Review
E-selectin as a target for drug delivery and molecular imaging

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Abstract

E-selectin, also known as CD62E, is a cell adhesion molecule expressed on endothelial cells activated by cytokines. Like other selectins, it plays an important part in inflammation and in the adhesion of metastatic cancer cells to the endothelium. E-selectin recognizes and binds to sialylated carbohydrates present on the surface proteins of certain leukocytes.

E-selectin has been chosen as a target for several therapeutic and medical imaging applications, based on its expression in the vicinity of inflammation, infection or cancer. These systems for drug delivery and molecular imaging include immunoconjugates, liposomes, nanoparticles, and microparticles prepared from a wide range of starting materials including lipids, synthetic polymers, polypeptides and organo-metallic structures.

After a brief introduction presenting the selectin family and their implication in physiology and pathology, this review focuses on the formulation of these new delivery systems targeting E-selectin at a molecular level.

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

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