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

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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.

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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

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ACKNOWLEDGMENTS AND DISCLOSURES

We acknowledge Fundação para a Ciência e a Tecnologia (FCT/MEC) for financial support (Project PTDC/BBB-NAN/1812/2012; UCIBIO UID/Multi/04378/2013; UID/DTP/04138/2013). We thank M.Gajewska for MG85 synthesis and P. Borralho from iMed for Cetuximab.

M. Luísa Corvo and Ana Soraia Mendo contributed equally to the work.

Author information

Authors and Affiliations

  1. Instituto de Investigação do Medicamento (iMed.ULisboa), Faculdade de Farmácia, Universidade de Lisboa, Avenida Professor Gama Pinto, 1649-003, Lisboa, Portugal

    M. Luísa Corvo & Rogério Gaspar

  2. UCIBIO, Departamento de Ciências da Vida, Faculdade de Ciências e Tecnologia, Universidade NOVA de Lisboa, Campus de Caparica, 2829-516, Caparica, Portugal

    Ana Soraia Mendo, Sara Figueiredo, Miguel Larguinho, Pedro Viana Baptista & Alexandra R Fernandes

  3. ToxOmics, Faculdade de Ciências Médicas, Universidade NOVA de Lisboa, Rua Câmara Pestana, 1150-082, Lisboa, Portugal

    Sara Figueiredo & Pedro Viana Baptista

  4. CQE, Centro de Química Estrutural, Instituto Superior Técnico, Av. Rovisco Pais, 1096-001, Lisboa, Portugal

    M. Fátima C. Guedes da Silva & Alexandra R Fernandes

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  1. M. Luísa Corvo
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Correspondence to Pedro Viana Baptista or Alexandra R Fernandes.

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Corvo, M.L., Mendo, A.S., Figueiredo, S. et al. Liposomes as Delivery System of a Sn(IV) Complex for Cancer Therapy. Pharm Res 33, 1351–1358 (2016). https://doi.org/10.1007/s11095-016-1876-6

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  • DOI: https://doi.org/10.1007/s11095-016-1876-6

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