111In-1,4,7,10-Tetraazacyclododecane-1,4,7,10-tetraacetic acid-Ac-RWQPCPAESWT-Cha-CWDPGGGK-NH2 (FibPep)

Excerpt

Extracellular matrix adhesion molecules consist of a complex network of fibronectins, collagens, chondroitins, laminins, glycoproteins, heparin sulfate, tenascins, and proteoglycans that surround connective tissue cells, and they are mainly secreted by fibroblasts, chondroblasts, and osteoblasts (1). Cell substrate adhesion molecules are considered essential regulators of cell migration, differentiation, and tissue integrity and remodeling. These molecules play a role in inflammation and atherogenesis, but they also participate in the process of invasion and metastasis of malignant cells in the host tissue (2). A meshwork of clotted plasma protein is present in the tumor stroma but not in normal tissues, providing a functional matrix for angiogenesis, cell migration, and tumor cell invasion (3). There are high levels of collagens, fibronectin, and fibrin in the tumor connective tissues.

Thrombosis plays a major role in many cardiovascular diseases such as myocardial infarction, pulmonary embolism, deep venous thrombosis, and cerebral venous thrombosis (4). Thrombosis occurs by an activation process of thrombin (F2 coagulation factor II), which then converts fibrinogen into fibrin. Thrombin initiates the cross-linking of the polymerized fibrin via the activation of a transglutamase enzyme called coagulation factor XIII (FXIIIa indicates activated factor XIII) (5). Atherosclerotic lesions often contain microthrombi and fibrin on their surface (6). Fibrin is associated with a variety of malignant tumors (7). Fibrin is essential for stroma formation in the tumor with deposition of fibrin, which leads to tumor angiogenesis and metastasis. The cyclic fibrin-binding peptide Ac-RWQPCPAESWT-Cha-CWDPGGGK-NH₂ (FibPep), containing the fibrin-binding motif RWQPCPAESWT-Cha-CWDP (previously identified via phage-display screening) was radiolabeled with ¹¹¹In via 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA) conjugation to the N-terminal Lys (¹¹¹In-DOTA-FibPep) for use with single-photon emission computed tomography (SPECT) imaging of fibrin (8).