiled intracellular response followed with decreased stem characteristics of highly invasive A375 melanoma cells.

Graphical abstract


SBA-15 Organotin(IV) compound A375 melanoma cell line Drug uptake Stemness 



This work was supported by the Serbian Ministry of Education, Science and Technological Development (Grant no. 173013) as well as the German Academic Exchange Service (DAAD).

Supplementary material

775_2019_1640_MOESM1_ESM.docx (1.2 mb)
Electronic Supplementary Material: XRD, nitrogen sorption, pore diameter distribution, 13C and 29Si CP/MAS NMR spectra for SBA-15p|Sn6; MTT and CV cell viability results for A375 after treatment with Ph3Sn(CH2)6OH and SBA-15p|Sn6; TEM of SBA-15p|Sn6 uptake, morphological changes of A375 upon treatment of A375 cells with SBA-15p|Sn6. (docx 1210 kb)


  1. 1.
    Lila ASA, Kiwada H, Ishida T (2014) Selective delivery of oxaliplatin to tumor tissue by nanocarrier system enhances overall therapeutic efficacy of the encapsulated oxaliplatin. Biol Pharm Bull 37:206–211CrossRefPubMedGoogle Scholar
  2. 2.
    Yue Z, Cao Z (2016) Current strategy for cisplatin delivery. Curr Cancer Drug Targets 16:480–488CrossRefPubMedGoogle Scholar
  3. 3.
    Duan X, He C, Kron SJ, Lin W (2016) Nanoparticle formulations of cisplatin for cancer therapy. WIREs Nanomed Nanobiotechnol 8:776–791CrossRefGoogle Scholar
  4. 4.
    Gómez-Ruiz S, Maksimović-Ivanić D, Mijatović S, Kaluđerović GN (2012) On the discovery, biological effects, and use of cisplatin and metallocenes in anticancer chemotherapy. Bioinorg Chem Appl 2012:140284CrossRefPubMedPubMedCentralGoogle Scholar
  5. 5.
    Kaluđerović GN, Paschke R (2011) Anticancer metallotherapeutics in preclinical development. Curr Med Chem 18:4738–4752CrossRefPubMedGoogle Scholar
  6. 6.
    Mjos KD, Orvig C (2014) Metallodrugs in medicinal inorganic chemistry. Chem Rev 114:4540–4563CrossRefPubMedGoogle Scholar
  7. 7.
    Kelland L (2007) The resurgence of platinum-based cancer chemotherapy. Nat Rev Cancer 7:573–584CrossRefPubMedGoogle Scholar
  8. 8.
    Bulatović MZ, Maksimović-Ivanić D, Bensing C, Gómez-Ruiz S, Steinborn D, Schmidt H, Mojić M, Korać A, Golić I, Pérez-Quintanilla D, Momčilović M, Mijatović S, Kaluđerović GN (2014) Organotin(IV)-loaded mesoporous silica as a biocompatible strategy in cancer treatment. Angew Chem Int Ed Engl 53:5982–5987CrossRefPubMedGoogle Scholar
  9. 9.
    Seeta Rama Raju G, Benton L, Pavitra E, Yu JS (2015) Multifunctional nanoparticles: recent progress in cancer therapeutics. Chem Commun Camb Engl 51:13248–13259CrossRefGoogle Scholar
  10. 10.
    Hartinger CG, Zorbas-Seifried S, Jakupec MA, Kynast B, Zorbas H, Keppler BK (2006) From bench to bedside-preclinical and early clinical development of the anticancer agent indazolium trans-[tetrachlorobis(1H-indazole)ruthenate(III)] (KP1019 or FFC14A). J Inorg Biochem 100:891–904CrossRefPubMedGoogle Scholar
  11. 11.
    Hartinger CG, Jakupec MA, Zorbas-Seifried S, Groessl M, Egger A, Berger W, Zorbas H, Dyson PJ, Keppler BK (2008) KP1019, a new redox-active anticancer agent-preclinical development and results of a clinical phase I study in tumor patients. Chem Biodivers 5:2140–2155CrossRefPubMedGoogle Scholar
