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Platelets can sense their surroundings as they crawl in search of optimal surface to adhere beforeactivation, but the detailed mechanism has not been fully explored in different microenvironments. Herein, various aspects of platelet behavior, including morphology, movement and biomarkerexpression, were multilaterally examined on mechanically stimulating surfaces, with controlled rigidityand roughness, to elucidate the effect of microenvironment without chemical stimulus. The plateletsdemonstrated different movement behavior (e.g. back-and-forth and forward crawling), and motility, aswell as varying degrees of spreading with lamellipodial andfilopodial projections, based on varyingmechanical microenvironments. Furthermore, after initial activation, the platelets all became stationaryand the cell spreading became more prominent, while still maintaining their movement potential. Pselectinexpression, along with α-granule and open canalicular system (OCS) distributions, all supportedthe morphological and movement behavior. These results strongly indicated that the mechanicalmicroenvironment played a key role in the regulation of complex platelet activities.
<P>A thrombus (blood clot) is formed in injured vessels to maintain the integrity of vasculature. However, obstruction of blood vessels by thrombosis slows blood flow, leading to death of tissues fed by the artery and is the main culprit of various life-threatening cardiovascular diseases. Herein, we report a rationally designed nano medicine that could specifically image obstructed vessels and inhibit thrombus formation. On the basis of the physicochemical and biological characteristics of thrombi such as an abundance of fibrin and an elevated level of hydrogen peroxide (H2O2), we developed a fibrin-targeted imaging and antithrombotic nanomedicine, termed FTIAN, as a theranostic system for obstructive thrombosis. FTIAN inhibited the generation of H2O2 and suppressed the expression of tumor necrosis factor-alpha (TNF-alpha) and soluble CD40 ligand (sCD40L) in activated platelets, demonstrating its intrinsic antioxidant, anti-inflammatory, and antiplatelet activity. In a mouse model of ferric chloride (FeCl3)-induced carotid thrombosis, FTIAN specifically targeted the obstructive thrombus and significantly enhanced the fluorescence/photoacoustic signal. When loaded with the antiplatelet drug tirofiban, FTIAN remarkably suppressed thrombus formation. Given its thrombus-specific imaging along with excellent therapeutic activities, FTIAN offers tremendous translational potential as a nanotheranostic agent for obstructive thrombosis.</P>
<P><B>Abstract</B></P> <P>Muscles of peripheral artery disease (PAD) patients are under oxidative stress associated with a significantly elevated level of reactive oxygen species (ROS) including hydrogen peroxide (H<SUB>2</SUB>O<SUB>2</SUB>). Curcumin is a major active constituent of turmeric and is well known for its highly potent antioxidant, anti-inflammatory and angiogenic effects. We previously reported antioxidant vanillyl alcohol-incorporated copolyoxalate (PVAX) which is designed to rapidly scavenge H<SUB>2</SUB>O<SUB>2</SUB> and release bioactive vanillyl alcohol and CO<SUB>2</SUB> in a H<SUB>2</SUB>O<SUB>2</SUB>-triggered manner. In this work, we developed curcumin-loaded PVAX (CUR-PVAX) nanoparticles as contrast-enhanced ultrasound imaging agents as well as on-demand therapeutic agents for ischemic injuries based on the hypothesis that PVAX nanoparticles generate echogenic CO<SUB>2</SUB> bubbles through H<SUB>2</SUB>O<SUB>2</SUB>-triggered oxidation of peroxalate esters and the merger of curcumin and PVAX exerts H<SUB>2</SUB>O<SUB>2</SUB>-activatable synergistic therapeutic actions. CUR-PVAX nanoparticles also displayed the drastic ultrasound signal in ischemic areas by generating CO<SUB>2</SUB> bubbles. CUR-PVAX nanoparticles exhibited significantly higher antioxidant and anti-inflammatory activities than empty PVAX nanoparticles and equivalent curcumin in vascular endothelial cells. A mouse model of ischemic injury was used to evaluate the potential of CUR-PVAX nanoparticles as ultrasound imaging agents and on-demand therapeutic agents. CUR-PVAX nanoparticles significantly suppressed the expression of pro-inflammatory cytokines such as tumor necrosis factor-alpha (TNF-α) and interleukin-1 beta (IL-1β). Moreover, CUR-PVAX nanoparticles significantly enhanced the level of vascular endothelial growth factor (VEGF) and platelet endothelial cell adhesion molecule-1 (PECAM-1, also known as CD31), leading to blood perfusion into ischemic tissues. We, therefore, believe that CUR-PVAX nanoparticles hold great translational potential as novel theranostic agents for ischemic diseases such as PAD.</P> <P><B>Graphical abstract</B></P> <P>[DISPLAY OMISSION]</P>
