Hydrophilic polymer-coated iron oxide nanoparticles are potential materials for a plethora of applications in the biotechnological field. Typical such polymers, e.g. dextran or poly(ethylene glycol), lack the ability to tailor the biological response to an environmental trigger, while common responsive polymers such as poly(N-isopropylacrylamide) or poly(acrylic acid) are not suitable for biomedical applications. We present the synthesis and characterization of superparamagnetic iron oxide nanoparticles with thermoresponsive polyoxazoline brushes grafted at unprecedented density using nitrodopamine anchor chemistry. Reversible aggregation/deaggregation is observed in water and biological medium, confirming control over the colloidal stability. Thermal switching of the solubility could only be achieved by global heating of the sample, while local magnetothermal heating did not produce a sufficiently strong temperature gradient through the brush. Varying the polymer composition allows for tuning of the lower critical solution temperature (LCST) as well as the average nanoparticle cluster size obtained upon heating. The LCST of polyoxazolines and the thermal colloidal stability are shown to be greatly affected by ion concentration, by polymer grafting density and also by the presence of serum protein; this shows that transition temperatures of free polymers in water can be very misleading for the design of polymer-coated nanomaterials for biomedical applications. Finally, the thermoresponsive SPION are shown to be non-cytotoxic and with a low cell uptake scaling with the hydration of the polymer brush, which is tuned by the polymer composition. Thus, we demonstrate that pozylated nanoparticles provide the advantages of PEG- and PNIPAM-grafted nanoparticles, but provide a tunable and more easily functionalizable platform for further development.

Ionic liquids (ILs) are a class of diverse organic salts with relatively low melting points (below 100°C) which have attracted considerable interest as a promising "green" substitute for organic solvents. The broad solvation properties of ILs and their high solubility in water, however, present health risks, in particular since it was shown that many ILs exhibit cytotoxic properties. In this context, interactions of ILs with the cellular membrane are believed to constitute a primary culprit for toxicity. We present a comprehensive biophysical and microscopy study of membrane interactions of a series of ILs having different side-chain compositions and lengths, and cationic head-group structures and orientations. The experimental data reveal that the ILs studied exhibit distinct mechanisms of membrane binding, insertion, and disruption which could be correlated with their biological activities. The results indicate, in particular, that both the side chain composition and particularly the head-groups of ILs constitute determinants for membrane activity and consequent cell toxicity. This work suggests that tuning membrane interactions of ILs should be an important factor for designing future compounds with benign environmental impact.

Core–shell nanoparticles receive much attention for their current and potential applications in life sciences. Commonly, a dense shell of hydrated polymer, a polymer brush, is grafted to improve colloidal stability of functional nanoparticles and to prevent protein adsorption, aggregation, cell recognition, and uptake. Until recently, it was widely assumed that a polymer brush shell indeed prevents strong association of proteins and that this leads to their superior “stealth” properties in vitro and in vivo. We show using T-dependent isothermal titration calorimetry on well-characterized monodisperse superparamagnetic iron oxide nanoparticles with controlled dense stealth polymer brush shells that “stealth” core–shell nanoparticles display significant attractive exothermic and enthalpic interactions with serum proteins, despite having excellent colloidal stability and negligible nonspecific cell uptake. This observation is at room temperature shown to depend only weakly on variation of iron oxide core diameter and type of grafted stealth polymer: poly(ethylene glycol), poly(ethyl oxazoline), poly(isopropyl oxazoline), and poly(N-isopropyl acrylamide). Polymer brush shells with a critical solution temperature close to body temperature showed a strong temperature dependence in their interactions with proteins with a significant increase in protein binding energy with increased temperature. The stoichiometry of interaction is estimated to be near 1:1 for PEGylated nanoparticles and up to 10:1 for larger thermoresponsive nanoparticles, whereas the average free energy of interaction is enthalpically driven and comparable to a weak hydrogen bond.

Targeted nanomedicine builds on the concept that nanoparticles can be directed to specific tissues while remaining inert to others organs. Many studies have been performed on the synthesis and cellular interactions of core− shell nanoparticles, in which a functional inorganic core is coated with a biocompatible polymer layer that should reduce nonspecific uptake and cytotoxicity. However, work is lacking that relates structural parameters of the core−shell structure and colloidal properties directly to interactions with cell membranes and further correlates these interactions to cell uptake. We have synthesized monodisperse (SD < 10%), single-crystalline, and superparamagnetic iron oxide nanoparticles (SPION) of different core size (3−8 nm) that are densely grafted with nitrodopamine-poly(ethylene glycol) (NDA-PEG(5 kDa)) brushes. We investigated the interactions of the PEGylated SPION with biomimetic membranes and cancer and kidney cells. It is shown that a dense homogeneous PEG shell suppresses membrane interactions and cell uptake but that nanoparticle curvature can influence membrane interactions for similarly grafted nanoparticles. Weak adsorption to anionic lipid membranes is shown to correlate with eukaryote cell uptake and is attributed to double-layer interactions without direct membrane penetration. This attraction is strongly suppressed during physiological conditions and leads to unprecedented low cell uptake and full cell viability when compared to those of traditional dextran-coated SPION. Less curved (larger core) PEGylated SPION show weaker membrane adsorption and lower cell uptake due to effectively denser shells. These results provide a better understanding of design criteria for core−shell nanoparticles in terms of avoiding nonspecific uptake by cells, reducing toxicity, and increasing circulation time.

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