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Superoxide Dismutase Enzymosomes: Carrier Capacity Optimization, in Vivo Behaviour and Therapeutic Activity

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Abstract

Purpose

A strategy not usually used to improve carrier-mediated delivery of therapeutic enzymes is the attachment of the enzymes to the outer surface of liposomes. The aim of our work was to design a new type of enzymosomes with a sufficient surface-exposed enzyme load while preserving the structural integrity of the liposomal particles and activity of the enzyme.

Methods

The therapeutic antioxidant enzyme superoxide dismutase (SOD) was covalently attached to the distal terminus of polyethylene glycol (PEG) polymer chains, located at the surface of lipid vesicles, to obtain SOD-enzymosomes.

Results

The in vivo fate of the optimized SOD-enzymosomes showed that SOD attachment at the end of the activated PEG slightly reduced the residence time of the liposome particles in the bloodstream after IV administration. The biodistribution studies showed that SOD-enzymosomes had a similar organ distribution profile to liposomes with SOD encapsulated in their aqueous interior (SOD-liposomes). SOD-enzymosomes showed earlier therapeutic activity than both SOD-liposomes and free SOD in rat adjuvant arthritis. SOD-enzymosomes, unlike SOD-liposomes, have a therapeutic effect, decreasing liver damage in a rat liver ischemia/reperfusion model.

Conclusions

SOD-enzymosomes were shown to be a new and successful therapeutic approach to oxidative stress-associated inflammatory situations/diseases.

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Abbreviations

ID/g:

Injected dose per gram of tissue

maleimide-PEG-PE:

1,2-distearoyl-sn-glycero-3-phosphoethanolamine-N- [maleimide (polyethylene glycol)-2000] (ammonium salt)

Conjugation/encapsulation efficiency (%):

[final (protein/lipid)/initial(protein/lipid)] × 100

PEG:

Polyethylene glycol

SATA:

N-succinimidyl S-acethylthioacetate

SOD-ATA:

Thiolated Superoroxide dismutase

SOD-AT:

Deacetylated SOD-ATA

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Acknowledgements and Disclosures

The authors gratefully acknowledge the support of: Fundação para a Ciência e Tecnologia, Portugal (grants POCTI/42259/FCB/2001; SFRH/BD/12264/2003; PEst-OE/QUI/UI0612/2013; PEst-OE/SAU/UI4013/2011); Sociedade Portuguesa de Transplantação - Bolsa de Investigação SPT/Astellas and Instituto de Investigação Bento da Rocha Cabral for animal supply (ischemia/reperfusion model); we thank Filipa Fontes for laboratory assistance in the preparation of liposomal formulation (ischemia/reperfusion model).

Author information

Authors and Affiliations

  1. Intracellular Trafficking Modulation for Advanced Drug Delivery iMED.ULisboa, Faculdade de Farmácia, Universidade de Lisboa, Campus do Lumiar Estrada do Paço do Lumiar, 22, 1649-038, Lisbon, Portugal

    M. Luísa Corvo & M. Bárbara A.F. Martins

  2. Departamento de Química e Bioquímica and Centro de Química e Bioquímica, Faculdade de Ciências, Universidade de Lisboa, Campo Grande, 1749-016, Lisbon, Portugal

    H. Susana Marinho

  3. Chronic Disease Research Center, Faculdade de Ciências, Médicas Universidade Nova de Lisboa, Campo dos Mártires da Pátria, Lisbon, Portugal

    Paulo Marcelino

  4. iMED.ULisboa, Faculdade de Farmácia, Universidade de Lisboa, Campus do Lumiar Estrada do Paço do Lumiar, 22, Lisbon 1649-038, Portugal

    Rui M. Lopes, Carlos A. Vale, Claúdia R. Marques & Luísa C.D. Martins

  5. Department of Radiology and Nuclear Medicine, Radboud University Medical Center, Nijmegen, The Netherlands

    Peter Laverman

  6. Department of Pharmaceutics, Utrecht Institute for Pharmaceutical Sciences (UIPS), Utrecht University, Utrecht, The Netherlands

    Gert Storm

Authors
  1. M. Luísa Corvo
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  2. H. Susana Marinho
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  3. Paulo Marcelino
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  4. Rui M. Lopes
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  5. Carlos A. Vale
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  6. Claúdia R. Marques
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  7. Luísa C.D. Martins
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  8. Peter Laverman
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  9. Gert Storm
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  10. M. Bárbara A.F. Martins
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Corresponding author

Correspondence to M. Luísa Corvo.

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Corvo, M.L., Marinho, H.S., Marcelino, P. et al. Superoxide Dismutase Enzymosomes: Carrier Capacity Optimization, in Vivo Behaviour and Therapeutic Activity. Pharm Res 32, 91–102 (2015). https://doi.org/10.1007/s11095-014-1447-7

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  • DOI: https://doi.org/10.1007/s11095-014-1447-7

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