Urokinase-Conjugated Magnetite Nanoparticles as a Promising Drug Delivery System for Targeted Thrombolysis: Synthesis and Preclinical Evaluation.

Mortality and disabilities as outcomes of cardiovascular diseases are primarily related to blood clotting. Optimization of thrombolytic drugs is aimed at the prevention of side effects (in particular, bleeding) associated with a disbalance between coagulation and anticoagulation caused by systemically administered agents. Minimally invasive and efficient approaches to deliver the thrombolytic agent to the site of clot formation are needed. Herein, we report a novel nanocomposite prepared by heparin-mediated cross-linking of urokinase with magnetite nanoparticles (MNPs@uPA). We showed that heparin within the composition evoked no inhibitory effects on urokinase activity. Importantly, the magneto-control further increased the thrombolytic efficacy of the composition. Using our nanocomposition, we demonstrated efficient lysis of experimental clots in vitro and in animal vessels followed by complete restoration of blood flow. No sustained toxicity or hemorrhagic complications were registered in rats and rabbits after single bolus i.v. injection of therapeutic doses of MNPs@uPA. We conclude that MNPs@uPA is a prototype of easy-to-prepare, inexpensive, biocompatible, and noninvasive thrombolytic nanomedicines potentially useful in the treatment of blood clotting.

Author Correction: Dispersion of TiO2 nanoparticles improves burn wound healing and tissue regeneration through specific interaction with blood serum proteins.

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Dispersion of TiO2 nanoparticles improves burn wound healing and tissue regeneration through specific interaction with blood serum proteins.

Burn wounds are one of the most important causes of mortality and especially morbidity around the world. Burn wound healing and skin tissue regeneration remain thus one of the most important challenges facing the mankind. In the present study we have addressed this challenge, applying a solution-stabilized dispersion TiO2 nanoparticles, hypothesizing that their ability to adsorb proteins will render them a strong capacity in inducing body fluid coagulation and create a protective hybrid material coating. The in vitro study of interaction between human blood and titania resulted at enhanced TiO2 concentrations in formation of rather dense gel composite materials and even at lower content revealed specific adsorption pattern initiating the cascade response, promising to facilitate the regrowth of the skin. The subsequent in vivo study of the healing of burn wounds in rats demonstrated formation of a strongly adherent crust of a nanocomposite, preventing infection and inflammation with quicker reduction of wound area compared to untreated control. The most important result in applying the TiO2 dispersion was the apparently improved regeneration of damaged tissues with appreciable decrease in scar formation and skin color anomalies.

Leach-proof magnetic thrombolytic nanoparticles and coatings of enhanced activity.

Despite the fact that magnetic thrombolytic composites is an emerging area, all known so far systems are based on the similar mechanism of action: thrombolytic enzyme releases from the magnetic carrier leaving non-active matrix, thus making the whole system active only for a limited period of time. Such systems often have very complex structure organization and composition, consisting of materials not approved for parenteral injection, making them poor candidates for real clinical trials and implementation. Here we report, for the first time, the production of thrombolytic magnetic composite material with non-releasing behavior and prolonged action. Obtained composite shows good thrombolytic activity, consists of fully biocompatible materials and could be applied as infinitely active thrombolytic coatings or magnetically-targetable thrombolytic agents.

Streptokinase@alumina nanoparticles as a promising thrombolytic colloid with prolonged action.

The present study is devoted to the development of a new class of thrombolytic systems - nanocolloids. A non-direct plasminogen activator, streptokinase, was entrapped in a sol-gel matrix based on boehmite nanoparticles used in medical practice as the most common vaccine adjuvant. It is shown that when the enzyme content in the composite is less than 10%, only minor release is observed, while thrombolytic properties are maintained at a relatively high level, demonstrating the prolonged effect. Based on the obtained composites, thrombolytic nanocolloids containing nanoparticles of less than 500 nm size and suitable for parenteral administration were produced. The thrombolytic properties were studied using the plasminogen activation tests, human plasma clots and a model thrombus made from a whole human blood. Based on the obtained results, the structure of the composites and the mechanism of their action are suggested.

Synthesis of Thrombolytic Sol-Gel Coatings: Toward Drug-Entrapped Vascular Grafts.

As is evident from numerous investigations, drug-eluting vascular grafts and stents have not solved the main problems associated with thrombosis and due to drug release only postpone their advance for a longer period. Here we point to a potential solution of this problem by developing thrombolytic sol-gel coatings which potentially could lead to drug-entrapped vascular grafts: urokinase-type plasminogen activator was entrapped within a porous alumina sol-gel film with a subsequent deposition on a polymer graft.