Site Of Thrombus Research Articles

Neutrophil-Mimetic Upconversion Photosynthetic Nanosystem Derived from Microalgae for Targeted Treatment of Thromboembolic Stroke.

Thromboembolic stroke constitutes the majority of brain strokes, resulting in elevated mortality and morbidity rates, as well as significant societal and economic burdens. Although intravenous thrombolysis serves as the standard clinical treatment, its narrow therapeutic window and the inflammatory response induced by tissue plasminogen activator (tPA) administration limit its efficacy. In the initial stages of stroke, the abrupt cessation of blood flow leads to an energy metabolism disorder, marked by a substantial decrease in adenosine triphosphate (ATP) and nicotinamide adenine dinucleotide phosphate (NADPH) levels, causing irreversible damage to neural cells. In this study, we introduce a neutrophil-mimetic, microalgae-derived upconversion photosynthetic nanosystem designed for targeted treatment of thromboembolic stroke. This system features upconversion nanoparticles coated with a thylakoid membrane and wrapped in an activated neutrophil membrane, further decorated with ROS-responsive thrombolytic tPA on its surface. The neutrophil-mimetic design facilitates high targeting specificity and accumulation at the thrombus site after intravenous administration. Upon exposure to elevated levels of reactive oxygen species (ROS) at the thrombus location, the nanosystem promptly demonstrated potent thrombolytic efficacy through the surface-modified tPA. Furthermore, near-infrared II (NIR-II) laser irradiation activated the generation of ATP and NADPH, which inhibited inflammatory cell infiltration, platelet activation, oxidative stress, and neuronal injury. This constructed nanoplatform not only showcases exceptional targeting efficiency at the stroke site and controllable release of the thrombolytic agent but also facilitates ATP/NADPH-mediated thrombolytic, anti-inflammatory, antioxidative stress, and neuroprotective effects. Additionally, it offers valuable insights into the potential therapeutic applications of microalgae-based derivatives in managing thromboembolic stroke.

Platelet membrane coated r-SAK to improve thrombolytic efficacy by targeting thrombus

Abstract Background Thrombolytic therapy is one of the most effective treatments to achieve rapid thrombus clearance and recanalization of blocked vessels in thrombotic diseases. However, the application of thrombolytic strategy has been limited due to unsatisfied thrombolytic efficacy, relatively higher bleeding complications, and consequently restricted indications.[1] With the development of nanotechnology and biotechnology, platelet membrane nanoparticles have been developed to enable the targeted delivery of thrombolytic agents to local thrombus sites.[2] Recombinant staphylokinase (r-SAK) is a third-generation thrombolytic agent produced by genetic engineering technology. In this study, platelet membrane coated r-SAK (PLT-r-SAK) was constructed, and its thrombolytic efficacy was evaluated in in-vitro and in-vivo experiments. Purpose We aimed to construct a thrombus-targeting agent of PLT-r-SAK and investigate its thrombolytic efficacy. Methods PLT-r-SAK was prepared by encapsulating r-SAK into platelet membrane vesicles using a membrane extrusion method. An in-vitro thrombolytic experiment was performed to examine the thrombolytic efficacy of PLT-r-SAK, and a totally occluded femoral artery thrombosis model of rabbit was developed to evaluate the in-vivo thrombolytic efficacy of PLT-r-SAK. The changes in femoral artery pressure were adopted to assess the vessel opening status. Besides, the effect of the antiplatelet drugs on the thrombolytic efficacy of PLT-r-SAK was explored. Finally, near-infrared fluorescence imaging system was used to verify the thrombus-targeting effect of PLT-r-SAK. Results PLT-r-SAK was firstly constructed, which exhibited a uniformly dispersed spherical morphology with a diameter of 185.8 ± 1.5 nm and a zeta potential of -26.1 ± 0.8 mV. In the in-vitro animal experiment, the thrombolysis rate of PLT-r-SAK was significantly higher than that of the same (low) dose and 4-fold (high) dose r-SAK (Figure 1a, 1b). In the in-vivo experiment, the initial recanalization time of PLT-r-SAK was significantly shorter than that of the low dose and high dose r-SAK, and the duration of the reperfusion time of PLT-r-SAK was prolonged compared to low dose and high dose r-SAK (Figure 1c). Another in-vitro experiment showed that the increased thrombolysis rate of PLT-r-SAK could be inhibited by platelet poor plasma (PPP) from aspirin- and ticagrelor-treated patients. Finally, both the in-vitro and in-vivo near-infrared fluorescence imaging showed significantly higher radiant efficiency in the PLT-r-SAK group as compared to the NS group (Figure 2). Conclusions Platelet membrane coating significantly improves the thrombolytic efficacy of r-SAK, which is related to the thrombus-targeting activity of the platelet membrane and can be inhibited by aspirin- and ticagrelor-treated plasma.Thrombolytic efficacy of PLT-r-SAKThrombus-targeting evidence of PLT-r-SAK

