Preparation of Robust Metal‐Free Magnetic Nanoemulsions Encapsulating Low‐Molecular‐Weight Nitroxide Radicals and Hydrophobic Drugs Directed Toward MRI‐Visible Targeted Delivery

Abstract

With a view to developing a theranostic nanomedicine for targeted drug delivery systems visible by magnetic resonance (MR) imaging, robust metal-free magnetic nanoemulsions (mean particle size less than 20 nm) consisting of a biocompatible surfactant and hydrophobic, low molecular weight 2,2,5-trimethyl-5-(4-alkoxy)phenylpyrrolidine-N-oxyl radicals were prepared in pH 7.4 phosphate-buffered saline (PBS). The structure of the nanoemulsions was characterized by electron paramagnetic resonance spectroscopy, and dynamic light scattering and small-angle neutron-scattering measurements. The nanoemulsions showed high colloidal stability, low cytotoxicity, enough reduction resistance to excess ascorbic acid, and sufficient contrast enhancement in the proton longitudinal relaxation time (T ) weighted MR images in PBS in vitro (and preliminarily in vivo). Furthermore, the hydrophobic anticancer drug paclitaxel could be encapsulated inside the nanoparticles, and the resulting paclitaxel-loaded nanoemulsions were efficiently incorporated into HeLa cells to suppress cell growth.

Magnetic Mixed Micelles Composed of a Non-Ionic Surfactant and Nitroxide Radicals Containing a d-Glucosamine Unit: Preparation, Stability, and Biomedical Application

“…The micelle 2 / 4 14 collapsed within one day to give white precipitates of 4 14 after 24 h. From these results, summarized in Table 1, the relative stability of the micelles 2 / 4 n in PBS was in the following order: 2 / 4 18 > 2 / 4 16 > 2 / 4 14 . The similar dependence of the micellar stability on the alkyl chain length in the nitroxide radicals 4 n was also observed in the cases of the mixed micelles 1 / 3 and 2 / 3 [18,19]. The mean diameters of the resulting magnetic mixed micelles 2 / 4 n in PBS were determined to be 13 to 16 nm by DLS analysis (Table 1 and Figure 2).…”

“…However, the reduction resistance should potentially improve through the molecular design and/or the micelle construction of nitroxide radicals [12,13,14,15,16,17]. In this context, we have recently prepared metal-free magnetic mixed micelles comprised of a surfactant, Brij 58 ( 1 ) or Tweens 80 ( 2 ), and pyrrolidine- N -oxyl radical 3 , namely 1 / 3 or 2 / 3 (Figure 1), according to a simple experimental procedure [18,19]. These micelles showed high colloidal stability, reduction resistance to ascorbic acid, and contrast enhancement in the T 1 -weighted MRI in phosphate-buffered saline (PBS) in vitro and in vivo.…”

2-Butyl-2-tert-butyl-5,5-diethylpyrrolidine-1-oxyls: Synthesis and Properties

“…The new nitroxides are very lipophilic compounds with poor solubility in water; however, their hydroxyl groups may be employed for chemical binding to a delivery vehicle. The utility of lipophilic nitroxides with large hydrophobic groups for the design of lipid nanoparticles or micelles for MRI contrast and MRI-controlled drug delivery has been demonstrated by various research groups [22][23][24].…”

Unique Superparamagnetic‐like Behavior Observed in Non‐π‐delocalized Nitroxide Diradical Compounds Showing Discotic Liquid Crystalline Phase

“…These results would provide important information for the development of metal‐free magnetic advanced soft materials, such as magneto‐active emulsions which are expected to be used for biomedical applications including magnetically transportable oxidation and reduction resistant magnetic microcarriers, magnetic resonance imaging (MRI) contrast agents and magnetic nanocarriers for a magnetically targeted drug delivery system (DDS), in place of magnetoliposomes containing superparamagnetic iron oxides (magnetite Fe 3 O 4 or maghemite γFe 2 O 3 ), because nitroxide radicals are known to show very low toxicity to cell and animals …”

“…[16,18,19] Our theoretical studies by molecular dynamic simulations on the mechanism of al arge increase in the magnetic susceptibility in the solid and LC phases will be reported in due course in terms of the influence of the coherentc ollective molecularm otion and inhomogeneous intermolecular short contacts on the magnetic susceptibility,t ogether with the in-depth data concerning the spin glass-like properties. These results would provide importanti nformationf or the development of metal-free magnetic advanced soft materials, such as magneto-active emulsions which are expected to be used for biomedical applicationsi ncluding magnetically transportable oxidation and reduction resistant magnetic microcarriers, [45] magnetic resonance imaging (MRI) contrasta gents and magnetic nanocarriersf or am agnetically targeted drug delivery system (DDS), [46] in place of magnetoliposomes containing superparamagnetic iron oxides (magnetite Fe 3 O 4 or maghemite gFe 2 O 3 ), [47] because nitroxide radicals are known to show very low toxicity to cell and animals. [48][49][50][51][52]…”