<P><B>Abstract</B></P> <P>Reactive oxygen species (ROS) are closely related with various pathological disorders. Therefore, real-time detection of ROS is essential for understanding the procedure of diseases and diagnosing the accurate lesion sites. Hydrogen peroxide (H<SUB>2</SUB>O<SUB>2</SUB>) accounts for a large portion of ROS and has a longer half-life than other ROS, which makes it a highly promising diagnostic and therapeutic biomarker. In this work, we developed H<SUB>2</SUB>O<SUB>2</SUB>-activatable CO<SUB>2</SUB> bubble generating indocyanine green-loaded boronated maltodextrin (ICG-BM) nanoparticles for imaging and therapy of peripheral arterial disease. ICG-BM nanoparticles displayed increasing fluorescence, ultrasound and photoacoustic signals in H<SUB>2</SUB>O<SUB>2</SUB>-triggered manners and exerted significant anti-inflammatory and proangiogenic effects in H<SUB>2</SUB>O<SUB>2</SUB>-stimulated vascular endothelial cells. In mouse models of hindlimb ischemia, ICG-BM nanoparticles also showed H<SUB>2</SUB>O<SUB>2</SUB>-triggered amplification of fluorescence, ultrasound and photoacoustic signals in the ischemic hindlimb muscles. ICG-BM nanoparticles also significantly reduced the level of overproduced H<SUB>2</SUB>O<SUB>2</SUB> and exerted highly potent anti-inflammatory and proangiogenic activities in the ischemic tissues. We therefore believe that pathological stimulus-activatable echogenic ICG-BM nanoparticles provide a new avenue for imaging and treatment of peripheral arterial disease.</P> <P><B>Graphical abstract</B></P> <P>[DISPLAY OMISSION]</P>
<P>A thrombus (blood clot), composed mainly of activated platelets and fibrin, obstructs arteries or veins, leading to various life-threatening diseases. Inspired by the distinctive physicochemical characteristics of thrombi such as abundant fibrin and an elevated level of hydrogen peroxide (H<SUB>2</SUB>O<SUB>2</SUB>), we developed thrombus-specific theranostic (T-FBM) nanoparticles that could provide H<SUB>2</SUB>O<SUB>2</SUB>-triggered photoacoustic signal amplification and serve as an antithrombotic nanomedicine. T-FBM nanoparticles were designed to target fibrin-rich thrombi and be activated by H<SUB>2</SUB>O<SUB>2</SUB> to generate CO<SUB>2</SUB> bubbles to amplify the photoacoustic signal. In the phantom studies, T-FBM nanoparticles showed significant amplification of ultrasound/photoacoustic signals in a H<SUB>2</SUB>O<SUB>2</SUB>-triggered manner. T-FBM nanoparticles also exerted H<SUB>2</SUB>O<SUB>2</SUB>-activatable antioxidant, anti-inflammatory, and antiplatelet activities on endothelial cells. In mouse models of carotid arterial injury, T-FBM nanoparticles significantly enhanced the photoacoustic contrast specifically in thrombosed vessels and significantly suppressed thrombus formation. We anticipate that T-FBM nanoparticles hold great translational potential as nanotheranostics for H<SUB>2</SUB>O<SUB>2</SUB>-associated cardiovascular diseases.</P><P><B>Graphic Abstract</B> <IMG SRC='http://pubs.acs.org/appl/literatum/publisher/achs/journals/content/ancac3/2018/ancac3.2018.12.issue-1/acsnano.7b06560/production/images/medium/nn-2017-06560s_0007.gif'></P><P><A href='http://pubs.acs.org/doi/suppl/10.1021/nn7b06560'>ACS Electronic Supporting Info</A></P>
<P><B>Abstract</B></P> <P>There has been increasing interest in the development of pathological stimulus-activatable nanoplatforms with theranostic functions. Here, we report ketalized maltodextrin (KMD) nanoparticles which are able to deliver therapeutic and imaging functions to the acidic conditions simultaneously, as may be found in the site of inflammation. KMD was synthesized as a platform of the theranostic nanoparticles by conjugating acid-cleavable hydrophobic moieties to maltodextrin through carbonate bonds. KMD nanoparticles could undergo acid-triggered hydrolytic degradation to generate carbon dioxide (CO<SUB>2</SUB>) bubbles, amplifying the ultrasound signal. The potential of KMD nanoparticles as a drug carrier was evaluated using silymarin as a model drug. KMD nanoparticles displayed significantly enhanced ultrasound contrast at acidic pH and released drug payloads in acid-triggered manners. The translational potential of silymarin-loaded KMD (s-KMD) nanoparticles as ultrasound contrast agents and therapeutic agents was thoroughly evaluated using cell culture models and mouse models of acetaminophen (APAP)-induced acute liver failure. s-KMD nanoparticles exhibited significantly enhanced ultrasound contrast in the APAP-intoxicated liver and also remarkably suppressed the hepatic damages by inhibiting the expression of pro-inflammatory cytokines. These results suggest that KMD nanoparticles hold tremendous potential as theranostic agents for various inflammatory diseases.</P> <P><B>Graphical abstract</B></P> <P>[DISPLAY OMISSION]</P>