Thrombin and NIR dual-responsive system driven by heat-gas for thrombus targeted therapy

Drug thrombolysis is the main means of clinical treatment for thrombotic-related diseases. However, serious bleeding complications caused by low drug delivery efficiency and secondary vascular embolism usually lead to unsatisfactory therapeutic effects. Herein, we constructed a thrombin and near-infrared (NIR) dual-responsive drug-loaded intelligent system to solve the above problems. The CREKA-modified polydopamine (PDA) nanoparticles (NPs) were crosslinked by thrombin-responsive peptide (Pep), to obtain Pep-PPC nanocarriers with special mesoporous nanostructures. Subsequently, NO donor BNN6 and thrombolytic drug UK were loaded on the surface and into the mesoporous of Pep-PPC, to get the multifunctional Pep-NO@PPC/UK. In vitro and in vivo results proved that Pep-NO@PPC/UK could effectively recognize and aggregate at the thrombus site via CREKA-mediated active targeting. Then local abundant thrombin cleaved the nanoplatform to release UK. Meanwhile, PDA converted NIR light into heat and synchronously triggered NO release. This transformed the DDS into a “heat-gas” dual propulsion nanomotor in situ, driving deep penetration of UK in thrombus tissue. Under the combined action of UK and PTT, arterial thrombosis rapidly dissolved with relatively low bleeding risk. More importantly, NO generated in situ could prevent re-embolism of blood vessels at the thrombolytic site by inhibiting activated platelet aggregation, ultimately improving vascular reperfusion rate through a combination of attack and defense mode.

"One-Stone-Three-Birds" H2S-Photothermal Therapy for Enhanced Thrombolysis and Vascular Healing.

Thrombus causes a serious condition characterized by the formation of blood clots in blood vessels or heart, potentially leading to life-threatening emergencies. Photothermal therapy (PTT) serves as a treatment for thrombosis that provides noninvasive thrombus dissolution and fewer bleeding side effects.However, the high temperatures generated by PTT can exacerbate vascular inflammation and promote thrombus recurrence. In this study, a photothermal hydrogen sulfide (H2S) nanogenerator (PSA@ADT-OH) is constructed using a perylene-cored photothermal agent (PSA) coassembled with a H2S donor ADT-OH. The system PSA@ADT-OH demonstrates outstanding targeting and accumulation efficiency against blood flow shear forces. It also provides sustained H2S release at thrombus sites, contributing to antiplatelet aggregation, reactive oxygen species clearance, and vascular healing. This approach opens up new possibilities for advanced thrombus treatment.

Dual-mode nanoprobe strategy integrating ultrasound and near-infrared light for targeted and synergistic arterial thrombolysis

Efficient thrombolysis in time is crucial for prognostic improvement of patients with acute arterial thromboembolic disease, while limitations and complications still exist in conventional thrombolytic treatment methods. Herein, our study sought to investigate a novel dual-mode strategy that integrated ultrasound (US) and near-infrared light (NIR) with establishment of hollow mesoporous silica nanoprobe (HMSN) which contains Arginine-glycine-aspartate (RGD) peptide (thrombus targeting), perfluoropentane (PFP) (thrombolysis with phase-change and stable cavitation) and indocyanine green (ICG) (thrombolysis with photothermal conversion). HMSN is used as the carrier, the surface is coupled with targeted RGD to achieve high targeting and permeability of thrombus, PFP and ICG are loaded to achieve the collaborative diagnosis and treatment of thrombus by US and NIR, so as to provide a new strategy for the integration of diagnosis and treatment of arterial thrombus. From the in vitro and in vivo evaluation, RGD/ICG/PFP@HMSN can aggregate and penetrate at the site of thrombus, and finally establish the dual-mode directional development and thrombolytic treatment under the synergistic effect of US and NIR, providing strong technical support for the accurate diagnosis and treatment of arterial thrombosis.Graphical

Efficacy of Mechanical Thrombectomy in Preventing Post-Thrombotic Syndrome in Acute DVT: A Retrospective Study.

