ROS-responsive microspheres for on demand antioxidant therapy in a model of diabetic peripheral arterial disease

Abstract

A new microparticle-based delivery system was synthesized from reactive oxygen species (ROS)-responsive poly(propylene sulfide) (PPS) and tested for “on demand” antioxidant therapy. PPS is hydrophobic but undergoes a phase change to become hydrophilic upon oxidation and thus provides a useful platform for ROS-demanded drug release. This platform was tested for delivery of the promising anti-inflammatory and antioxidant therapeutic molecule curcumin, which is currently limited in use in its free form due to poor pharmacokinetic properties. PPS microspheres efficiently encapsulated curcumin through oil-in-water emulsion and provided sustained, on demand release that was modulated in vitro by hydrogen peroxide concentration. The cytocompatible, curcumin-loaded microspheres preferentially targeted and scavenged intracellular ROS in activated macrophages, reduced in vitro cell death in the presence of cytotoxic levels of ROS, and decreased tissue-level ROS in vivo in the diabetic mouse hind limb ischemia model of peripheral arterial disease. Interestingly, due to the ROS scavenging behavior of PPS, the blank microparticles also showed inherent therapeutic properties that were synergistic with the effects of curcumin in these assays. Functionally, local delivery of curcumin-PPS microspheres accelerated recovery from hind limb ischemia in diabetic mice, as demonstrated using non-invasive imaging techniques. This work demonstrates the potential for PPS microspheres as a generalizable vehicle for ROS-demanded drug release and establishes the utility of this platform for improving local curcumin bioavailability for treatment of chronic inflammatory diseases.

Biodegradable micelles enhance the antiglioma activity of curcumin in vitro and in vivo

“…[8][9][10][11][24][25][26][27] It has received extensive attention with its unique effectiveness in glioma therapy. Previous studies demonstrated that Cur can significantly inhibit the proliferation of glioma cells by downregulating multidrug resistance proteins that cause the efflux of many chemotherapeutic agents.…”

The Natural Rotenoid Deguelin Ameliorates Diabetic Neuropathy by Decreasing Oxidative Stress and Plasma Glucose Levels in Rats via the Nrf2 Signalling Pathway

“…We estimated the levels of H 2 S in diabetic and deguelintreated rats; deguelin significantly increased H 2 S levels in diabetes-induced rats, suggesting a possible role for H 2 S in activating the antioxidant defence system. A previous study reported involvement of the Nrf2-dependent pathway in the effects of H 2 S against oxidative stress [31]. Therefore, we measured the levels of both HO-1 and Nrf2 in DRG neurons; both were markedly increased in diabetes-induced rats after treatment with deguelin.…”

Engineering Integrative Stem Cell and Biomaterial Therapies for Peripheral Artery Disease

“…In one study, reactive oxygen species (ROS)-responsive microspheres (polypropylene sulfide) loaded with curcumin were delivered to mouse ischemic limbs via intramuscular injection to the gastrocnemius and adductor muscles [116]. Curcumin has been known to exhibit strong antioxidant and anti-inflammatory properties to keep inflammatory cells at bay within wound sites.…”