Lectin-mediated drug targeting: history and applications

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Abstract

The purpose of this paper is to review the history of using lectins to target and deliver drugs to their site of action. The hour of birth of “lectinology” may be defined as the description of the agglutinating properties of ricin, by Herrmann Stillmark in 1888, however, the modern era of lectinology began almost 100 years later in 1972 with the purification of different plant lectins by Sharon and Lis. The idea to use lectins for drug delivery came in 1988 from Woodley and Naisbett, who proposed the use of tomato lectin (TL) to target the luminal surface of the small intestine. Besides the targeting to specific cells, the lectin–sugar interaction can also been used to trigger vesicular transport into or across epithelial cells. The concept of bioadhesion via lectins may be applied not only for the GI tract but also for other biological barriers like the nasal mucosa, the lung, the buccal cavity, the eye and the blood–brain barrier.

Introduction

Lectins are proteins that recognise and bind to sugar complexes attached to proteins and lipids. They do this with very high specificity for the chemical structure of the glycan arrays. It is generally acknowledged by the lectin scientific community that “lectinology” began in 1888 when a young doctor, Hermann Stillmark, at the University of Dorpat (now Tartu in Estonia), presented a thesis describing the agglutinating properties of ricin, which had been extracted and partially purified from castor seeds [1]. It has been noted [2], however, that even earlier, in the 1860s, the agglutinating activity of certain snake venoms had been observed. The word ‘agglutinin’ was widely used to describe molecules and extracts that caused the clumping together or agglutination of erythrocytes and other cells. It was not until the 1950s that the word ‘lectin’ was coined to describe the substances from plants that recognised and distinguished the blood group substances on the basis of the different sugars expressed [3].

The modern era of lectinology might be considered to have started with the seminal paper of Sharon and Lis in 1972. Most lectins described at that time were isolated from plants and were being widely used as tools, particularly in histopathology; thanks to the high levels of specificity that lectins demonstrated for different cell types, both normal and pathological, as well as for subcellular structures. Sharon and Lis listed different lectins that had been purified and a further seven plant extracts known to agglutinate red cells and since then the number has increased dramatically [4]. In that 1972 article, a number of potential uses for lectins are mentioned, but ‘drug delivery’ is not one of them. Since 1972, a considerable number of lectins have also been identified from animal sources (for a recent review, see [2]).

Section snippets

The rationale behind lectin-mediated drug targeting

The rationale behind lectin-mediated drug targeting is very simple. Most cell surface proteins and many lipids in cell membranes are glycosylated and these glycans are binding sites for lectins. The combination of a small number of sugars can produce a vast range of different chemical structures. Different cell types express different glycan arrays and in particular, diseased cells, such as transformed or cancerous cells, often express different glycans compared with their normal counterparts.

Lectin-mediated targeting to the gastrointestinal (GI) tract: the early studies

It was just 100 years after Stillmark's thesis presentation that Woodley suggested that lectins might be used to target the GI tract. In a paper presented at the 15th Annual Conference of the Controlled Release Society in Basle in 1988, he proposed the use of tomato lectin (TL) to target and bind to the luminal surface of the small intestine, that is the lectin would demonstrate bioadhesion [6]. Bioadhesion has been defined as the attachment of a drug carrier to a specific biological location

Bioadhesion studies with lectin-conjugated micro- and nanoparticles

Lehr et al. conjugated TL to the surface of polystyrene microspheres and demonstrated that they bound to isolated enterocytes. Inhibition of binding by tetra-N-acetyl glucosamine confirmed that the lectin was responsible for the interaction, and it was also observed that mucin reduced the binding [15]. As observed by Naisbett and Woodley, the transit time of the TL-conjugated particles down the gut was not significantly different from control particles [18]. Similar results were obtained with

Lectin-mediated drug absorption enhancement

The early studies of Woodley and Naisbett had shown that TL could cross the intestinal mucosa in vitro [12]. They used an improved everted rat gut sac to demonstrate that the lectin was endocytosed by small intestine into the enterocytes and that intact lectin could be detected on the serosal side of the gut. At a saturating concentration (15 μg/ml) the uptake into the cells was some 40-fold greater than that of the control inert polymer, PVP, and transfer across the mucosa some 8-fold greater.

The reverse situation: targeting to endogenous lectins

While the majority of lectins used and studied are from plant or microbial origin, it has become clear in recent years that there exist numerous animal lectins [2]. In the gut, it was known that certain bacteria expressed glycan containing molecules in their cell walls that bound to the epithelial surfaces via lectin interactions, indicating that there were endogenous lectins exposed on epithelial cell surfaces which could be targeted by sugar bearing drug formulations [28], [29] In the 1980s,

Other lectin targeting possibilies in the GI tract: specific cell types and diseased tissues

Given the fact that different cell types, both normal and diseased, express different glycan arrays on their surfaces as well as demonstrated over the years by the use of lectins as histochemical tools; the idea of using lectins as targeting molecules for cell specific drug delivery is both attractive and feasible, and has generated considerable interest. In particular the targeting to the gut associated lymphoid tissue (GALT), manifested as the Peyer's patches, has clear possibilities for the

Lectin-mediated delivery to the nasal mucosa

While the surface area of the nasal mucosa is relatively small (150 cm2), it is highly vascularised and has a relatively permeable membrane. In addition, ease of access via the nasal cavity, the lack of first pass metabolism and rapid onset of action make it an interesting site for drug administration. The nasal cavity also contains the equivalent of the GALT in the form of the nasal-associated lymphoid tissue (NALT) covered by an epithelial layer of M-cells. Thus it is also a site of

Lectin-mediated delivery to the lungs

Compared with the nasal cavity, the lungs have a very large surface area (75 m2) and the thinness of the alveolar epithelium (0.1–0.5 μm) may facilitate rapid drug absorption. As with the nasal cavity, first pass metabolism is avoided, and the relative lack of proteolytic enzymes (compared with the gut, for example) makes the pulmonary administration of peptides and proteins an attractive proposition.