Background Lower limb deep vein thrombosis (DVT) is associated with significant morbidity and death. DVT can result in complications such as postphlebitic syndrome, pulmonary embolism, and death. Combining pretest probability, D-dimer testing, and compression ultrasound imaging enables a safe and convenient study of suspected lower-extremity thrombosis. This study aimed to assess the expanding body of research supporting thrombectomy as a form of DVT therapy. Materials and Methods A retrospective study was performed on individuals with venous Doppler-confirmed DVT and occlusive thrombus. Four-hundred fifty-one consecutive patients were selected for the study based on the inclusion and exclusion criteria. In this investigation, thrombectomy was the preferred therapeutic approach. Results The study reports a male predominance of 56.1%. Most patients (25.7%) were between the age of 51 and 60, with 84.7% reporting pain and lower-extremity swelling as the two most common clinical symptoms. The femoral vein was noted as the most frequent site of thrombus in the current research (51.0%), with acute DVT accounting for most cases (85.1%). Most of the patients (97.3%) were primarily asymptomatic after one year of follow-up. Conclusion Thrombectomy is a reliable treatment modality for DVT patients in regaining venous patency, preventing DVT recurrence, treating post-thrombotic syndrome, and preventing pulmonary embolism.

Advances in Nano-Functional Materials in Targeted Thrombolytic Drug Delivery.

Thrombotic disease has been listed as the third most fatal vascular disease in the world. After decades of development, clinical thrombolytic drugs still cannot avoid the occurrence of adverse reactions such as bleeding. A number of studies have shown that the application of various nano-functional materials in thrombus-targeted drug delivery, combined with external stimuli, such as magnetic, near-infrared light, ultrasound, etc., enrich the drugs in the thrombus site and use the properties of nano-functional materials for collaborative thrombolysis, which can effectively reduce adverse reactions such as bleeding and improve thrombolysis efficiency. In this paper, the research progress of organic nanomaterials, inorganic nanomaterials, and biomimetic nanomaterials for drug delivery is briefly reviewed.

Profile of Cases of Death Due to Coronary Artery Disease: An Autopsy Based Descriptive Study

Background: Most common cause of sudden cardiac death is coronary artery disease, which contributes to 75 to 90%. The present study is undertaken to describe the profile of autopsy cases of coronary artery disease. Methods:Descriptive cross-sectional study was conducted in all cases of sudden and unexpected death brought for autopsy a tertiary level centre in southern Kerala during a period of one year. Gross and microscopical examination of heart and coronary arteries were studied and in cases with coronary artery disease, associated factors like previous history of illness, personal habits, family history of illness, body mass index, abdominal circumference, horizontal earlobe crease were described in detail. Categorical variables were represented as frequency and percentage, continuous variables as mean and standard deviation and association was tested using Chi square test. Conclusions: Statistically significant association (p value = 0.001) was observed between the horizontal earlobe crease and occlusive coronary artery disease. No significant association was obtained between the obesity parameters like body mass index, waist to hip ratio and occlusive coronary artery disease. Majority of the cases with significant occlusion was observed in the left anterior descending artery.The most common site of thrombus was in the proximal third of left anterior descending artery.

Tea polyphenol-derived nanomedicine for targeted photothermal thrombolysis and inflammation suppression

Thrombotic diseases impose a significant global health burden, and conventional drug-based thrombolytic therapies are encumbered by the risk of bleeding complications. In this study, we introduce a novel drug-free nanomedicine founded on tea polyphenols nanoparticles (TPNs), which exhibits multifaceted capabilities for localized photothermal thrombolysis. TPNs were synthesized through a one-pot process under mild conditions, deriving from the monomeric epigallocatechin-3-gallate (EGCG). Within this process, indocyanine green (ICG) was effectively encapsulated, exploiting multiple intermolecular interactions between EGCG and ICG. While both TPNs and ICG inherently possessed photothermal potential, their synergy significantly enhanced photothermal conversion and stability. Furthermore, the nanomedicine was functionalized with cRGD for targeted delivery to activated platelets within thrombus sites, eliciting robust thrombolysis upon laser irradiation across diverse thrombus types. Importantly, the nanomedicine’s potent free radical scavenging abilities concurrently mitigated vascular inflammation, thus diminishing the risk of disease recurrence. In summary, this highly biocompatible multifunctional nanomaterial holds promise as a comprehensive approach that combines thrombolysis with anti-inflammatory actions, offering precision in thrombosis treatment.

