The main culprit in the pathogenesis of ischemia/reperfusion (I/R) injury is the overproduction of reactive oxygen species (ROS). Hydrogen peroxide (H2O2), the most abundant form of ROS produced during I/R, causes inflammation, apoptosis and subsequent tissue damages. Here, we report H2O2-responsive antioxidant nanoparticles formulated from copolyoxalate containing vanillyl alcohol (VA) (PVAX) as a novel I/R-targeted nanotherapeutic agent. PVAX was designed to incorporate VA and H2O2-responsive peroxalate ester linkages covalently in its backbone. PVAX nanoparticles therefore degrade and release VA, which is able to reduce the generation of ROS, and exert anti-inflammatory and anti-apoptotic activity. In hind-limb I/R and liver I/R models in mice, PVAX nanoparticles specifically reacted with overproduced H2O2 and exerted highly potent anti-inflammatory and anti-apoptotic activities that reduced cellular damages. Therefore, PVAX nanoparticles have tremendous potential as nanotherapeutic agents for I/R injury and H2O2-associated diseases.

Hydrogen peroxide (H2O2) is one of essential oxygen metabolites in living organisms, but is generated in large amounts during inflammatory responses. Therefore, H2O2 has great potential as diagnostic and therapeutic markers of several inflammatory and life‐threatening diseases. Here, chemiluminescent and antioxidant micelles are reported as novel theranostic agents for H2O2‐associated inflammatory diseases. The chemiluminescent micelles composed of amphiphilic block copolymer Pluronic F‐127, hydroxybenzyl alcohol‐incorporated copolyoxalate (HPOX) and fluorescent dyes perform peroxalate chemiluminescence reactions to detect H2O2 as low as 100 nM and image H2O2 generated in inflamed mouse ankles. The micelles encapsulating HPOX reduce the generation of reactive oxygen species in lipopolysaccharide (LPS)‐activated macrophages by scavenging overproduced H2O2 and releasing antioxidant hydroxybenzyl alcohol (HBA). They also exert inhibitory effects on H2O2‐induced apoptosis. HPOX‐based chemiluminescent and antioxidant micelles have great potential as a theranostic agent for H2O2‐associated inflammatory diseases.

Hydrogen peroxide plays a key role as a second messenger in the normal cellular signaling but its overproduction has been implicated in various life-threatening diseases. Peroxalate chemiluminescence is the light emission from a three component reaction between peroxalate, hydrogen peroxide and fluorophores. It has proven great potential as a methodology to detect hydrogen peroxide in physiological environments because of its excellent sensitivity and specificity to hydrogen peroxide. We developed chemiluminescent micelles composed of amphiphilic polymers, peroxalate and fluorescent dyes to detect hydrogen peroxide at physiological concentrations. In this work, we studied the relationship between the chemiluminescence reactivity and stability of peroxalate by varying the substitutes on the aryl rings of peroxalate. Alkyl substitutes on the aryl ring of peroxalate increased the stability against water hydrolysis, but diminished the reactivity to hydrogen peroxide. Chemiluminescent micelles encapsulating diphenyl peroxalate showed significantly higher chemiluminescence intensity than the counterpart encapsulating dimethylphenyl or dipropylphenyl peroxalate. Diphenyl peroxalate-encapsulated micelles could detect hydrogen peroxide generated from macrophage cells stimulated by lipopolysaccharide (LPS) and image hydrogen peroxide generated during LPS-induced inflammatory responses in a mouse.

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