Pharmaceutical Research

, Volume 33, Issue 6, pp 1351–1358 | Cite as

Liposomes as Delivery System of a Sn(IV) Complex for Cancer Therapy

  • M. Luísa Corvo
  • Ana Soraia Mendo
  • Sara Figueiredo
  • Rogério Gaspar
  • Miguel Larguinho
  • M. Fátima C. Guedes da Silva
  • Pedro Viana Baptista
  • Alexandra R Fernandes
Research Paper

ABSTRACT

Propose

Tin complexes demonstrate antiproliferative activities in some case higher than cisplatin, with IC50 at the low micromolar range. We have previously showed that the cyclic trinuclear complex of Sn(IV) bearing an aromatic oximehydroxamic acid group [nBu2Sn(L)]3 (L=N,2-dihydroxy-5-[N-hydroxyethanimidoyl]benzamide) (MG85) shows high anti-proliferative activity, induces apoptosis and oxidative stress, and causes destabilization of tubulin microtubules, particularly in colorectal carcinoma cells. Despite the great efficacy towards cancer cells, this complex still shows some cytotoxicity to healthy cells. Targeted delivery of this complex specifically towards cancer cells might foster cancer treatment.

Methods

MG85 complex was encapsulated into liposomal formulation with and without an active targeting moiety and cancer and healthy cells cytotoxicity was evaluated.

Results

Encapsulation of MG85 complex in targeting PEGylated liposomes enhanced colorectal carcinoma (HCT116) cancer cell death when compared to free complex, whilst decreasing cytotoxicity in non-tumor cells. Labeling of liposomes with Rhodamine allowed assessing internalization in cells, which showed significant cell uptake after 6 h of incubation. Cetuximab was used as targeting moiety in the PEGylated liposomes that displayed higher internalization rate in HCT116 cells when compared with non-targeted liposomes, which seems to internalize via active binding of Cetuximab to cells.

Conclusions

The proposed formulation open new avenues in the design of innovative transition metal-based vectorization systems that may be further extended to other novel metal complexes towards the improvement of their anti-cancer efficacy, which is usually hampered by solubility issues and/or toxicity to healthy tissues.

KEY WORDS

(targeted) long circulating liposomes antiproliferative colorectal carcinoma Sn(IV) complexes 

ABBREVIATIONS

DMPC

Dimyristoylphosphatidylcholine

DMPG

Dimyristoylphosphoglycerol

DSPE-PEG2000

Distearoylphosphatidylethanolamine-poly(ethyleneglycol) 2000

DSPE-PEG-NHS

1,2-Distearoyl-sn-glycero-3-phosphoethanolamine-poly(ethylene-glycol)-2000-N-hydroxysuccinimide

EGFR

Epidermal growth factor receptor

HCT116

Colorectal carcinoma cells

HepG2

Hepatocellular carcinoma cells

ICP

Inductively Coupled Plasma Mass Spectrometry

L

Empty Liposomes

MG85

[nBu2Sn(L)]3 (L=N,2-dihydroxy-5-[N-hydroxyethanimidoyl]benzamide)

MG85-L

MG85 incorporated in conventional/non-PEGylated liposomes

MG85-PEG-Rho-L-Cetuxi

MG85 incorporated in Cetuximab targeted PEGylated liposomes labelled with Rho

MPS

Mononuclear phagocyte system

PDI

Polydispersity index

PEG

Polyethylene glycol

PEG-Rho-L

PEGylated liposomes labelled with Rho

PEG-Rho–L-Cetuxi

Cetuximab targeted PEGylated liposomes labelled with Rho

PMA

phorbol 12-myristate-13 acetate

Rho

Rhodamine B

Rho-PE

L-α-phosphoethanolamine-N-(lissamine Rhodamine B sulfonyl)

THP1

Human monocytic leukemia (THP1) cell line

Supplementary material

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ESM 1(DOCX 18 kb)
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Supplementary Figure S1