Thrombotic microenvironment responsive crosslinking cyclodextrin metal-organic framework nanocarriers for precise targeting and thrombolysis

Global public health is seriously threatened by thrombotic disorders because of their high rates of mortality and disability. Most thrombolytic agents, especially protein-based pharmaceuticals, have a short half-life in circulation, reducing their effectiveness in thrombolysis. The creation of an intelligent drug delivery system that delivers medication precisely and releases it under regulated conditions at nearby thrombus sites is essential for effective thrombolysis. In this article, we present a unique medication delivery system (MCRUA) that selectively targets platelets and releases drugs by stimulation from the thrombus' microenvironment. The thrombolytic enzyme urokinase-type plasminogen-activator (uPA) and the anti-inflammatory medication Aspirin (acetylsalicylic acid, ASA) are both loaded onto pH-sensitive CaCO3/cyclodextrin crosslinking metal-organic frameworks (MC) that make up the MCRUA system. c(RGD) is functionalized on the surface of MC, which is functionalized by RGD to an esterification reaction. Additionally, the thrombus site's acidic microenvironment causes MCRUA to disintegrate to release uPA for thrombolysis and aiding in vessel recanalization. Moreover, cyclodextrin-encapsulated ASA enables the treatment of the inflammatory environment within the thrombus, enhancing the antiplatelet aggregation effects and promoting cooperative thrombolysis therapy. When used for thrombotic disorders, our drug delivery system (MCRUA) promotes thrombolysis, suppresses rethrombosis, and enhances biosafety with fewer hemorrhagic side effects.

NIR Light-Fuse Drug-Free Photothermal Armor-Piercing Microcapsule for Femoral Vein Thrombosis Therapy.

Acute thrombosis and its complications are leading global causes of disability and death. Existing thrombolytic drugs, such as alteplase and urokinase (UK), carry a significant bleeding risk during clinical treatments. Thus, the development of a novel thrombolysis strategy is of utmost urgency. Based on the previous work, the hollow structure of microcapsules (MC) is fabricated. Subsequently, armor-piercing MC, known as Fucoidan/S-Nitrosoglutathione/Melanin@MC (FGM@MC) is obtained, using a layer-by-layer (LBL) self-assembly method. Utilizing near-infrared (NIR) light as a trigger, the FGM@MC demonstrated photothermal thrombolysis at the site of thrombus due to its stable and outstanding photothermal properties. Simultaneously, photothermal stimulation leads to the release of a significant amount of nitric oxide from the FGM@MC, resulting in cavitation effects for mechanical thrombolysis. In vivo experiments confirmed the stable release of nitric oxide under NIR light irradiation. Treatment of femoral vein thrombosis in rats revealed that the thrombolytic effectiveness of FGM@MC+NIR (53.71%) is comparable to that of UK (59.70%). Notably, FGM@MC does not interfere with the coagulation function of rats and exhibits a favorable safety profile. In conclusion, this study demonstrates that the drug-free armor-piercing microcapsule has significant potential in the treatment of thrombosis, offering a safe and effective alternative to traditional thrombolytic therapies.

Dual‐modality imaging for identifying thrombosis via platelet GPIIb/IIIa receptor targeted cyclic RGDfK microbubbles

AbstractBackgroundAcute thrombotic events play a major role in various cardiovascular diseases. Therefore, direct thrombus imaging can be proved beneficial for early diagnosis and prompt therapy of thrombosis. Our study investigated targeted dual‐modality cyclic arginine‐glycine‐aspartic micro bubbles (cRGD‐MBs) for direct imaging of thrombi by fluorescence and ultrasound.MethodscRGD‐MBs were prepared by mechanical vibration and chemical chelation methods.ResultsCoulter counter analysis demonstrated that the cRGD‐MBs were well dispersed, with diameters ranging from 1 to 3 μm. They emitted bright red fluorescence under an excitation wavelength of 660 nm. In vivo fluorescence and ultrasound imaging revealed that cRGD‐MBs accumulated at the site of thrombus in the carotid artery with significant fluorescence and ultrasonic signal.ConclusionsThis study showed that novel microbubble cRGD‐MBs were successfully synthesized, and that these could potentially be used as contrast agents for immediate diagnosis of acute thrombus in vivo.

