Non-Enzymatic Remodeling of Fibrin Biopolymers via Photothermally Triggered Radical-Generating Nanoparticles

Abstract

Thrombosis is a hallmark of several chronic diseases leading to potentially fatal heart attacks and strokes. Frontline interventions include intravenous delivery of potent, enzymatic fibrinolytics that possess a high risk for inducing systemic bleeding. As a conceptual countermeasure, we have developed a water-soluble PEGylated gold nanoparticle appended with the enediyne diamine (Z)-octa-4-en-2,6-diyne-1,8-diamine that is capable of photothermally generating 1,4-diradical species under visible excitation (λ = 514 nm, 100 mW, 2−6 h). In the absence of biopolymer substrate, photothermal excitation of these particles leads to self-quenching polymer coating formation in water. When these radical-generating nanoparticles are intrinsically applied toward the blood clot structural protein assembly fibrin, as well as its nonpolymerized precursor protein fibrinogen, scanning electron microscopy images reveal significantly modified fibrin clot morphology, as evidenced by larger void spaces and collapsed fiber regions. Quantitatively, laser confocal microscopy images of Alexa Fluor 488-labeled fibrin clots extrinsically treated with nanoparticles at the clot/solution interface show that photothermal radical formation by these particles leads to marked increase in the number of larger pore sizes (>2.0 μm) within the fibrin matrix, which derive from a corresponding decrease in the histogram of smaller pore sizes (1.5−2.0 μm). These larger pore sizes ultimately result in total perfusion of solution through the entire clot volume. The chemical manifestation of this is that radical-induced modifications occur mainly at the protein level but lead to morphological changes at the micron scale. Overall, this technology could have significant impact for disease states such as deep vein thrombosis via a localized, catheter-delivered approach.

Metal–Organic‐Framework‐Derived Carbon Nanostructures for Site‐Specific Dual‐Modality Photothermal/Photodynamic Thrombus Therapy

“…Currently, reactive oxygen species (ROS)‐mediated photodynamic therapy (PDT) has been explored for peptide damages of fibrin biopolymers, e.g., polypeptide linkages, noncovalent interactions, and N‐attached biantennary glycan region, under the assistance of photosensitizers (PSs) . Therefore, PDT might break the fibrin skeleton of blood clots and prevent secondary embolism from post‐photothermal fragments.…”

Shear-, Sound-, and Light-Sensitive Nanoparticles for Thrombolytic Drug Delivery

“…Walker and Zaleski have developed a water-soluble PEGylated gold nanoparticle appended with the enediyne diamine (Z)-octa-4-en-2,6-diyne-1,8-diamine, which could generate 1,4-diradical species (a nonenzymatic thrombolytic agent) under visible excitation (514 nm). 37 Recently, for realizing on-demand thrombolytic agent release, our research group presented a near-infrared-triggered and noninvasive drug delivery system based on gold@mesoporous silica core-shell nanospheres with phase-changed materials 1-tetradecanol for releasing urokinase. 38 Hyperthermia induced by the photothermal effect of gold nanoparticles via near infrared laser (808 nm) not only triggered the release of urokinase but also enhanced a localized thrombolysis.…”

Au-Cu@PANI Alloy Core Shells for Aerobic Fibrin Degradation under Visible Light Exposure

“…Fibrin also induces neuroinflammation by activating microglia and promoting the recruitment and activation of peripheral inflammatory macrophages into the central nervous system. Moreover, glycation of fibrinogen and its effect on fibrin clots has been found to contribute to the onset of diabetes and obesity. − …”

“…The third antithrombotic approach involves activating the body’s natural fibrinolytic system via the intravenous delivery of plasminogen as a precursor to plasmin. − Plasmin is a serine protease that cleaves peptidic bonds in fibrin (Lys-X and Arg-X) causing dissolution of the fiber structure . Although plasmin is a very effective enzyme for fibrinolysis, its administration is risky due to the inability to distinguish between harmful and beneficial clotting events that can result in uncontrollable hemorrhaging . Thus, there is a significant need for clot dissolution approaches that do not rely on biologics such as plasminogen.…”

“…21 Although plasmin is a very effective enzyme for fibrinolysis, its administration is risky due to the inability to distinguish between harmful and beneficial clotting events that can result in uncontrollable hemorrhaging. 12 Thus, there is a significant need for clot dissolution approaches that do not rely on biologics such as plasminogen.…”