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Supplementary Figure S2

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Supplementary Figure S3

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Supplementary Figure S4

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Supplementary Figure S5

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Supplementary Figure S6

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REFERENCES

  1. 1.
    Varela-Ramirez M, Costanzo YP, Carrasco KH, Pannell, Aguilera RJ. Cytotoxic effects of two organotin compounds and their mode of inflicting cell death on four mammalian cancer cells. Cell Biol Toxicol. 2011;27:159–68. doi:10.1007/s10565-010-9178-y.CrossRefPubMedPubMedCentralGoogle Scholar
  2. 2.
    Gielen M. Organotin compounds and their therapeutic potential: a report from the organometallic chemistry department of the free University of Brussels. Appl Organomet Chem. 2002;16:81–494. doi:10.1002/aoc.331.Google Scholar
  3. 3.
    Hadjikakou SK, Hadjiliadis N. Antiproliferative and anti-tumor activity of organotin compounds. Coord Chem Rev. 2009;253:235–49. doi:10.1016/j.ccr.2007.12.026.CrossRefGoogle Scholar
  4. 4.
    Pellerito L, Nagy L, Pellerito PM, Szorcsik A. Biological activity studies on organotin(IV)n+ complexes and parent compounds. J Organomet Chem. 2006;691:1733–47. doi:10.1016/j.jorganchem.2005.12.025.CrossRefGoogle Scholar
  5. 5.
    Mahmudov KT, Guedes da Silva MFC, Kopylovich MN, Fernandes AR, Silva A, Mizar A, et al. Di- and tri-organotin(IV) complexes of arylhydrazones of methylene active compounds and their antiproliferative activity. J Organomet Chem. 2014;760:67–73. doi:10.1016/j.jorganchem.2013.12.019.CrossRefGoogle Scholar
  6. 6.
    Sirajuddin M, Ali S, McKee V, Sohail M, Pasha H. Potentially bioactive organotin(IV) compounds: synthesis, characterization, in vitro bioactivities and interaction with SS-DNA. Eur J Med Chem. 2014;84:343–63. doi:10.1016/j.ejmech.2014.07.028.CrossRefPubMedGoogle Scholar
  7. 7.
    Awang N, Kamaludin NF, Hamid A, Mokhtar NW, Rajab NF. Cytotoxicity of triphenyltin(IV) methyl- and ethylisopropyldithiocarbamate compounds in chronic myelogenus leukemia cell line (K-562). Pak J Biol Sci. 2012;15:833–8. doi:10.3923/pjbs.2012.833.838.CrossRefPubMedGoogle Scholar
  8. 8.
    Alama A, Tasso B, Novelli F, Sparatore F. Organometallic compounds in oncology: implications of novel organotins as antitumor agents. Drug Discov Today. 2009;14:500–8. doi:10.1016/j.drudis.2009.02.002.CrossRefPubMedGoogle Scholar
  9. 9.
    Gajewska M, Luzyanin KV, MFC G d S, Li Q, Cui J, Pombeiro AJL. Cyclic trinuclear diorganotin(IV) complexes—the first tin compounds bearing oximehydroxamate ligands: synthesis, structural characterization and high in vitro cytotoxicity. Eur J Inorg Chem. 2009;2009:3765–9. doi:10.1002/ejic.200900388.CrossRefGoogle Scholar
  10. 10.
    Tabassum S, Pettinari C. Chemical and biotechnological developments in organotin cancer chemotherapy. J Organomet Chem. 2006;691:1761–6. doi:10.1016/j.jorganchem.2005.12.033.CrossRefGoogle Scholar
  11. 11.
    Gielen M, Biesemans M, Willem R. Organotin compounds: from kinetics to stereochemistry and antitumour activities. Appl Organomet Chem. 2005;19:440–50. doi:10.1002/aoc.771.CrossRefGoogle Scholar
  12. 12.
    Pettinari C, Marchetti F. In: Tin chemistry: fundamentals, frontiers, and applications. John Wiley & Sons, ch. 4; 2008. p. 454–468. doi:10.1002/9780470758090.
