Drug-Free ROS Sponge Polymeric Microspheres Reduce Tissue Damage from Ischemic and Mechanical Injury

Abstract

The inherent antioxidant function of poly(propylene sulfide) (PPS) microspheres (MS) was dissected for different reactive oxygen species (ROS), and therapeutic benefits of PPS-MS were explored in models of diabetic peripheral arterial disease (PAD) and mechanically induced post-traumatic osteoarthritis (PTOA). PPS-MS (∼1 μm diameter) significantly scavenged hydrogen peroxide (H2O2), hypochlorite, and peroxynitrite but not superoxide in vitro in cell-free and cell-based assays. Elevated ROS levels (specifically H2O2) were confirmed in both a mouse model of diabetic PAD and in a mouse model of PTOA, with greater than 5- and 2-fold increases in H2O2, respectively. PPS-MS treatment functionally improved recovery from hind limb ischemia based on ∼15–25% increases in hemoglobin saturation and perfusion in the footpads as well as earlier remodeling of vessels in the proximal limb. In the PTOA model, PPS-MS reduced matrix metalloproteinase (MMP) activity by 30% and mitigated the resultant articular cartilage damage. These results suggest that local delivery of PPS-MS at sites of injury-induced inflammation improves the vascular response to ischemic injury in the setting of chronic hyperglycemia and reduces articular cartilage destruction following joint trauma. These results motivate further exploration of PPS as a stand-alone, locally sustained antioxidant therapy and as a material for microsphere-based, sustained local drug delivery to inflamed tissues at risk of ROS damage.

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

“…PPS‐NPs have recently been used as versatile vaccine delivery systems, and interestingly a very similar NP formulation, also consisting of a ROS‐reactive thioether and cross‐linked core, has been shown to reduce neuroinflammation and improve the therapeutic outcome in a mouse model of traumatic brain injury, although the PPS‐NPs tested in our study are less toxic at higher concentration, less hydrophilic (hence lower ROS solubility at early time points) and larger (therefore better suited for a slower and prolonged scavenging effect). Despite their potent ROS scavenging abilities and negligible cytotoxicity, 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 . Here we show that PPS‐NPs exhibit antioxidant properties for multiple types of ROS in vitro with negligible cytotoxicity and a remarkable therapeutic activity in an in vivo model of ischemic stroke.…”

Oxidation‐Responsive Materials: Biological Rationale, State of the Art, Multiple Responsiveness, and Open Issues

“…It is therefore of little surprise to realize that synthetic ROS scavengers, sometimes also similar in composition (e.g., sulfur(II)‐based systems) are also inherently endowed with anti‐inflammatory properties. The recent literature provides a certain number of cases where this feature has been exploited; for example, PPS‐PEG diblock copolymers used to alleviate the symptoms of sepsis, or for the cytoprotection of stem cell in injectable formulations, PPS microparticles for those of ischemia, poly(ester sulfide) nanoparticles and copolymers of 2‐(methylthio)ethyl methacrylate for those of traumatic brain injury, boronated cyclodextrins for those of peritonitis, and PEGylated bilirubin nanoparticles for colon inflammation . It is worth mentioning that ROS scavenging are not a prerogative of oxidation‐responsive polymers: a number of organic materials can remove ROS/radicals without significantly changing their properties, but produce anti‐inflammatory effects, for example, carbon particles and above all 2,2,6,6‐tetramethylpiperidine‐N‐oxyl (TEMPO)‐containing systems (see also a recent review on the latter materials).…”

Polymeric Antioxidant Materials for Treatment of Inflammatory Disorders

“…Similarly, there has been a study exploiting drug‐free PPS based microspheres (PPS‐MSs) for treating ischemia injury and mechanical injury. [ 166 ] PPS‐MSs were simply prepared via emulsification and they scavenged H 2 O 2 , HOCl, and even ONOO – in vitro. Surprisingly, in both diabetic peripheral arterial disease and mechanically induced post‐traumatic OA model, PPS‐MSs provided therapeutic benefits, recovering the functions of hind limbs in ischemia and articular cartilage in the OA model.…”