Chemical specificity in REDOX-responsive materials: the diverse effects of different Reactive Oxygen Species (ROS) on polysulfide nanoparticles

Abstract

REDOX responsive (nano)materials typically exhibit chemical changes in response to the presence and concentration of oxidants/reductants. Due to the complexity of biological environments, it is critical to ascertain whether the chemical response may depend on the chemical details of the stimulus, in addition to its REDOX potential, and whether chemically different responses can determine a different overall performance of the material. Here, we have used oxidation-sensitive materials, although these considerations can be extended also to reducible ones. In particular, we have used poly(propylene sulfide) (PPS) nanoparticles coated with a PEGylated emulsifier (Pluronic F127); inter alia, we here present also an improved preparative method. The nanoparticles were exposed to two Reactive Oxygen Species (ROS) typically encountered in inflammatory reactions, hydrogen peroxide (H 2 O 2) and hypochlorite (ClO À); their response was evaluated with a variety of techniques, including diffusion NMR spectroscopy that allowed to separately characterize the chemically different colloidal species produced. The two oxidants triggered a different chemical response: H 2 O 2 converted sulfides to sulfoxides, while ClO À partially oxidized them further to sulfones. The different chemistry correlated to a different material response: H 2 O 2 increased the polarity of the nanoparticles, causing them to swell in water and to release the surface PEGylated emulsifier; the uncoated oxidized particles still exhibited very low toxicity. On the contrary, ClO À rapidly converted the nanoparticles into water-soluble, depolymerized fragments with a significantly higher toxicity. The take-home message is that it is more correct to discuss 'smart' materials in terms of an environmentally specific response to (REDOX) stimuli. Far from being a problem, this could open the way to more sophisticated and precisely targeted applications.

Reactive Oxygen Species‐Responsive Nanoparticles for the Treatment of Ischemic Stroke

“…In primary cultures, treatment with PPS-NPs (1 mg mL −1 ; 24 h) of different sizes (50,75,115 nm) significantly decreased IL-6 (78%, 47%, 53%, respectively; Figure 1A) and TNF-α levels (97%, 84%, 76%, respectively; Figure 1B) compared to LPS control, demonstrating their potent anti-inflammatory properties in a NP-size dependent fashion (smaller particles displaying a higher potency than larger particles). [26] As 50 nm NPs were found to have the strongest anti-inflammatory effects as well as negligible cytotoxicity, all further experiments were carried out using NPs of this size; however, it should be noted that in applications where a slower and more prolonged anti-inflammatory/anti-oxidant effect is desired (e.g., chronic inflammatory diseases) larger particles may be better suited. [26] As 50 nm NPs were found to have the strongest anti-inflammatory effects as well as negligible cytotoxicity, all further experiments were carried out using NPs of this size; however, it should be noted that in applications where a slower and more prolonged anti-inflammatory/anti-oxidant effect is desired (e.g., chronic inflammatory diseases) larger particles may be better suited.…”

“…The core is made of chemically cross-linked PPS, which is an organic polymer with a high density of sulfur (II) atoms (sulfides, also known as thioethers); such groups are potent ROS scavengers, for example, methionine residues offer a well-known biological example of this activity. [26] In particular, exposure to hydrogen peroxide (H 2 O 2 ) induces swelling and loss of the PEGylated surface layer without affecting the NPs (lack of) cytotoxicity. Typi-cally, this increase in polarity/solubilization has been exploited as a ROS-responsive release mechanism of encapsulated payloads for targeted drug-release.…”

“…Despite their potent ROS scavenging abilities and negligible cytotoxicity, [25,26,31,32] PPS-NPs have not yet been tested in the context of ischemic stroke, although PPS-derived microspheres have recently shown promise in a mouse model of hind leg ischemia. Despite their potent ROS scavenging abilities and negligible cytotoxicity, [25,26,31,32] PPS-NPs have not yet been tested in the context of ischemic stroke, although PPS-derived microspheres have recently shown promise in a mouse model of hind leg ischemia.…”

Oxidation-Responsive and “Clickable” Poly(ethylene glycol) via Copolymerization of 2-(Methylthio)ethyl Glycidyl Ether

“…This remarkable work inspired the design of various oxidation-responsive nanocarriers based on thioether-functional polymers. [8][9][10][11][12][13][14][15][16][17][18][19] Additionally, the nucleophilicity of sulfides allows for sulfonium salt formation with alkyl halides, similar to the quaternization of amines. Deming and co-workers demonstrated the suitability of thioether moieties as precursors for a variety of stable, water-soluble and highly functional polypeptide sulfonium derivatives, by click-type "quaternization" of poly(L-methionine).…”

Fishing for fire: strategies for biological targeting and criteria for material design in anti‐inflammatory therapies

“…Upon exposure to hydrogen peroxide, the vesicles evolve into higher curvature structures, such as work‐like micelles, and ultimately into water soluble unimolecular objects . It is noteworthy that the chemical identity of the oxidant matters more than its REDOX potential: for example, while substantially insensitive to superoxide, polysulfides are oxidized predominantly to sulfoxides with peroxides and to sulfones (with successive depolymerisation) with hypochlorite . Peroxynitrite appears to produce effects qualitatively similar to those of hydrogen peroxide .…”