Wearable and implantable devices require conductive, stretchable and biocompatible materials. However, obtaining composites that simultaneously fulfil these requirements is challenging due to a ...trade-off between conductivity and stretchability. Here, we report on Ag-Au nanocomposites composed of ultralong gold-coated silver nanowires in an elastomeric block-copolymer matrix. Owing to the high aspect ratio and percolation network of the Ag-Au nanowires, the nanocomposites exhibit an optimized conductivity of 41,850 S cm
(maximum of 72,600 S cm
). Phase separation in the Ag-Au nanocomposite during the solvent-drying process generates a microstructure that yields an optimized stretchability of 266% (maximum of 840%). The thick gold sheath deposited on the silver nanowire surface prevents oxidation and silver ion leaching, making the composite biocompatible and highly conductive. Using the nanocomposite, we successfully fabricate wearable and implantable soft bioelectronic devices that can be conformally integrated with human skin and swine heart for continuous electrophysiological recording, and electrical and thermal stimulation.
The signal-to-background ratio (SBR) is the key determinant of sensitivity, detectability and linearity in optical imaging. As signal strength is often constrained by fundamental limits, background ...reduction becomes an important approach for improving the SBR. We recently reported that a zwitterionic near-infrared (NIR) fluorophore, ZW800-1, exhibits low background. Here we show that this fluorophore provides a much-improved SBR when targeted to cancer cells or proteins by conjugation with a cyclic RGD peptide, fibrinogen or antibodies. ZW800-1 outperforms the commercially available NIR fluorophores IRDye800-CW and Cy5.5 in vitro for immunocytometry, histopathology and immunoblotting and in vivo for image-guided surgery. In tumor model systems, a tumor-to-background ratio of 17.2 is achieved at 4 h after injection of ZW800-1 conjugated to cRGD compared to ratios of 5.1 with IRDye800-CW and 2.7 with Cy5.5. Our results suggest that introducing zwitterionic properties into targeted fluorophores may be a general strategy for improving the SBR in diagnostic and therapeutic applications.
Doxorubicin (DOX) is a commonly used anti-neoplastic agent but its clinical use is limited due to serious hepatic and cardiac side effects. DOX-induced toxicity is mainly associated with ...overproduction of reactive species oxygen (ROS) such as hydrogen peroxide (H2O2). We have recently developed H2O2-responsive anti-oxidant polymer, polyoxalate containing vanillyl alcohol (PVAX), which is designed to rapidly scavenge H2O2 and release vanillyl alcohol with anti-oxidant, anti-inflammatory and anti-apoptotic properties. In this study, we report that PVAX nanoparticles are novel therapeutic agents for treating DOX-induced cardiac and hepatic toxicity. Intraperitoneal injection of PVAX nanoparticles (4 mg/kg/day) resulted in significant inhibition in apoptosis in liver and heart of DOX-treated mice by suppressing the activation of poly (ADP ribose) polymerase 1 (PARP-1) and caspase-3. PVAX treatment also prevented DOX-induced cardiac dysfunction. Furthermore, survival rate (vehicle = 35% vs. PVAX = 75%; p < 0.05) was significantly improved in a PVAX nanoparticles-treated group compared with vehicle treated groups. Taken together, we anticipate that PVAX nanoparticles could be a highly specific and potent treatment modality in DOX-induced cardiac and hepatic toxicity.
Previous studies have reported the sex differences in heart susceptibility to ischemia/reperfusion (I/R) injury, but the mechanisms are not understood. The present study tested the hypothesis that ...Akt and protein kinase C (PKC)epsilon play an important role in the sexual dimorphism of heart susceptibility to I/R injury. Isolated hearts from 2-month-old male and female rats were subjected to I/R in the Langendorff preparation. The postischemic recovery of left ventricular function was significantly better, and infarct size was significantly smaller in female (37.1 +/- 1.9%) than in male (48.3 +/- 2.3%) hearts after 25-min ischemia followed by 2-h reperfusion. Inhibition of phosphatidylinositol 3-kinase/Akt pathway by wortmannin or PKC by chelerythrine chloride before ischemia significantly reduced postischemic recovery and increased infarct size in female but not male hearts. There were no differences in myocardial protein levels of heat shock protein 70, Akt, and PKCepsilon, respectively, between male and female rats. However, the ratio of phosphorylated (p)-Akt/Akt (0.58 +/- 0.05 versus 0.22 +/- 0.04; P < 0.05) and p-PKCepsilon/PKCepsilon (0.35 +/- 0.03 versus 0.22 +/- 0.02; P < 0.05) was significantly higher in female than in male hearts. In addition, there were significant increases in p-Akt and p-PKCepsilon levels during reperfusion in female but not in male hearts. The results suggest that increased p-Akt and p-PKCepsilon levels in female hearts contribute to the gender-related differences in heart susceptibility to I/R and play an important role in cardioprotection against I/R injury in females.
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.
