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Plasma protein adsorption on Fe3O4-PEG nanoparticles activates the complement system and induces an inflammatory response

Authors Escamilla-Rivera V, Solorio-Rodríguez A, Uribe-Ramírez M, Lozano O, Lucas S, Chagolla-López A, Winkler R, De Vizcaya-Ruiz A

Received 3 November 2018

Accepted for publication 8 February 2019

Published 25 March 2019 Volume 2019:14 Pages 2055—2067


Checked for plagiarism Yes

Review by Single anonymous peer review

Peer reviewer comments 2

Editor who approved publication: Prof. Dr. Anderson Oliveira Lobo

V Escamilla-Rivera,1 A Solorio-Rodríguez,1 M Uribe-Ramírez,1 O Lozano,2–4 S Lucas,2,3 A Chagolla-López,5 R Winkler,5,6 A De Vizcaya-Ruiz1

1Departamento de Toxicología, Centro de Investigación y de Estudios Avanzados del IPN (CINVESTAV-IPN), Ciudad de México, México; 2Namur Nanosafety Centre, Namur Research Institute for Life Sciences, University of Namur, Namur, Belgium; 3Research Centre for the Physics of Matter and Radiation, University of Namur, Namur, Belgium; 4Cátedra de Cardiología y Medicina Vascular, Escuela de Medicina y Ciencias de la Salud, Tecnologico de Monterrey, Monterrey, México; 5Departmento de Biotecnología y Bioquímica, CINVESTAV-IPN, Unidad Irapuato, Irapuato, México; 6Max Planck Institute for Chemical Ecology, Mass Spectrometry Group, Beutenberg Campus, Jena, Germany

Background: Understanding of iron oxide nanoparticles (IONP) interaction with the body milieu is crucial to guarantee their efficiency and biocompatibility in nanomedicine. Polymer coating to IONP, with polyethyleneglycol (PEG) and polyvinylpyrrolidone (PVP), is an accepted strategy to prevent toxicity and excessive protein binding.
Aim: The aim of this study was to investigate the feature of IONP adsorption of complement proteins, their activation and consequent inflammatory response as a strategy to further elucidate their biocompatibility.
Methods: Three types of IONP with different surface characteristics were used: bare (IONP-bare), coated with PVP (IONP-PVP) and PEG-coated (IONP-PEG). IONPs were incubated with human plasma and adsorbed proteins were identified. BALB/c mice were intravenously exposed to IONP to evaluate complement activation and proinflammatory response.
Results: Protein corona fingerprinting showed that PEG surface around IONP promoted a selective adsorption of complement recognition molecules which would be responsible for the complement system activation. Furthermore, IONP-PEG activated in vitro, the complement system and induced a substantial increment of C3a and C4a anaphylatoxins while IONP-bare and IONP-PVP did not. In vivo IONP-PEG induced an increment in complement activation markers (C5a and C5b-9), and proinflammatory cytokines (IL-1β, IL-6, TNF-α).
Conclusion: The engineering of nanoparticles must incorporate the association between complement proteins and nanomedicines, which will regulate the immunostimulatory effects through a selective adsorption of plasma proteins and will enable a safer application of IONP in human therapy.

Keywords: iron oxide nanoparticles, complement, inflammatory response, protein corona

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