  12. 12.
    Romero-Canelón I, Sadler PJ (2013) Next-generation metal anticancer complexes: multitargeting via redox modulation. Inorg Chem 52:12276–12291CrossRefPubMedGoogle Scholar
  13. 13.
    Navakoski de Oliveira K, Andermark V, von Grafenstein S, Onambele LA, Dahl G, Rubbiani R, Wolber G, Gabbiani C, Messori L, Prokop A, Ott I (2013) Butyltin(IV) benzoates: inhibition of thioredoxin reductase, tumor cell growth inhibition, and interactions with proteins. ChemMedChem 8:256–264CrossRefPubMedGoogle Scholar
  14. 14.
    Alama A, Tasso B, Novelli F, Sparatore F (2009) Organometallic compounds in oncology: implications of novel organotins as antitumor agents. Drug Discov Today 14:500–508CrossRefPubMedGoogle Scholar
  15. 15.
    Hadjikakou SK, Hadjiliadis N (2009) Antiproliferative and anti-tumor activity of organotin compounds. Coord Chem Rev 253:235–249CrossRefGoogle Scholar
  16. 16.
    Ishiwata H, Inoue T, Yoshihira K (1986) Migration of copper and some other metals from copper tableware. Bull Environ Contam Toxicol 37:638–642CrossRefPubMedGoogle Scholar
  17. 17.
    Casas JS, Castellano EE, Couce MD, Ellena J, Sánchez A, Sánchez JL, Sordo J, Taboada C (2004) The reaction of dimethyltin(IV) dichloride with thiamine diphosphate (H2TDP): synthesis and structure of [SnMe2(HTDP)(H2O)]Cl.H2O, and possibility of a hitherto unsuspected role of the metal cofactor in the mechanism of vitamin-B1-dependent enzymes. Inorg Chem 43:1957–1963CrossRefPubMedGoogle Scholar
  18. 18.
    Qingshan L, Nan J, Pin Y, Jindong W, Wenshi W, Jiazhu W (1997) Interaction of Et2SnCl2(phen) with nucleotides. Synth React Inorg Met Org Chem 27:811–823CrossRefGoogle Scholar
  19. 19.
    Gerasimchuk N, Maher T, Durham P, Domasevitch KV, Wilking J, Mokhir A (2007) Tin(IV) cyanoximates: synthesis, characterization, and cytotoxicity. Inorg Chem 46:7268–7284CrossRefPubMedGoogle Scholar
  20. 20.
    Danhier F, Feron O, Préat V (2010) To exploit the tumor microenvironment: Passive and active tumor targeting of nanocarriers for anti-cancer drug delivery. J Control Release 148:135–146CrossRefPubMedGoogle Scholar
  21. 21.
    Slowing II, Vivero-Escoto JL, Wu C-W, Lin VS-Y (2008) Mesoporous silica nanoparticles as controlled release drug delivery and gene transfection carriers. Adv Drug Deliv Rev 60:1278–1288CrossRefPubMedGoogle Scholar
  22. 22.
    Tang F, Li L, Chen D (2012) Mesoporous silica nanoparticles: synthesis, biocompatibility and drug delivery. Adv Mater Deerfield Beach Fla 24:1504–1534CrossRefGoogle Scholar
  23. 23.
    Edeler D, Kaluđerović MR, Dojčinović B, Schmidt H, Kaluđerović GN (2016) SBA-15 mesoporous silica particles loaded with cisplatin induce senescence in B16F10 cells. RSC Adv 6:111031–111040CrossRefGoogle Scholar
  24. 24.
    Tao Z, Toms B, Goodisman J, Asefa T (2010) Mesoporous silica microparticles enhance the cytotoxicity of anticancer platinum drugs. ACS Nano 4:789–794CrossRefPubMedGoogle Scholar
  25. 25.
    Fisichella M, Dabboue H, Bhattacharyya S et al (2010) Uptake of functionalized mesoporous silica nanoparticles by human cancer cells. J Nanosci Nanotechnol 10:2314–2324CrossRefPubMedGoogle Scholar
  26. 26.