A microthrombus-driven fixed-point cleaved nanosystem for preventing post-thrombolysis recurrence via inhibiting ferroptosis

Thrombus-induced cardiovascular diseases threaten human health. Current treatment strategies often rely on urokinase plasminogen activator (uPA) for its efficacy, yet it has such limiting factors as short half-life, lack of thrombus targeting, and systemic side effects leading to unintended bleeding. In addition, thrombolytic interventions can trigger inflammation-induced damage at thrombus sites, which affects endothelial function. To address these challenges, Fer-1/uPA@pep-CREKA-Lipo (Fu@pep-CLipo) has been developed. This system achieves precise and efficient thrombolysis while enhancing the thrombus microenvironment and mitigating ischemia-reperfusion injury, with exceptional thrombus targeting ability via the strong affinity of the Cys-Arg-Glu-Lys-Ala (CREKA) peptide for fibrin. The Cys-Nle-TPRSFL-DSPE (pep) could respond to the thrombus microenvironment and fixed-point cleavage. The uPA component linked to the liposome surface is strategically cleaved upon exposure to abundant thrombin at thrombus sites. Importantly, the inclusion of Fer-1 within Fu@pep-CLipo contributes to reactive oxygen species (ROS) scavenging and significantly improves the thrombus microenvironment. This innovative approach not only achieves highly efficient and precise thrombolysis but also positively influences the expression of eNOS protein while suppressing inflammatory factors like TNF-α and IL-6. This dual action contributes to improved thrombus inflammatory microenvironment and mitigated ischemia-reperfusion injury.

Ultrasound-powered hydrogen peroxide-responsive Janus micromotors for targeted thrombolysis and recurrence inhibition

Thrombosis seriously endangers human health with high incidence and mortality worldwide, and the clinical treatment is challenged by low bioavailability of thrombolytic agents, high bleeding risk and thrombosis relapse. Herein, ultrasound-powered Janus micromotors with stimuli-responsive multiple release capabilities are developed for efficient thrombolysis and inhibition of thrombosis recurrence. Resveratrol-loaded hyaluronic acid (HARes) nanoparticles (NPs) and urokinase plasminogen activator (uPA) were entrapped into H2O2-sensitive poly(1,4-cyclohexanedimethanol-co-oxalate) (POX) microparticles (MPs), followed by polydopamine capping and RGD grafting to obtain Janus rJPox@u-HARes MPs. After RGD-mediated delivery to the thrombus site, the peroxalate ester bonds of POX are oxidized by the elevated H2O2 to produce CO2, and the MP collapse accelerates the local release of uPA and HARes NPs. The resulting CO2 bubbles amplify the cavitation effect of ultrasound to promote thrombus penetration and site-specific uPA thrombolysis. The endothelial cell targeting and sustained resveratrol release from HARes NPs dramatically improve endothelial cell viability, nitric oxide production and migration. Compared with free drug administration, the uPA loading into MPs significantly extends the half-life (15 folds) and bioavailability (7 folds), while the resveratrol inoculation into NPs increases the bioavailability 29 times. On an acute lower limb thrombosis model, the thrombus accumulation of MPs is promoted by RGD-mediated interactions with the activated platelets and ultrasound-driven penetration into thrombi, leading to almost full removal of blood clots. The H2O2-scavenging capability of POX, sustained resveratrol release and efficient thrombolysis alleviate oxidative stresses, eliminate coagulation biomarkers and repair the damaged endothelial layer to effectively inhibit thrombosis relapse. It is demonstrated that rJPox@u-HARes/US treatment could not only achieve safe and site-specific thrombolytic therapy at the early stage but also restore vascular homeostasis to effectively prevent thrombosis recurrence.