  13. 13.
    Silva A, Luis D, Santos S, Silva J, Mendo AS, Coito L, et al. Biological characterization of the antiproliferative potential of Co(II) and Sn(IV) coordination compounds in human cancer cell lines: a comparative proteomic approach. Drug Metabol Drug Interact. 2013;8:167–76. doi:10.1515/dmdi-2013-0015.Google Scholar
  14. 14.
    Bansal SS, Goel M, Aqil F, Vadhanam MV, Gupta RC. Advanced drug delivery systems of curcumin for cancer chemoprevention. Cancer Prev Res. 2011;4:1158–71. doi:10.1158/1940-6207.CAPR-10-0006.CrossRefGoogle Scholar
  15. 15.
    Kaasgaard T, Andresen TL. Liposomal cancer therapy: exploiting tumor characteristics. Expert Opin Drug Deliv. 2010;7:225–43. doi:10.1517/17425240903427940.CrossRefPubMedGoogle Scholar
  16. 16.
    Malam Y, Loizidou M, Seifalian AM. Liposomes and nanoparticles: nanosized vehicles for drug delivery in cancer. Trends Pharmacol Sci. 2009;30:592–9. doi:10.1016/j.tips.2009.08.004.CrossRefPubMedGoogle Scholar
  17. 17.
    Mangiapia G, D’Errico G, Simeone L, Irace C, Radulescu A, Di Pascale A, et al. Ruthenium-based complex nanocarriers for cancer therapy. Biomaterials. 2012;33:3770–82. doi:10.1016/j.biomaterials.2012.01.057.CrossRefPubMedGoogle Scholar
  18. 18.
    Mangiapia G, Vitiello G, Irace C, Santamaria R, Colonna A, Angelico R, et al. Anticancer cationic ruthenium nanovetors: from rational molecular design to cellular uptake and bioactivity. Biomacromolecules. 2013;14:2549–60. doi:10.1021/bm400104b.CrossRefPubMedGoogle Scholar
  19. 19.
    Montesarchio D, Mangiapia G, Vitiello G, Musumeci D, Irace C, Santamaria R, et al. A new design for nucleolipid-based Ru(III) complexes as anticancer agents. Dalton Trans. 2013;42:16697–708. doi:10.1039/c3dt52320a.CrossRefPubMedGoogle Scholar
  20. 20.
    Lopes SCA, Giuberti CS, Rocha TGR, Ferreira DS, Leite EA, Oliveira MC. Liposomes as Carriers of Anticancer Drugs. In: Rangel L, editor. Cancer treatment—conventional and innovative approaches. Chapter 4. InTech, 2013. doi:10.5772/55290.
  21. 21.
    Charron DM, Chen J, Zheng G. Theranostic lipid nanoparticles for cancer medicine. Cancer Treat Res. 2015;166:103–27. doi:10.1007/978-3-319-16555-4_5.CrossRefPubMedGoogle Scholar
  22. 22.
    Cole JT, Holland NB. Multifunctional nanoparticles for use in theranostic applications. Drug Deliv Transl Res. 2015;5:295–309. doi:10.1007/s13346-015-0218-2.CrossRefPubMedGoogle Scholar
  23. 23.
    Mamot C, Ritschard R, Wicki A, Stehle G, Dieterle T, Bubendorf L, et al. Tolerability, safety, pharmacokinetics, and efficacy of doxorubicin-loaded anti-EGFR immunoliposomes in advanced solid tumours: a phase 1 dose-escalation study. Lancet Oncol. 2012;13:1234–41. doi:10.1016/S1470-2045(12)70476-X.CrossRefPubMedGoogle Scholar
  24. 24.
    Andresen TL, Jensen SS, Jørgensen K. Advanced strategies in liposomal cancer therapy: problems and prospects of active and tumor specific drug release. Prog Lipid Res. 2005;44:68–97. doi:10.1016/j.plipres.2004.12.001.CrossRefPubMedGoogle Scholar
  25. 25.
    Kao HW, Lin YY, Chen CC, Chi KH, Tien DC, Hsia CC, et al. Biological characterization of cetuximab-conjugated gold nanoparticles in a tumor animal model. Nanotechnology. 2014;25:295102. doi:10.1088/0957-4484/25/29/295102.CrossRefPubMedGoogle Scholar
  26. 26.