    Peer D, Karp JM, Hong S, Lelong G, Saboungi ML, Warmont F, Midoux P, Pichon C, Guérin M, Hevor T, Salvetat JP (2007) Nanocarriers as an emerging platform for cancer therapy. Nat Nanotechnol 2:751–760CrossRefPubMedGoogle Scholar
  27. 27.
    Ekmekcioglu S, Ellerhorst J, Smid CM, Prieto VG, Munsell M, Buzaid AC, Grimm EA (2000) Inducible nitric oxide synthase and nitrotyrosine in human metastatic melanoma tumors correlate with poor survival. Clin Cancer Res 6:4768–4775PubMedGoogle Scholar
  28. 28.
    Grimm EA, Ellerhorst J, Tang CH, Ekmekcioglu S (2008) Constitutive intracellular production of iNOS and NO in human melanoma; possible role in regulation of growth and resistance to apoptosis. Nitric Oxide 19:133–137CrossRefPubMedPubMedCentralGoogle Scholar
  29. 29.
    Hiraga T, Ito S, Nakamura H (2013) Cancer stem-like cell marker CD44 promotes bone metastases by enhancing tumorigenicity, cell motility, and hyaluronan production. Cancer Res 73:4112–4122CrossRefPubMedGoogle Scholar
  30. 30.
    Chen Z, Zhu P, Zhang Y, Liu Y, He Y, Zhang L, Gao Y (2016) Enhanced sensitivity of cancer stem cells to chemotherapy using functionalized mesoporous silica nanoparticles. Mol Pharm 13:2749–2759CrossRefPubMedGoogle Scholar
  31. 31.
    Wang D, Huang J, Wang X, Yu Y, Zhang H, Chen Y, Liu J, Sun Z, Zou H, Sun D, Zhou G, Zhang G, Lu Y, Zhong Y (2013) The eradication of breast cancer cells and stem cells by 8-hydroxyquinoline-loaded hyaluronan modified mesoporous silica nanoparticle-supported lipid bilayers containing docetaxel. Biomaterials 34:7662–7673CrossRefPubMedGoogle Scholar
  32. 32.
    Zhao D, Huo Q, Feng J, Chmelka BF, Stuckyet GD (1998) Nonionic triblock and star diblock copolymer and oligomeric surfactant syntheses of highly ordered, hydrothermally stable, mesoporous silica structures. J Am Chem Soc 120:6024–6036CrossRefGoogle Scholar
  33. 33.
    Srinivas D, Ratnasamy P (2007) Spectroscopic and catalytic properties of SBA-15 molecular sieves functionalized with acidic and basic moieties. Microporous Mesoporous Mater 105:170–180CrossRefGoogle Scholar
  34. 34.
    Krajnović T, Kaluđerović GN, Wessjohann LA, Mijatović S, Maksimović-Ivanić D (2016) Versatile antitumor potential of isoxanthohumol: enhancement of paclitaxel activity in vivo. Pharmacol Res 105:62–73CrossRefPubMedGoogle Scholar
  35. 35.
    Mayor S, Pagano RE (2007) Pathways of clathrin-independent endocytosis. Nat Rev Mol Cell Biol 8:603–612CrossRefPubMedGoogle Scholar
  36. 36.
    Faklaris O, Joshi V, Irinopoulou T, Tauc P, Sennour M, Girard H, Gesset C, Arnault JC, Thorel A, Boudou JP, Curmi PA, Treussart F (2009) Photoluminescent diamond nanoparticles for cell labeling: study of the uptake mechanism in mammalian cells. ACS Nano 3:3955–3962CrossRefPubMedGoogle Scholar
  37. 37.
    Morrison SJ, White PM, Zock C, Anderson DJ (1999) Prospective identification, isolation by flow cytometry, and in vivo self-renewal of multipotent mammalian neural crest stem cells. Cell 96(737–74):9Google Scholar
  38. 38.
    Reed JA, Finnerty B, Albino AP (1999) Divergent cellular differentiation pathways during the invasive stage of cutaneous malignant melanoma progression. Am J Pathol 155:549–555CrossRefPubMedPubMedCentralGoogle Scholar
