H2O2-responsive molecularly engineered polymer nanoparticles as ischemia/reperfusion-targeted nanotherapeutic agents

Abstract

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.

Vanillin and Vanillin Analogs Relax Porcine Coronary and Basilar Arteries by Inhibiting L-Type Ca2+Channels

“…Based on these properties, VA, VAA, and EtVA could be used to prevent or relieve exaggerated Ca 21 influx resulting in PKC activation in coronary (Ito et al, 1994;Kadokami, et al, 1996) or cerebral (Laher and Zhang, 2001) vasospasm and other cardiovascular disorders (Khalil, 2013). However, the concentrations of VA and its analogs needed to act as antioxidants (Shyamala et al, 2007;Jung et al, 2010;Kwon et al, 2013;Lee et al, 2013) or as vasodilators (present study) are larger than the measured plasma level [0.0005 mM] reached after oral administration of 30 mg/kg VA in male ICR (imprinting control region) mice (Tai et al, 2011). This comparison implies that to obtain a therapeutically favorable coronary and/or cerebral vasodilator, larger doses of VA and its analogs would be required than are achieved with their use as additives.…”

“…They are commonly used as flavoring agents or as additives by the food, cosmetic, and pharmaceutic industries. VA and its analogs have antioxidant (Shyamala et al, 2007;Jung et al, 2010;Tai et al, 2011;Kwon et al, 2013;Lee et al, 2013), antiinflammatory (Jung et al, 2010;Kwon et al, 2013;Lee et al, 2013), antiproliferative, and antiangiogenic (Fukuoka et al, 2004;Lirdprapamongkol et al, 2009;Jung et al, 2010) properties as well as antitumor properties (Lirdprapamongkol et al, 2009) in vitro and in vivo. VA provides protection against global cerebral ischemia in Mongolian gerbils (Kim et al, 2007), and VAA protects against apoptosis induced by a neurotoxin )] in dopaminergic MN9D cells (a mesencephalic cell line) (Kim et al, 2011).…”

Mesoporous silica nanoparticles for stimuli-responsive controlled drug delivery: advances, challenges, and outlook

“…Hydrogen peroxide (H 2 O 2 ) is the most abundant form of ROS produced during ischemia/reperfusion, which usually induces the release of pro-inflammatory cytokines and triggers apoptosis, leading to the oxidative damage of tissues. [116][117][118] Therefore, targeting H 2 O 2 as a diagnostic marker and therapeutic agent shows great potentials.…”

Exploiting Oxidative Microenvironments in the Body as Triggers for Drug Delivery Systems

“…For example, a novel redox nanoparticle (RNP O ) consisting of a self-assembling ampiphilic block copolymer containing a derivative of the antioxidant TEMPOL (4-hydroxy-2,2,6,6-tetramethylpiperidin-1-oxyl) in the hydrophobic segment has been shown to be more effective than free TEMPOL or mesalamine (an anti-inflammatory compound) at treating colitis in mice (190).The confinement of the nitroxide radical-containing TEMPOL derivative in the hydrophobic core of RNP O nanoparticles enhanced its biocompatibility, and the nanoparticles' size (40 nm) caused them to accumulate in the colonic mucosa. A recent report described the antioxidant properties of nanoparticles (PVAX) formulated from copolyoxylate containing vanillyl alcohol (VA) (110). The PVAX polymer consists of peroxalate ester bonds along with VA in the backbone.…”