Shear Stress‐Triggered Theranostic Nanoparticles for Piezoelectric‐Fenton‐Photodynamic Thrombolysis and Endogenous Thrombus Imaging

AbstractThrombus therapy is challenged by potential bleeding risk of thrombolytic agents, and external irradiation is usually needed in thrombus imaging. Herein, highly efficient theranostic platforms are designed for piezoelectric‐Fenton‐photodynamic thrombolysis and endogenous thrombus imaging in response to the elevated shear stress at the thrombus site. Piezoelectric tetragonal barium titanate (tBT) nanoparticles (NPs) are coated with Fe3+‐coordinated metal‐organic frameworks (MOFs), followed by inoculation of chlorin e6‐luminol conjugates and heparin absorption to obtain theranostic tBT@MOFCL/Hep NPs. Shear stress‐induced piezopotential on NPs accelerates Fe3+/Fe2+ transformation to deplete MOF layers, activates Fenton reaction and produces reactive oxidative species (ROS) for non‐pharmacological thrombolysis. In the meantime, the site‐specific ROS generation oxidizes luminol and the chemiluminescent resonance energy transfer with chlorin e6 generates red fluorescence for thrombus imaging without using external light irradiation. After intravenous injection into a carotid artery thrombosis model, the heparin‐mediated thrombus targeting yields 6.5‐fold higher luminescent intensity at the thrombus site. Thrombi in the carotid arteries are almost completely dissolved with integration of piezoelectric dynamic therapy, piezopotential‐enhanced Fenton reaction, and chemiluminescence‐excited photodynamic therapy, while causing no haematologic and histopathologic abnormality. This study demonstrates a concise strategy to generate shear stress‐responsive built‐in piezoelectric potentials, site‐specific non‐pharmacological thrombolysis, self‐illuminating, and stenosis degree‐adaptable thrombus imaging.

Nattokinase Encapsulated Nanomedicine for Targeted Thrombolysis: Development, Improved in Vivo Thrombolytic Effects, and Ultrasound/Photoacoustic Imaging.

Nattokinase (NK), a potent thrombolytic enzyme that dissolves blood clots, is highly used in the treatment of cardiovascular disorders. However, its effective delivery remains demanding because of stability and bioavailability problems owing to its high molecular weight and proteineous nature. In this research, we have developed novel NK-loaded nontargeted liposomes (NK-LS) and targeted liposomes (RGD-NK-LS and AM-NK-LS) by the reverse phase evaporation method. The physiochemical characterizations (particle size, polydispersity index, zeta potential, and morphology) were performed by a Zetasizer, SEM, TEM, and AFM. The Bradford assay and XPS analysis confirmed the successful surface conjugation of the targeting ligands. Platelet interaction studies by CLSM, photon imager optima, and flow cytometry showed significantly higher (P < 0.05) platelet binding affinity of targeted liposomes. In vitro evaluations were performed using human blood and a fibrinolysis study by CLSM imaging demonstrating the potent antithrombotic efficacy of AM-NK-LS. Furthermore, bleeding and clotting time studies revealed that the targeted liposomes were free from any bleeding complications. Moreover, the in vivo FeCl3 model on Sprague-Dawley (SD) rats using a Doppler flow meter and ultrasound/photoacoustic imaging indicated the increased % thrombolysis and potent affinity of targeted liposomes toward the thrombus site. Additionally, in vitro hemocompatibility and histopathology studies demonstrated the safety and biocompatibility of the nanoformulations.

Targeting Nanomotor with Near-Infrared/Ultrasound Triggered-Transformation for Polystage-Propelled Cascade Thrombolysis and Multimodal Imaging Diagnosis.

Nowadays, cardiovascular and cerebrovascular diseases caused by venous thromboembolism become main causes of mortality around the world. The current thrombolytic strategies in clinics are confined primarily due to poor penetration of nanoplatforms, limited thrombolytic efficiency, and extremely-low imaging accuracy. Herein, a novel nanomotor (NM) is engineered by combining iron oxide/perfluorohexane (PFH)/urokinase (UK) into liposome nanovesicle, which exhibits near-infrared/ultrasound (NIR/US) triggered transformation, achieves non-invasive vein thrombolysis, and realizes multimodal imaging diagnosis altogether. Interestingly, a three-step propelled cascade thrombolytic therapy is revealed from such intelligent NM. First, the NM is effectively herded at the thrombus site under guidance of a magnetic field. Afterwards, stimulations of NIR/US propel phase transition of PFH, which intensifies penetration of the NM toward deep thrombus dependent on cavitation effect. Ultimately, UK is released from the collapsed NM and achieves pharmaceutical thrombolysis in a synergistic way. After an intravenous injection of NM invivo, the whole thrombolytic process is monitored in real-time through multimodal photoacoustic, ultrasonic, and color Doppler ultrasonic imagings. Overall, such advanced nanoplatform provides a brand-new strategy for time-critical vein thrombolytic therapy through efficient thrombolysis and multimodal imaging diagnosis.