  39. 39.
    Krajnović T, Maksimović-Ivanić D, Mijatović S, Drača D, Wolf K, Edeler D, Wessjohann LA, Kaluđerović GN (2018) Drug delivery system for emodin based on mesoporous silica SBA-15. Nanomaterials 8(5):322CrossRefPubMedCentralGoogle Scholar
  40. 40.
    Pérez-Quintanilla D, Gómez-Ruiz S, Žižak Ž, Sierra I, Prashar S, del Hierro I, Fajardo M, Juranić ZD, Kaluderović GN (2009) A new generation of anticancer drugs: mesoporous materials modified with titanocene complexes. Chem Eur J 15:5588–5597CrossRefPubMedGoogle Scholar
  41. 41.
    Roiter Y, Ornatska M, Rammohan AR, Balakrishnan J, Heine DR, Minko S (2008) Interaction of nanoparticles with lipid membrane. Nano Lett 8:941–944CrossRefPubMedGoogle Scholar
  42. 42.
    Meng H, Yang S, Li Z, Xia T, Chen J, Ji Z, Zhang H, Wang X, Lin S, Huang C, Zhou ZH, Zink JI, Nel AE (2011) Aspect ratio determines the quantity of mesoporous silica nanoparticle uptake by a small GTPase-dependent macropinocytosis mechanism. ACS Nano 5:4434–4447CrossRefPubMedPubMedCentralGoogle Scholar
  43. 43.
    Lu J, Liong M, Sherman S, Xia T, Kovochich M, Nel AE, Zink JI, Tamanoi F (2007) Mesoporous silica nanoparticles for cancer therapy: energy-dependent cellular uptake and delivery of paclitaxel to cancer cells. NanoBiotechnology 3:89–95CrossRefPubMedPubMedCentralGoogle Scholar
  44. 44.
    Green DR, Evan GI (2002) A matter of life and death. Cancer Cell 1:19–30CrossRefPubMedGoogle Scholar
  45. 45.
    Schmitt CA, Fridman JS, Yang M, Lee S, Baranov E, Hoffman RM, Lowe SW (2002) A senescence program controlled by p53 and p16INK4a contributes to the outcome of cancer therapy. Cell 109:335–346CrossRefPubMedGoogle Scholar
  46. 46.
    Nardella C, Clohessy JG, Alimonti A, Pandolfi PP (2011) Pro-senescence therapy for cancer treatment. Nat Rev Cancer 11:503–511CrossRefPubMedGoogle Scholar
  47. 47.
    Xue W, Zender L, Miething C, Dickins RA, Hernando E, Krizhanovsky V, Cordon-Cardo C, Lowe SW (2007) Senescence and tumour clearance is triggered by p53 restoration in murine liver carcinomas. Nature 445:656–660CrossRefPubMedPubMedCentralGoogle Scholar
  48. 48.
    Maksimovic-Ivanic D, Mijatovic S, Miljkovic D, Harhaji-Trajkovic L, Timotijevic G, Mojic M, Dabideen D, Cheng KF, McCubrey JA, Mangano K, Al-Abed Y, Libra M, Garotta G, Stosic-Grujicic S, Nicoletti F (2009) The antitumor properties of a nontoxic, nitric oxide-modified version of saquinavir are independent of Akt. Mol Cancer Ther 8:1169–1178CrossRefPubMedGoogle Scholar
  49. 49.
    Keilhoff G, Goihl A, Langnäse K, Fansa H, Wolf G (2006) Transdifferentiation of mesenchymal stem cells into Schwann cell-like myelinating cells. Eur J Cell Biol 85:11–24CrossRefPubMedGoogle Scholar
  50. 50.
    Cosgaya JM, Chan JR, Shooter EM (2002) The neurotrophin receptor p75NTR as a positive modulator of myelination. Science 298:1245–1248CrossRefPubMedGoogle Scholar
  51. 51.
    Radke J, Roßner F, Redmer T (2017) CD271 determines migratory properties of melanoma cells. Sci Rep 7:9834CrossRefPubMedPubMedCentralGoogle Scholar
  52. 52.
    Ballotti R (2015) Identification of melanoma initiating cells: does CD271 have a future? Future Oncol 11:1587–1590CrossRefPubMedGoogle Scholar
