Research Article

In vivo evaluation of toxicity and anti-inflammatory activity of iron oxide nanoparticles conjugated with ibuprofen

Department of Fundamental Chemistry, Laboratory of Supramolecular Chemistry & Nanotechnology, Institute of Chemistry, University of São Paulo, Avenida Professor Lineu Prestes, 748, São Paulo, São Paulo, 05508-000, Brazil

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Cristina B Hebeda

https://orcid.org/0000-0002-1259-6708

Department of Clinical & Toxicological Analysis, Laboratory of Experimental Toxicology, Faculty of Pharmaceutical Sciences, University of São Paulo, Avenida Professor Lineu Prestes, 580, São Paulo, São Paulo, 05508-000, Brazil

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Silvana Sandri

https://orcid.org/0000-0002-9211-945X

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Marina de Paula-Silva

https://orcid.org/0000-0002-8706-9910

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Mariana Romano

https://orcid.org/0000-0003-2881-2708

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Roberta M Cardoso

https://orcid.org/0000-0002-9903-5224

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Sergio H Toma

https://orcid.org/0000-0002-3003-7889

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Koiti Araki

*Author for correspondence:

E-mail Address: koiaraki@iq.usp.br

https://orcid.org/0000-0003-3485-4592

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Sandra HP Farsky

**Author for correspondence:

E-mail Address: sfarsky@usp.br

https://orcid.org/0000-0002-3943-977X

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Published Online:15 Apr 2021https://doi.org/10.2217/nnm-2020-0459

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Abstract

Aim: The low solubility and consequent poor bioavailability of ibuprofen (IBU) is a major drawback that can be overcome by anchoring IBU on ultrasmall superparamagnetic iron oxide nanoparticles (USPIONs) as effective multifunctional carriers for drug delivery. Methods: USPIONs were conjugated with glycerol phosphate (USPION-GP) and also co-conjugated with IBU (USPION-GP/IBU), and their in vivo toxicity and anti-inflammatory effects investigated. Phosphate buffer saline (control), IBU, USPION-GP and USPION-GP/IBU were intravenously administered 15 min before lipopolysaccharide-induced peritonitis in male Balb/c mice. Results: 4 h later, USPION bioconjugates did not appear to have caused toxicity to blood leukocytes or caused alterations in the spleen, liver or kidneys. Also, they inhibited lipopolysaccharide-induced neutrophil mobilization into the peritoneum. Conclusion: The absence of systemic toxicity and the unexpected anti-inflammatory action of USPION bioconjugates indicates that they could be a novel and effective approach to administer IBU and warrant further investigation.

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Papers of special note have been highlighted as: • of interest; •• of considerable interest

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Vol. 16, No. 9

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Received 10 December 2020

Accepted 16 March 2021

Published online 15 April 2021

Published in print April 2021

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Supplementary data

To view the supplementary data that accompany this paper please visit the journal website at: www.futuremedicine.com/doi/suppl/10.2217/nnm-2020-0459

Author contributions

K Araki, SHP Farsky and MK Uchiyama conceived the main idea; SH Toma conducted the experiments of SPIONs synthesis and characterization; RM Cardoso and M Romano conducted the experiments of USPIO functionalization, characterization and data analyses; SHP Farsky and K Araki contributed to the necessary structure for conducting in vivo experiments, and synthesis/characterization of nanomaterials, respectively; CB Hebeda and MK Uchiyama conducted the experiments with mice, data analyses and wrote the manuscript, MP Silva prepared the organs and slides for histology, and performed the histological analysis; S Sandri conducted the human blood experiments and their data analysis. S Sandri and RM Cardoso contributed to additional correction and interpretation. All authors reviewed the manuscript and gave final approval.

Financial & competing interests disclosure

The authors would like to thank the financial support granted by São Paulo Research Foundation (FAPESP, SHPF grant 2014/07328-4 and KA 2018/21489-1), National Council for Scientific and Technological Development (CNPq, KA grant 401581/2016-0, 303137/2016-9 and 402281/2013-6), Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (program 33002010191PO), M Romano is doctoral fellow (CAPES, program 33002010191PO), MK Uchiyama was postdoctoral Sibratec-Finep fellow, RM Cardoso was doctoral fellow (CAPES, program 33002010191P0). S Sandri and CB Hebeda were PNPD postdoctoral fellow of CAPES (grants no. 1569289 and 1529319, respectively). SH Toma would like to thank CNPq for the Scholarship in Technological Development Productivity (CNPq 305950/2016-9), and Brazilian Nanotechnology National Laboratory (LNNano-CNPEM) for access of TEM facilities (TEM-21785). K Araki, RM Cardoso and SH Toma also acknowledge the financial support granted by Petrobras (0050.0101557.16.9). The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

No writing assistance was utilized in the production of this manuscript.

Ethical conduct of research

The authors state that all procedures with animals and protocols were carried out according to ‘Conselho Nacional de Controle de Experimentação Animal’ (CONCEA) and approved by local ethical committee of School of Pharmaceutical Sciences, University of Sao Paulo (protocol number 548/569). Also, blood drawing followed a protocol approved by the School of Pharmaceutical Sciences Ethical Committee at the University of São Paulo (CEP approval number CAEE 75093617.1.0000.0067).

Blinded for review

All procedures and protocols were carried out according to ‘Conselho Nacional de Controle de Experimentação Animal’ (CONCEA) and approved by local ethical committee of School of Pharmaceutical Sciences, University of Sao Paulo (protocol number 548/569).

Blood drawing followed a protocol approved by the School of Pharmaceutical Sciences Ethical Committee at the University of São Paulo (CEP approval no. CAEE 75093617.1.0000.0067).

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