Articolo in rivista, 2021, ENG, 10.1016/j.jcis.2020.08.026

Towards bio-compatible magnetic nanoparticles Immune-related effects, in-vitro internalization, and in-vivo bio-distribution of zwitterionic ferrite nanoparticles with unexpected renal clearance

Ferretti A.M.; Usseglio S.; Mondini S.; Drago C.; La Mattina R.; Chini B.; Verderio C.; Leonzino M.; Cagnoli C.; Joshi P.; Boraschi D.; Italiani P.; Li Y.; Swartzwelter B.J.; Sironi L.; Gelosa P.; Castiglioni L.; Guerrini U.; Ponti A.

Istituto di Scienze e Tecnologie Chimiche "Giulio Natta" (SCITEC), Consiglio Nazionale delle Ricerche, Via G. Fantoli 16/15, Milano, 20138, Istituto di Scienze e Tecnologie Chimiche "Giulio Natta" (SCITEC), Consiglio Nazionale delle Ricerche, Via G. Fantoli 16/15, 20138 Milano, Italy, , Italy; Istituto di Chimica Biomolecolare (ICB), Consiglio Nazionale delle Ricerche, Via P. Gaifami, 18, Catania, 95126, Istituto di Chimica Biomolecolare (ICB), Consiglio Nazionale delle Ricerche, Via P. Gaifami, 18, 95126 Catania, Italy, , Italy; Istituto di Neuroscienze (IN), Consiglio Nazionale delle Ricerche, Via L. Vanvitelli 32, Milano, 20129, Istituto di Neuroscienze (IN), Consiglio Nazionale delle Ricerche, Via L. Vanvitelli 32, 20129 Milano, Italy, , Italy; Istituto di Biochimica e Biologia Cellulare (IBBC), Consiglio Nazionale delle Ricerche, Via P. Castellino 111, Napoli, 80131, Istituto di Biochimica e Biologia Cellulare (IBBC), Consiglio Nazionale delle Ricerche, Via P. Castellino 111, 80131 Napoli, Italy, , Italy; Dipartimento di Scienze Farmaceutiche, Università degli Studi di Milano, Via G. Balzaretti 9, Milano, 20133, Dipartimento di Scienze Farmaceutiche, Università degli Studi di Milano, Via G. Balzaretti 9, 20133 Milano, Italy, , Italy; Centro Cardiologico Monzino IRCCS, Via C. Parea 3, Milano, 20138, Centro Cardiologico Monzino IRCCS, Via C. Parea 3, 20138 Milano, Italy, , Italy; Dipartimento di Scienze Farmacologiche e Biomolecolari, Università degli Studi di Milano, Via G. Balzaretti 9, Milano, 20133, Dipartimento di Scienze Farmacologiche e Biomolecolari, Università degli Studi di Milano, Via G. Balzaretti 9, 20133 Milano, Italy, , Italy

Hypothesis: Iron oxide and other ferrite nanoparticles have not yet found widespread application in the medical field since the translation process faces several big hurdles. The incomplete knowledge of the interactions between nanoparticles and living organisms is an unfavorable factor. This complex subject should be made simpler by synthesizing magnetic nanoparticles with good physical (relaxivity) and chemical (colloidal stability, anti-fouling) properties and no biological activity (no immune-related effects, minimal internalization, fast clearance). Such an innocent scaffold is the main aim of the present paper. We systematically searched for it within the class of small-to-medium size ferrite nanoparticles coated by small (zwitter)ionic ligands. Once established, it can be functionalized to achieve targeting, drug delivery, etc. and the observed biological effects will be traced back to the functional molecules only, as the nanosized scaffold is innocent. Experiments: We synthesized nine types of magnetic nanoparticles by systematic variation of core composition, size, coating. We investigated their physico-chemical properties and interaction with serum proteins, phagocytic microglial cells, and a human model of inflammation and studied their biodistribution and clearance in healthy mice. The nanoparticles have good magnetic properties and their surface charge is determined by the preferential adsorption of anions. All nanoparticle types can be considered as immunologically safe, an indispensable pre-requisite for medical applications in humans. All but one type display low internalization by microglial BV2 cells, a process strongly affected by the nanoparticle size. Both small (3 nm) and medium size (11 nm) zwitterionic nanoparticles are in part captured by the mononuclear phagocyte system (liver and spleen) and in part rapidly (?1 h) excreted through the urinary system of mice. Findings: The latter result questions the universality of the accepted size threshold for the renal clearance of nanoparticles (5.5 nm). We suggest that it depends on the nature of the circulating particles. Renal filterability of medium-size magnetic nanoparticles is appealing because they share with small nanoparticles the decreased accumulation-related toxicity while performing better as magnetic diagnostic/therapeutic agents thanks to their larger magnetic moment. In conclusion, many of our nanoparticle types are a bio-compatible innocent scaffold with unexpectedly favorable clearance.

Journal of colloid and interface science (Print) 582 , pp. 678–700

Keywords

Bio-distribution, mmune-related effects, Internalization, Magnetic nanoparticles, Microglia, Renal clearance, Zwitterionic nanoparticle

CNR authors

Mondini Sara, Boraschi Diana, Ponti Alessandro, Chini Bice, Verderio Claudia, Drago Carmelo, Usseglio Nanot Sandro, Italiani Paola, Leonzino Marianna, Ferretti Anna Maria

CNR institutes

ICB – Istituto di chimica biomolecolare, IN – Istituto di neuroscienze, ISTM – Istituto di scienze e tecnologie molecolari, IBBC – Istituto di Biochimica e Biologia Cellulare, SCITEC – Istituto di Scienze e Tecnologie Chimiche "Giulio Natta"