ReviewE-selectin as a target for drug delivery and molecular imaging
Graphical abstract
Introduction
The selectin family is represented by three receptors composed of calcium-dependent type I transmembrane glycoproteins with an extracellular lectin-like domain. They are classified by their site of expression into E-selectin (activated endothelium [1], [2]), P-selectin (platelets [3], [4] and endothelial cells [5], [6]), and L-selectin (lymphocytes [7]). Selectins allow adhesion between leukocytes and platelets in contact with the vascular endothelium during inflammation or tissue damage [8]. At a molecular level they are able to recognize sialylated, fucosylated and sulfated glycans found on glycoproteins, glycolipids or proteoglycans [9] to mediate the initial attachment or “tethering” of free-flowing leukocytes to the vessel wall through reversible adhesion that permits the cells to roll in the direction of flow [10], [11]. The physiological expression of selectins is strictly controlled in order to limit inflammatory reactions, and is modified in inflammation and cancer metastasis to allow adherence of leukocytes or cancer cells, respectively, on endothelial cells.
Advances in molecular and cellular biology have elucidated the role played by each of these receptors in a range of pathological disorders involving aberrant trafficking of immune cells. P-selectin is involved in inflammatory disorders such as acute lung injury [12], psoriasis [13], and rheumatoid arthritis [14]. It plays a role in hemostasis [15], [16] and hematogenous spread of tumor cells [17], [18]. For detailed information about the pathological roles and therapeutic targeting of P-selectin, the reader is directed to the review published by Ludwig and co-workers [19]. It is also well documented today that E-selectin is deeply implicated in many disorders including inflammatory diseases, cardiovascular disorders, cancer and metastasis. On the other hand, there is little evidence for the direct involvement of L-selectin in pathology, although some studies have reported variations in levels of the receptor and/or its soluble form (sL-selectin) in serum in some patients with HIV-infection [20], insulin-dependent diabetes mellites [21], meningeal leukemia [22], multiple sclerosis [23] and sepsis [20]. However, its soluble form, sL-selectin, was found to be decreased in patients with Kawasaki Syndrome and in patients with risk factors for acute ischemic stroke even in the absence of disease [24].
In the light of these observations, interest in this family of receptors has been growing during the last 2 decades; in particular in the possibility of using them as a pharmacological target for the treatment of the diseases mentioned above. In fact, different selectin-based therapeutic strategies have been proposed, including the inhibition of their expression in pathological situations, targeting their ligands, or using them as molecular targets for delivery of therapeutic and diagnostic agents.
In this present review, a summary of physiological and pathological roles of E-selectin will be given, followed by a detailed presentation of systems which have been proposed to target it in inflammation, cancer, cardiovascular disorders, for drug delivery, gene transfer and medical molecular imaging. A general discussion summarizes the key points in the development of such systems.
Section snippets
Physiology of E-selectin
E-selectin (64 kDa) also known as CD62E, ELAM-1 and LECAM-2, is expressed specifically by endothelial cells. Relative molecular weight values of 100 and 115 kDa have been detected for different glycosylated forms [25]. The primary structure of E-selectin contains several domains: an amino terminal lectin-like domain, followed by an epidermal growth factor (EGF)-like domain and six repeated motifs (about 60 amino acids each) similar to those found in some complement-binding proteins [2]. The
E-selectin as a target
As a result of this demonstrated expression of E-selectin in the vicinity of inflammation, infection or cancer, it has become a natural target for therapeutic intervention. Different strategies to exploit and modulate E-selectin-mediated binding include blocking its interaction with its ligands, blocking its ligands and inhibiting the glycosyl transferases associated with biosynthesis of selectin carbohydrate binding determinants [51]. These strategies could inhibit immune and cancer cell
Discussion
Targeting therapeutic agents by means of specific molecular recognition is a very promising strategy for the treatment of complex diseases such as cancer, inflammation, autoimmune disorders, and neuropathologies. These systems could be expected to be more effective and to reduce side effects as well as allowing more accurate and earlier diagnosis by the development of more specific imaging agents.
The body of work described above shows how E-selectin has become one of the molecular targets for
Conclusion
Although many clinical trials have been carried out in the field of medical imaging, targeted systems for drug delivery to E-selectin are still mostly at the level of laboratory research with animal models and the in vivo toxicity data is still scarce. At the same time, new high-affinity ligands have been developed over the last few years and these could be interesting tools for targeting strategies. Much work is now needed to screen these ligands to confirm their specificity before clinical
References (151)
- et al.
A platelet membrane protein expressed during platelet activation and secretion. Studies using a monoclonal antibody specific for thrombin-activated platelets
J. Biol. Chem.
(1984) - et al.
PADGEM (GMP140) is a component of Weibel–Palade bodies of human endothelial cells
Blood
(1989) - et al.
Selectins — potential pharmacological targets?
Drug Discov. Today
(2006) - et al.
Leukocytes roll on a selectin at physiologic flow rates: distinction from and prerequisite for adhesion through integrins
Cell
(1991) - et al.
Leukocyte rolling and extravasation are severely compromised in P selectin-deficient mice
Cell
(1993) - et al.
Defects in hemostasis in P-selectin-deficient mice
Blood
(1996) - et al.
ELISA for quantitation of L-selectin shed from leukocytes in vivo
J. Immunol. Methods
(1992) - et al.
Cleaved L-selectin concentrations in meningeal leukaemia
Lancet
(1995) - et al.
Clustering endothelial E-selectin in clathrin-coated pits and lipid rafts enhances leukocyte adhesion under flow
Blood
(2008) - et al.
The P-selectin glycoprotein ligand from human neutrophils displays sialylated, fucosylated, O-linked poly-N-acetyllactosamine
J. Biol. Chem.
(1994)