Coronary balloon-assisted navigation of aspiration catheter for stroke thrombectomy.

In recent years, A Direct Aspiration First Pass Technique (ADAPT) has emerged as an effective and safe method of thrombectomy. Large trials have shown noninferiority of ADAPT compared to primary stent retriever approach, while new studies emphasize on its shorter procedural time with potentially fewer complications and costs.1,2. Failure of the A Direct Aspiration First Pass Technique (ADAPT) is often due to the inability to successfully navigate the aspiration catheter to the thrombus site. As a solution, several techniques have been considered such as the use of stiffer microcatheters or a wedge device.3 In Video 1, we present our technique of navigating aspiration catheters with the assistance of coronary balloons. This technique has been very successful in our experience of about 30 cases in the past 6 months. Thanks to its safety and efficacy, this technique has dramatically changed our technical management of acute ischemic stroke. It can increase the ADAPT success rate while potentially reducing procedural costs.

Design a dual-response two-photon fluorescent probe for simultaneous imaging of mitochondrial viscosity and peroxynitrite in a thrombosis model

BackgroundVenous thromboembolism is a sudden cardiovascular disease that can lead to death, and its pathologic development is closely related to vascular viscosity and inflammation. However, direct evidence from in vivo is really scarce. The key limitation is that the combined probes cannot detect multiple markers simultaneously, which may lead to unreliable results. Therefore, to develop a single probe that can simultaneously monitor the variations of viscosity in the vascular microenvironment as well as inflammation level during venous thrombosis. ResultsA dual-responsive two-photon fluorescent probe, Cou-ONOO, was designed and synthesized. Cou-ONOO provides a visualization tool for monitoring the viscosity of the vascular as well as the inflammatory marker ONOO‾ during thromboembolism via dual-channel simultaneous imaging. As a single probe that can recognize dual targets, Cou-ONOO effectively avoids the problems from unreliable results caused by complex synthesis and differences in intracellular localization, diffusion, and metabolism of different dyes as using combinatorial probes. Using Cou-ONOO, simultaneous imaging the variations of viscosity and ONOO‾at the cellular and tissue levels was successfully performed. In addition, Cou-ONOO also successfully visualized and tracked the viscosity of the vascular microenvironment and ONOO‾ during venous embolism in mice. SignificanceExperimental results show that both viscosity and inflammation are abnormally overexpressed in the microenvironment at the thrombus site during venous thrombosis. An intuitive visualization tool to elucidate the variations of viscosity as well as inflammation level in the vascular microenvironment during thrombosis was provided, which will facilitate a better clinical understanding of the pathological process of thrombosis.

Redox-responsive peptide-based complex coacervates as delivery vehicles with controlled release of proteinous drugs

Proteinous drugs are highly promising therapeutics to treat various diseases. However, they suffer from limited circulation times and severe off-target side effects. Inspired by active membraneless organelles capable of dynamic recruitment and releasing of specific proteins, here, we present the design of coacervates as therapeutic protocells, made from small metabolites (anionic molecules) and simple arginine-rich peptides (cationic motif) through liquid-liquid phase separation. These complex coacervates demonstrate that their assembly and disassembly can be regulated by redox chemistry, which helps to control the release of the therapeutic protein. A model proteinous drugs, tissue plasminogen activator (tPA), can rapidly compartmentalize inside the complex coacervates, and the coacervates formed from peptides conjugated with arginine-glycine-aspartic acid (RGD) motif (a fibrinogen-derived peptide sequence), show selective binding to the thrombus site and thus enhance on-target efficacy of tPA. Furthermore, the burst release of tPA can be controlled by the redox-induced dissolution of the coacervates. Our proof-of-principle complex coacervate system provides insights into the sequestration and release of proteinous drugs from advanced drug delivery systems and represents a step toward the construction of synthetic therapeutic protocells for biomedical applications.