Controlled aggregation and cell uptake of thermoresponsive polyoxazoline-grafted superparamagnetic iron oxide nanoparticles

Abstract

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.

Thermoresponsive Polypeptoid‐Coated Superparamagnetic Iron Oxide Nanoparticles by Surface‐Initiated Polymerization

“…A dense, stably anchored polypeptoid shell should allow for colloidal stability of the SPION by steric repulsion, [15,23,39] which was shown to be beneficial for SPION used as magnetic resonance contrast agent, [13] potential drug delivery vehicle [13,14,16] or magnetically actuated release vehicles. [40,41] The initial ligand replacement of oleic acid with nitrodopamine yields SPION with high initiator density that should convert into a high grafting density of the brush.…”

“…Many biomedical applications such as contrast agents or drug delivery vehicles benefit from grafting of the polymer to the surface, typically in a dense brush conformation that alters the surface properties and provides a tunable steric barrier to adsorption of proteins to the substrate. Surface grafting of polymer brushes can substantially change the physical properties of the brush such as its response to temperature . However, thermoresponsive polypeptoid brushes have not yet been investigated.…”

“…Surface grafting of polymer brushes can substantially change the physical properties of the brush such as its response to temperature. [15,16] However,…”

Design strategies for physical-stimuli-responsive programmable nanotherapeutics

“…They were reported to have low immunogenicity [44], biodegradability, [45] and good penetration through porcine gastric mucosa [46]. It is worthy to point out that poly(2-isopropyl-2-oxazoline) is a structural isomer of PNIPAAM with a LCST close to the physiological temperature [41,42]. Polyoxazolines are commonly used as nanostructure surface grafting agents [41–43].…”

“…Polyoxazolines are commonly used as nanostructure surface grafting agents [41–43]. For example, Kurzhals et al (2017) [42] grafted the surfaces of magnetic nanoparticles using poly(2-isopropyloxazoline) (LCST in cell culture medium = 32.5 °C) and poly(2-ethyloxazoline) (LCST in cell culture medium = 37 °C) to form core-shell magnetic nanoparticles. The permeability of poly(2-isopropyloxazoline)-grafted nanoparticles was about 4-fold greater than the permeability of poly(2-ethyloxazoline)-grafted nanoparticles in HeLa cells at 37 °C.…”