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Despite the large efforts to prepare super paramagnetic iron oxide nanoparticles (MNPs) for biomedical applications, the number of FDA or EMA approved formulations is few. It is not known commonly that the approved formulations in many instances have already been withdrawn or discontinued by the producers; at present, hardly any approved formulations are produced and marketed. Literature survey reveals that there is a lack for a commonly accepted physicochemical practice in designing and qualifying formulations before they enter in vitro and in vivo biological testing. Such a standard procedure would exclude inadequate formulations from clinical trials thus improving their outcome. Here we present a straightforward route to assess eligibility of carboxylated MNPs for biomedical tests applied for a series of our core-shell products, i.e., citric acid, gallic acid, poly(acrylic acid) and poly(acrylic acid-co-maleic acid) coated MNPs. The discussion is based on physicochemical studies (carboxylate adsorption/desorption, FTIR-ATR, iron dissolution, zeta potential, particle size, coagulation kinetics and magnetization measurements) and involves in vitro and in vivo tests. Our procedure can serve as an example to construct adequate physico-chemical selection strategies for preparation of other types of core-shell nanoparticles as well.

Graphical abstractH-type isotherms HA, PAM, GA, and CA Highlights  Organic acids either stabilize or destabilize oxide nanoparticles in natural waters.  The stabilizing/destabilizing effect depends on pH, salinity and organic concentration.  Specific configuration of carboxylic groups is necessary to surface complexation.  Surface complexation leads to high affinity adsorption isotherms.  Higher molecular weight organic acids provide better stability than smaller ones. AbstractThe adsorption of different organic acids and their influence on the pH-dependent charging, salt tolerance and so the colloidal stability of magnetite nanoparticles are compared. Adsorption isotherms of citric acid -CA, gallic acid -GA, poly(acrylic acid) -PAA, poly(acrylic-co-maleic acid) -PAM and humic acid -HA were measured. The pH-dependent charge state of MNPs was characterized by electrophoretic mobility and their aggregation by dynamic light scattering. The salt tolerance was tested in coagulation kinetic experiments. Although the adsorption capacities, the type of bonding (either H-bonds or metal ioncarboxylate complexes) and so the bond strengths are significantly different, the following general trends have been found. Small amount of organic acids at pH < ~8 (the pH of PZC of magnetite) -relevant condition in natural waters -only neutralizes the positive charges, and so promotes the aggregation and sedimentation of nanoparticles. Greater amounts of organic acid, above the charge neutralization, cause the sign reversal of particle charge, and at high

Magnetite nanoparticles were coated with surfactant double layers in order to prepare water based magnetic fluids (MFs). The effects of head group (sulfonate, carboxylate) and alkyl chain length (11-17 C atoms) and the combination of surfactants were studied. Adsorption, dynamic light scattering (DLS) and electrophoretic mobility measurements were performed. The quantity of surfactant varied between 0.3 and 0.5 g, i.e. their specific amount ranges over 1.5-2 mmol g(-1) magnetite in MFs. The adsorption isotherm of Na oleate on magnetite proved the double layer formation with 2 mmol g(-1) saturation value in good harmony with the empirical doses. The effect of diluting MFs, pH and salt concentration was studied. The pH-dependent stability and the salt tolerance of MFs were different owing to the dissociation of the outermost hydrophilic groups and the hydrophobic interactions scaling with the alkyl chain length of surfactant. The hydrophobic interactions are favored only for oleic and myristic acid double layers. In these MFs, aggregation cannot be observed even in fairly dilute systems up to the physiological salt concentration around neutral pH 6-8 favored in biomedical application. The stable oleic and myristic acid double layers can hinder effectively the aggregation of magnetite particles due to the combined steric and electrostatic stabilization.

a b s t r a c tThe formation of small and large molecular polyanionic coating on the surface of magnetite (Fe 3 O 4 ) nanoparticles and their role in the stability enhancement of aqueous magnetic fluids are compared. Magnetite was synthesized and stabilized with citric (CA) and humic (HA) acids. The macromolecular HA, a notable fraction of the natural organic matter (NOM), contains mainly carboxylic groups similarly to the CA, and both acids are able to form surface complexes on the ≡Fe-OH sites of iron oxides. The pHdependent charge state of particles and their aggregation were quantified, and the enhanced salt tolerance of stabilized systems was studied. The dynamic light scattering (DLS) method was used to characterize colloidal stability under different conditions. The average particle size and electrophoretic mobility were measured, and the electrolyte tolerance was tested in coagulation kinetic measurements. The colloidal stability of magnetite dispersions depends sensitively on the pH and the concentration of organic acids present. The trace amount of HA neutralizes the positive charges on magnetite surface under acidic condition only in part, and so it promotes the aggregation between the particles having both positive sites and negative humate patches on the surface. Above the adsorption saturation, the surface becomes completely covered causing the reversal of charge sign and overcharging of nanoparticles. The magnetite nanoparticles become stabilized in a way of combined steric and electrostatic effects. The thicker layer of macromolecular HA provides better electrosteric stability than that of CA coating. However, in the presence of either CA or HA, the dissolution of magnetite is enhanced due to the complexation of iron ions in the aqueous medium.