    Lehtinen J, Raki M, Bergström KA, Uutela P, Lehtinen K, Hiltunen A, et al. Pre-targeting and direct immunotargeting of liposomal drug carriers to ovarian carcinoma. PLoS One. 2012;7, e41410. doi:10.1371/journal.pone.0041410.CrossRefPubMedPubMedCentralGoogle Scholar
  27. 27.
    Lee J, Choi Y, Kim K, Hong S, Park HY, Lee T, et al. Characterization and cancer cell specific binding properties of anti-EGFR antibody conjugated quantum dots. Bioconjug Chem. 2010;21:940–6. doi:10.1021/bc9004975.CrossRefPubMedGoogle Scholar
  28. 28.
    Hertlein L, Lenhard M, Kirschenhofer A, Kahlert S, Mayr D, Burges A, et al. Cetuximab monotherapy in advanced cervical cancer: a retrospective study with five patients. Arch Gynecol Obstet. 2011;283:109–13. doi:10.1007/s00404-010-1389-1.CrossRefPubMedGoogle Scholar
  29. 29.
    Ocvirk J, Cencelj S. Management of cutaneous side-effects of cetuximab therapy in patients with metastatic colorectal cancer. J Eur Acad Dermatol Venereol. 2010;24:453–9. doi:10.1111/j.1468-3083.2009.03446.x.CrossRefPubMedGoogle Scholar
  30. 30.
    Liu L, Cao Y, Tan A, Liao C, Gao F. Cetuximab-based therapy versus non-cetuximab therapy for advanced cancer: a meta-analysis of 17 randomized controlled trials. Cancer Chemother Pharmacol. 2010;65:849–61. doi:10.1007/s00280-009-1090-x.CrossRefPubMedGoogle Scholar
  31. 31.
    Medina OP, Zhu Y, Kairemo K. Targeted liposomal drug delivery in cancer. Curr Pharm Des. 2004;10:2981–9. doi:10.2174/1381612043383467.CrossRefPubMedGoogle Scholar
  32. 32.
    Corvo ML, Marinho HS, Marcelino P, Lopes RM, Vale CA, Marques CR, et al. Superoxide dismutase enzymosomes: carrier capacity optimization, in vivo behaviour and therapeutic activity. Pharm Res. 2015;32:91–102. doi:10.1007/s11095-014-1447-7.CrossRefPubMedGoogle Scholar
  33. 33.
    Alavi SE, Esfahani MK, Ghassemi S, Akbarzadeh A, Hassanshahi G. In vitro evaluation of the efficacy of liposomal and pegylated liposomal hydroxyurea. Indian J Clin Biochem. 2014;29:84–8. doi:10.1007/s12291-013-0315-2.CrossRefPubMedPubMedCentralGoogle Scholar
  34. 34.
    de Menezes DE L, Pilarski LM, Allen TM. In vitro and in vivo targeting of immunoliposomal doxorubicin to human B-cell lymphoma. Cancer Res. 1998;58:3320–30.Google Scholar
  35. 35.
    Sapra P, Allen TM. Internalizing antibodies are necessary for improved therapeutic efficacy of antibody-targeted liposomal drugs. Cancer Res. 2002;62:7190–4.PubMedGoogle Scholar
  36. 36.
    Rouser G, Fkeischer S, Yamamoto A. Two dimensional then layer chromatographic separation of polar lipids and determination of phospholipids by phosphorus analysis of spots. Lipids. 1970;5:494–6.CrossRefPubMedGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2016

Authors and Affiliations

  • M. Luísa Corvo
    • 1
  • Ana Soraia Mendo
    • 2
  • Sara Figueiredo
    • 2
    • 3
  • Rogério Gaspar
    • 1
  • Miguel Larguinho
    • 2
  • M. Fátima C. Guedes da Silva
    • 4
  • Pedro Viana Baptista
    • 2
    • 3
  • Alexandra R Fernandes
    • 2
    • 4
  1. 1.Instituto de Investigação do Medicamento (iMed.ULisboa), Faculdade de FarmáciaUniversidade de LisboaLisboaPortugal
  2. 2.UCIBIO, Departamento de Ciências da Vida, Faculdade de Ciências e TecnologiaUniversidade NOVA de LisboaCaparicaPortugal
  3. 3.ToxOmics, Faculdade de Ciências MédicasUniversidade NOVA de LisboaLisboaPortugal
  4. 4.CQE, Centro de Química Estrutural, Instituto Superior TécnicoLisboaPortugal

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