  53. 53.
    Nelson WJ, Nusse R (2004) Convergence of Wnt, beta-catenin, and cadherin pathways. Science 303:1483–1487CrossRefPubMedPubMedCentralGoogle Scholar
  54. 54.
    Damsky WE, Curley DP, Santhanakrishnan M, Rosenbaum LE, Platt JT, Gould Rothberg BE, Taketo MM, Dankort D, Rimm DL, McMahon M, Bosenberg M (2011) β-Catenin signaling controls metastasis in Braf-activated Pten-deficient melanomas. Cancer Cell 20:741–754CrossRefPubMedPubMedCentralGoogle Scholar
  55. 55.
    Bray SJ (2006) Notch signalling: a simple pathway becomes complex. Nat Rev Mol Cell Biol 7:678–689CrossRefPubMedGoogle Scholar
  56. 56.
    Radtke F, Raj K (2003) The role of Notch in tumorigenesis: oncogene or tumour suppressor? Nat Rev Cancer 3:756–767CrossRefPubMedGoogle Scholar
  57. 57.
    Artavanis-Tsakonas S, Rand MD, Lake RJ (1999) Notch signaling: cell fate control and signal integration in development. Science 284:770–776CrossRefPubMedGoogle Scholar
  58. 58.
    Kumano K, Masuda S, Sata M, Saito T, Lee SY, Sakata-Yanagimoto M, Tomita T, Iwatsubo T, Natsugari H, Kurokawa M, Ogawa S, Chiba S (2008) Both Notch1 and Notch2 contribute to the regulation of melanocyte homeostasis. Pigment Cell Melanoma Res 21:70–78CrossRefPubMedGoogle Scholar
  59. 59.
    Hendrix MJC, Seftor EA, Seftor REB, Kasemeier-Kulesa J, Kulesa PM, Postovit LM (2007) Reprogramming metastatic tumour cells with embryonic microenvironments. Nat Rev Cancer 7:246–255CrossRefPubMedGoogle Scholar
  60. 60.
    Ramgolam K, Lauriol J, Lalou C, Lauden L, Michel L, de la Grange P, Khatib AM, Aoudjit F, Charron D, Alcaide-Loridan C, Al-Daccak R (2011) Melanoma spheroids grown under neural crest cell conditions are highly plastic migratory/invasive tumor cells endowed with immunomodulator function. PLoS One 6:e18784CrossRefPubMedPubMedCentralGoogle Scholar
  61. 61.
    Cheli Y, Bonnazi VF, Jacquel A, Allegra M, De Donatis GM, Bahadoran P, Bertolotto C, Ballotti R (2014) CD271 is an imperfect marker for melanoma initiating cells. Oncotarget 5:5272–5283CrossRefPubMedPubMedCentralGoogle Scholar
  62. 62.
    Abdullah LN, Chow EK-H (2013) Mechanisms of chemoresistance in cancer stem cells. Clin Transl Med 2:3CrossRefPubMedPubMedCentralGoogle Scholar
  63. 63.
    Mamaeva V, Niemi R, Beck M, Özliseli E, Desai D, Landor S, Gronroos T, Kronqvist P, Pettersen IK, McCormack E, Rosenholm JM, Linden M, Sahlgren C (2016) Inhibiting notch activity in breast cancer stem cells by glucose functionalized nanoparticles carrying γ-secretase inhibitors. Mol Ther 24:926–936CrossRefPubMedPubMedCentralGoogle Scholar

Copyright information

© Society for Biological Inorganic Chemistry (SBIC) 2019

Authors and Affiliations

  1. 1.Institute for Biological Research “Sinisa Stankovic”University of BelgradeBelgradeSerbia
  2. 2.Institute of ChemistryMartin Luther University Halle-WittenbergHalle (Saale)Germany
  3. 3.Center for Electron Microscopy, Faculty of BiologyUniversity of BelgradeBelgradeSerbia
  4. 4.Department of Engineering and Natural SciencesUniversity of Applied Sciences MerseburgMerseburgGermany

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