Engineered Nanoplatelets for Targeted Delivery of Plasminogen Activators to Reverse Thrombus in Multiple Mouse Thrombosis Models

Abstract

Rapid cut‐off of blood supply in diseases involving thrombosis is a major cause of morbidity and mortality worldwide. However, the current thrombolysis strategies offer limited results due to the therapeutics' short half‐lives, low targeting ability, and unexpected bleeding complications. Inspired by the innate roles of platelets in hemostasis and pathological thrombus, platelet membrane‐camouflaged polymeric nanoparticles (nanoplatelets) are developed for targeting delivery of the thrombolytic drug, recombinant tissue plasminogen activator (rt‐PA), to local thrombus sites. The tailor‐designed nanoplatelets efficiently accumulate at the thrombi in pulmonary embolism and mesenteric arterial thrombosis model mice, eliciting a significantly enhanced thrombolysis activity compared to free rt‐PA. In addition, the nanoplatelets exhibit improved therapeutic efficacy over free rt‐PA in an ischemic stroke model. Analysis of in vivo coagulation indicators suggests the nanoplatelets might possess a low risk of bleeding complications. The hybrid biomimetic nanoplatelets described offer a promising solution to improve the efficacy and reduce the bleeding risk of thrombolytic therapy in a broad spectrum of thrombosis diseases.

Accelerating thrombolysis using a precision and clot-penetrating drug delivery strategy by nanoparticle-shelled microbubbles

“…Ideally, the thrombus is considered to be a cylinder, and the quantification of the volume of the clots reveals the thrombolysis efficacy. Alternatively, quantification of the thrombus area (% vein lumen) by measuring the cross-sectional areas of the clots and the veins in the histological images provides a rough estimate of the thrombosis area ( 28 ). Still, MMB-SiO 2 -tPA treatment achieved the optimal thrombolysis efficacy, resulting in the least thrombus area (approximately 13%), whereas the percentages were 66, 40, and 50% for treatments with saline, native tPA, or SiO 2 -tPA, respectively ( Fig.…”

Drug Targeting via Platelet Membrane–Coated Nanoparticles

“…[28] Alternatively, PNPs can adhere to the activated platelets in the thrombus, likely via PSGL-1 or GPIb/V/IX, which can both bind to P-selectin on the activated platelets. [44][45][46] Based on these mechanisms, platelet membrane vesicles encapsulating gold nanorods and urokinase plasminogen activator (uPA), a thrombolytic drug, were . All formulations were made with PLGA cores labeled with 1,1 0 -dioctadecyl-3,3,3 0 ,3 0 -tetramethylindodicarbocyanine (DiD) dye.…”

“…Meanwhile, PDT uses the photosensitizers to generate singlet oxygen upon laser excitation to kill cancer cells. Both therapies are considered minimum [29] Rapamycin (used as an immunosuppressant) [31] Inserted with lipid-chelated gadolinium (an MRI contrast agent) in the membrane [27] Angioplasty-induced restenosis PLGA nanoparticles Docetaxel (a cytotoxic drug) [33] Poly(amidoamine)-polyvalerolactone nanoclusters JQ1 (an endothelium-protective epigenetic inhibitor) [34] Myocardial ischemia and reperfusion injuries PLGA nanoparticles Secretome of cardiac stem cells (promote cardiac repair and regeneration) [36] Ischemic stroke Sulfur hexafluoride gas Sulfur hexafluoride gas [38] Dextran nanoparticles ZL006e (a neuroprotectant) and rtPA (a thrombolytic drug) [39] Iron oxide (γ-Fe 2 O 3 ) nanoparticles L-arginine (a precursor for biosynthesis of nitric oxide gas) [40] Pulmonary embolism Gold nanorods Urokinase plasminogen activator (a thrombolytic drug) [47] PLGA nanoparticles rtPA [44] invasive for cancer treatment. Recently, verteporfin, a photodynamic agent, was encapsulated into PLGA nanoparticles and coated with platelet membrane (denoted as "NP-Ver@P") for cancer PDT.…”

“…[ 28 ] Alternatively, PNPs can adhere to the activated platelets in the thrombus, likely via PSGL‐1 or GPIb/V/IX, which can both bind to P‐selectin on the activated platelets. [ 44–46 ] Based on these mechanisms, platelet membrane vesicles encapsulating gold nanorods and urokinase plasminogen activator (uPA), a thrombolytic drug, were developed to treat PE. [ 47 ] When intravenously injected into mice with PE, these nanoparticles accumulated at the pulmonary thrombi and released uPA.…”

“…In another study, PLGA nanoparticles were coated with platelet membranes, and the membranes were further conjugated with rtPA for targeted delivery ( Figure ). [ 44 ] In a mouse model of PE, this formulation targeted the pulmonary thrombus, induced local clot degradation, improved the survival rate of mice, and reduced the risk for bleeding complications compared with free rtPA. Notably, these nanoparticles were also tested in mouse models of mesenteric arterial thrombosis and ischemic stroke.…”