Liposomes as Delivery System of a Sn(IV) Complex for Cancer Therapy
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.
MG85 complex was encapsulated into liposomal formulation with and without an active targeting moiety and cancer and healthy cells cytotoxicity was evaluated.
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.
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
Epidermal growth factor receptor
Colorectal carcinoma cells
Hepatocellular carcinoma cells
Inductively Coupled Plasma Mass Spectrometry
MG85 incorporated in conventional/non-PEGylated liposomes
MG85 incorporated in Cetuximab targeted PEGylated liposomes labelled with Rho
Mononuclear phagocyte system
PEGylated liposomes labelled with Rho
Cetuximab targeted PEGylated liposomes labelled with Rho
phorbol 12-myristate-13 acetate
L-α-phosphoethanolamine-N-(lissamine Rhodamine B sulfonyl)
Human monocytic leukemia (THP1) cell line
- 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
- 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
- 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.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
- 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.
- 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
- 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