Studies on Tissue Plasminogen Activator: Efficiency of Thrombolysis in the Presence of Iodinated Contrast Media and Development of a Novel Targeted t-PA Delivery System

Abstract

In Western world the obstruction of critical blood vessels due to thrombosis is the leading cause of death: acute ischemic stroke, deep vein thrombosis (DVT), pulmonary embolism (PE), and acute ischemic stroke (AIS) are the major causes of cardiovascular mortality, which results in over 1 million deaths each year in the US. Thrombosis is responsible for most of the pathophysiology of these diseases. Thrombolytic drug therapy can reduce mortality, and this therapeutic approach has been widely used in thrombosis treatment. Although a number of thrombolytic drugs are currently available, tissue plasminogen activator (t-PA) is currently the only US Food and Drug Administration-approved therapy for lysis of fibrin clot in treating ischemic stroke. t-PA is a serine protease that converts the zymogen plasminogen to plasmin, which initiates the process of lysis of the fibrin clot (fibrinolysis). As t-PA has a very short life in plasma (half-life ≈5 minutes), it needs to be administered at a high dose for a prolonged period of time in order to maintain an effective drug level during thrombolytic drug therapy, which leads to degradation of clotting factors and hemorrhage. It will therefore be highly desirable to deliver t-PA under guidance for targeted thrombolysis, which will allow t-PA to be localized to the target site and reduce its hemorrhagic side effects. The major treatment strategy for DVT, PE, heart attack, and AIS is pharmacological reperfusion using intravenous t-PA. In some cases, multimodal computed tomography (CT) is performed prior to t-PA administration. While this multimodal approach provides greater information than non-contrast CT alone, radiographic contrast agents may interfere with thrombolytic therapy. The relationship between the dosage of iodinated contrast media and the efficiency of the fibrinolysis via rt-PAis poorly understood in patients receiving intravenous tissue-type plasminogen activator. Thus, in this study, we compare the effect of five different contrast media such as Xenetix® (iobitridol), Ultravist® (iopromide), Omnipaque® (iohexol), Visipaque® (iodixanol) and Iomeron® (iomeprol) on fibrinolysis via t-PA. Magnetic nanoparticles (MNPs) offer several advantages when used as a drug carrier, including the large surface area, which can be properly modified to attach with drug molecules. Ensuring biocompatibility and non-toxicity, iron oxide based particles (magnetite) with superparamagnetic characteristics are commonly used as the magnetically responsive component, which can be manipulated by an external magnetic field gradient. Based on these properties, the superparamagnetic nanoparticles could be transported through the vascular system, concentrated in a specific part of the body with the aid of a magnetic field, and used as a carrier for t-PA delivery. For drug delivery applications, iron oxide MNP must be pre-coated with substances that assure their stability, biodegradability, and non-toxicity in the physiological medium to achieve combined properties of high magnetic saturation, biocompatibility and interactive functions on the surface. In this study, t-PA immobilized on the surface of bovine serum albumin (BSA) coated superparamagnetic nanoparticles. This thrombolytic nano-agent (t-PA–NCs) has demonstrated three orders of magnitude higher dissolution efficiency as compared to free t-PA and is capable of recanalizing occluded vessels in animal models with sever thrombosis. Also, their favorable toxicity profiles make t-PA–NCs a promising platform for the application of nanomedicine in thrombolytic diseases.