Overproduction of hydrogen peroxide (H2O2) causes oxidative stress and is the main culprit in the pathogenesis of ischemia/reperfusion (I/R) injury. Suppression of oxidative stress is therefore ...critical in the treatment of I/R injury. Here, we report H2O2-activatable antioxidant prodrug (BRAP) that is capable of specifically targeting the site of oxidative stress and exerting anti-inflammatory and anti-apoptotic activities. BRAP with a self-immolative boronic ester protecting group was designed to scavenge H2O2 and release HBA (p-hydroxybenzyl alcohol) with antioxidant and anti-inflammatory activities. BRAP exerted potent antioxidant and anti-inflammatory activity in lipopolysaccharide (LPS)- and H2O2-stimulated cells by suppressing the generation of ROS and pro-inflammatory cytokines. In mouse models of hepatic I/R and cardiac I/R, BRAP exerted potent antioxidant, anti-inflammatory and anti-apoptotic activities due to the synergistic effects of H2O2-scavenging boronic esters and therapeutic HBA. In addition, administration of high doses of BRAP daily for 7 days showed no renal or hepatic function abnormalities. Therefore BRAP has tremendous therapeutic potential as H2O2-activatable antioxidant prodrug for the treatment of I/R injuries.
Background
During myocardial ischemia/reperfusion (I/R), a large amount of reactive oxygen species (ROS) is produced. In particular, overproduction of hydrogen peroxide (H2O2) is considered to be a ...main cause of I/R‐mediated tissue damage. We generated novel H2O2‐responsive antioxidant polymer nanoparticles (PVAX and HPOX) that are able to target the site of ROS overproduction and attenuate the oxidative stress‐associated diseases. In this study, nanoparticles were examined for their therapeutic effect on myocardial I/R injury.
Methods and Results
The therapeutic effect of nanoparticles during cardiac I/R was evaluated in mice. A single dose of PVAX (3 mg/kg) showed a significant improvement in both cardiac output and fraction shortening compared with poly(lactic‐coglycolic acid) (PLGA) particle, a non‐H2O2‐activatable nanoparticle. PVAX also significantly reduced the myocardial infarction/area compared with PLGA (48.7±4.2 vs 14.5±2.1). In addition, PVAX effectively reduced caspase‐3 activation and TUNEL‐positive cells compared with PLGA. Furthermore, PVAX significantly decreased TNF‐α and MCP‐1 mRNA levels. To explore the antioxidant effect of PVAX by scavenging ROS, dihydroethidium staining was used as an indicator of ROS generation. PVAX effectively suppressed the generation of ROS caused by I/R, whereas a number of dihydroethidium‐positive cells were observed in a group with PLGA I/R. In addition, PVAX significantly reduced the level of NADPH oxidase (NOX) 2 and 4 expression, which favors the reduction in ROS generation after I/R.
Conclusions
Taken together, these results suggest that H2O2‐responsive antioxidant PVAX has tremendous potential as a therapeutic agent for myocardial I/R injury.
Abstract Therapeutic angiogenesis has achieved promising results for ischemic diseases or peripheral artery disease in preclinical and early-phase clinical studies. We examined the therapeutic ...angiogenic effects of HPOX, which is biodegradable polymer composing the antioxidant p -hydroxybenzyl alcohol (HBA), in a mouse model of hindlimb ischemia. HPOX effectively stimulated blood flow recovery, compared with its degraded compounds HBA and 1,4-cyclohexendimethanol, via promotion of capillary vessel density in the ischemic hindlimb. These effects were highly correlated with levels of angiogenic inducers, vascular endothelial cell growth factor (VEGF), heme oxygenase-1 (HO-1), and Akt/AMPK/endothelial nitric oxide synthase (eNOS) in ischemic mouse hindlimb muscle. Blood perfusion and neovascularization induced by HPOX were reduced in eNOS−/− and HO-1+/− mice. HPOX also elevated the endothelial cell markers VEGF receptor-2, CD31, and eNOS mRNAs in the ischemic hindlimb, indicating that HPOX increases endothelial cell population and angiogenesis in the ischemic muscle. However, this nanoparticle suppressed expression levels of several inflammatory genes in ischemic tissues. These results suggest that HPOX significantly promotes angiogenesis and blood flow perfusion in the ischemic mouse hindlimb via increased angiogenic inducers, along with suppression of inflammatory gene expression. Thus, HPOX can be used potentially as a noninvasive drug intervention to facilitate therapeutic angiogenesis.
Altered vitamin D signaling is associated with cardiac dysfunction, but the pathogenic mechanism is not clearly understood. We examine the mechanism and the role of vitamin D signaling in the ...development of cardiac dysfunction.
We analyzed 1α-hydroxylase (1α-OHase) knockout (1α-OHase-/-) mice, which lack 1α-OH enzymes that convert the inactive form to hormonally active form of vitamin D. 1α-OHase-/- mice showed modest cardiac hypertrophy at baseline. Induction of pressure overload by transverse aortic constriction (TAC) demonstrated exaggerated cardiac dysfunction in 1α-OHase-/- mice compared to their WT littermates with a significant increase in fibrosis and expression of inflammatory cytokines. Analysis of calcium (Ca2+) transient demonstrated profound Ca2+ handling abnormalities in 1α-OHase-/- mouse cardiomyocytes (CMs), and treatment with paricalcitol (PC), an activated vitamin D3 analog, significantly attenuated defective Ca2+ handling in 1α-OHase-/- CMs. We further delineated the effect of vitamin D deficiency condition to TAC by first correcting the vitamin D deficiency in 1α-OHase-/- mice, followed then by either a daily maintenance dose of vitamin D or vehicle (to achieve vitamin D deficiency) at the time of sham or TAC. In mice treated with vitamin D, there was a significant attenuation of TAC-induced cardiac hypertrophy, interstitial fibrosis, inflammatory markers, Ca2+ handling abnormalities and cardiac function compared to the vehicle treated animals.
Our results provide insight into the mechanism of cardiac dysfunction, which is associated with severely defective Ca2+ handling and defective vitamin D signaling in 1α-OHase-/- mice.
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