Thrombolytic therapy based on fucoidan-functionalized polymer nanoparticles targeting P-selectin

Abstract

Injection of recombinant tissue plasminogen activator (rt-PA) is the standard drug treatment for thrombolysis. However, rt-PA shows risk of hemorrhages and limited efficiency even at high doses. Polysaccharide-poly(isobutylcyanoacrylate) nanoparticles functionalized with fucoidan and loaded with rt-PA were designed to accumulate on the thrombus. Fucoidan has a nanomolar affinity for the P-selectin expressed by activated platelets in the thrombus. Solid spherical fluorescent nanoparticles with a hydrodynamic diameter of 136 ± 4 nm were synthesized by redox radical emulsion polymerization. The clinical rt-PA formulation was successfully loaded by adsorption on aminated nanoparticles and able to be released in vitro. We validated the in vitro fibrinolytic activity and binding under flow to both recombinant P-selectin and activated platelet aggregates. The thrombolysis efficiency was demonstrated in a mouse model of venous thrombosis by monitoring the platelet density with intravital microscopy. This study supports the hypothesis that fucoidan-nanoparticles improve the rt-PA efficiency. This work establishes the proof-of-concept of fucoidan-based carriers for targeted thrombolysis.

Erythrocyte-Inspired Discoidal Polymeric Nanoconstructs Carrying Tissue Plasminogen Activator for the Enhanced Lysis of Blood Clots

“…17 Recently, the group of Letourneur demonstrated that fucoidan-labeled polymeric nanoparticles exhibit a strong tropism for the clot fibrin network and facilitate vessel recanalization. 18 Non-organic nanoparticles have also been used for thrombolysis. Clusters of iron oxide nanocubes, coated and stabilized by a tPA multi-layer, were proposed by the authors for the combined chemical and thermal treatment of blood clots upon stimulation with exogenous alternating magnetic fields.…”

Advanced Functional Materials and Cell‐Based Therapies for the Treatment of Ischemic Stroke and Postischemic Stroke Effects

“…Aiming at reducing the side‐effects of tPA, polymeric nanoparticles (poly(isobutyl cyanoacrylate)) were used for its delivery to the thrombus. In this study it was shown that these nanoparticles after their functionalization with a P‐selectin molecule (fucoidan), enhanced thrombolysis. However, no data concerning ischemia were presented.…”

Peptide-biofunctionalization of biomaterials for osteochondral tissue regeneration in early stage osteoarthritis: challenges and opportunities

“…CAMs are grouped into several families, namely, immunoglobulins, cadherins, integrins, selectins and ECM proteins (Table 1). 38,39,48,[40][41][42][43][44][45][46][47] These proteins can mediate cell adhesion by heterophilic (between cells of a different type) and homophilic (between cells of a single type) interactions. CAMs have specific affinities for cell surface glycoproteins, helping the specific location of cells within the tissues and transport of biochemical information to coordinate homeostasis including signal transduction, cellular communication, and recognition.…”

“…84 Juenet et al produced polymer nanoparticles using the polysaccharide fucoidan (Fuco-NPs) to target P-selectin. 42 These nanostructures showed enhanced thrombolytic efficiency with overexpression of P-selectin.…”