Early histological data and more recent studies revealed the binding of lectins to tissues of

Lectin-mediated drug delivery to the buccal cavity

The buccal cavity has a surface area of ∼50 cm2 with a relatively poor permeable non-keratinised epithelium. Like the nasal cavity, due to the large flow of saliva, substances in the buccal cavity have a low residence time (<5–10 min) and hence it is a prime site for the use of bioadhesive formulations, some of which are now marketed. Lectin targeting to this site is being actively investigated and is dealt with in detail in a later section of this volume (J. Smart).

Lectin-mediated ocular drug delivery

There are two major surface tissues of the eye facing the outside world, the conjunctiva and the cornea. The conjunctiva contains goblet cells secreting mucin, but there are no goblet cells on the cornea. Mucus is spread over both epithelia by the action of blinking, and bioadhesive polymers will attach to the conjunctival mucus. The turnover rate of the mucin is ∼15–20 h, whereas normal tear turnover time is 16%/min. It has been suggested that ocular drug delivery may be prolonged by

Lectin-mediated delivery at the blood–brain barrier

The endothelial cells of brain capillaries lack fenestrations, have few pinocytic vesicles and form very tight junctions, which are responsible for the formation of the blood–brain barrier (BBM), which restricts the movement of most molecules from the blood to the brain [57]. The BBM is a formidable barrier to entry of many drugs into the brain, notably anticancer drugs, and a number of different approaches have been proposed to overcome the limited access of drugs to the brain. Fischer and

Targeting the liver asialoglycoprotein receptor: drug and gene delivery

As already described for gene targeting to lung cells, genes can be targeted to their destination by conjugation to sugar moieties specific for animal or reverse lectins. The best-described example of such an animal lectin is the asialoglycoprotein receptor (ASGPr), a C-type animal lectin that is expressed on the surface of hepatocytes [60]. It plays a role in the clearance (endocytosis and lysosomal degradation) of deasialylated proteins from the serum [61], [62]. The ASGPr recognises terminal

Conclusions

From modest beginnings as potential tools for specific drug targeting and bioadhesion applications some 20 years ago, lectins are realising a number of important applications in the field, as reflected by the articles in this issue. Some of the problems associated with any macromolecular targeting system still have to be tackled, notably those of toxicity and immunogenicity. It is hoped that some of these problems might be overcome in the future by the application of biotechnology techniques to

References (79)

  • G.J Russell-Jones

    The potential use of receptor-mediated endocytosis for oral drug delivery

    Adv. Drug Deliv. Rev.

    (2001)
  • J.F Bridges et al.

    Soluble N-(2-hydroxypropyl) methacrylamide copolymers as a potential oral, controlled-release, drug delivery system. I. Bioadhesion to the rat intestine in vitro

    Int. J. Pharm.

    (1988)
  • K Ley

    The role of selectins in inflammation and disease

    Trends Mol. Med.

    (2003)
  • A Bernkop-Schnürch et al.

    An adhesive drug delivery system based on K99-fimbriae

    Eur. J. Pharm. Sci.

    (1995)
  • K Yanagihara et al.

    Lectin enhancement of the lipofection efficiency in human lung carcinoma cells

    Biochim. Biophys. Acta

    (1999)
  • M.J Evans et al.

    Transformation of alveolar type 2 cells to type 1 cells following exposure to NO2

    Exp. Mol. Pathol.

    (1975)
  • M Kasper et al.

    LR Gold and LR White embedding of lung tissue for immunoelectron microscopy

    Acta Histochem.

    (1993)
  • R Abu-Dahab et al.

    Lectin-functionalized liposomes for pulmonary drug delivery: effect of nebulization on stability and bioadhesion

    Eur. J. Pharm. Sci.

    (2001)
  • A Gebert et al.

    M cells at locations outside the gut

    Semin. Immunol.

    (1999)
  • T.J Nicholls et al.

    Lectins in ocular drug delivery: an investigation of lectin binding sites on the corneal and conjunctival surfaces

    Int. J. Pharm.

    (1996)
  • D Fischer et al.

    Histochemical characterization of primary capillary endothelial cells from porcine brains using monoclonal antibodies and fluorescein isothiocyanate-labelled lectins: implications for drug delivery

    Eur. J. Pharm. Biopharm.

    (2001)
  • J.U Baenziger et al.

    Human hepatic lectin. Physiochemical properties and specificity

    J. Biol. Chem.

    (1980)
  • P.J Julyan et al.

    Preliminary clinical study of the distribution of HPMA copolymers bearing doxorubicin and galactosamine

    J. Control. Release

    (1999)
  • C.H Wu et al.

    Targeting genes: delivery and persistent expression of a foreign gene driven by mammalian regulatory elements in vivo

    J. Biol. Chem.

    (1989)
  • G.Y Wu et al.

    Receptor-mediated in vitro gene transformation by a soluble DNA carrier system

    J. Biol. Chem.

    (1987)
  • J.M Wilson et al.

    A novel mechanism for achieving transgene persistence in vivo after somatic gene transfer into hepatocytes

    J. Biol. Chem.

    (1992)
  • G.Y Wu et al.

    Receptor-mediated gene delivery in vivo. Partial correction of genetic analbuminemia in Nagase rats

    J. Biol. Chem.

    (1991)
  • G Liu et al.

    Biological properties of poly-l-lysine-DNA complexes generated by cooperative binding of the polycation

    J. Biol. Chem.

    (2001)
  • K Shimada et al.

    Biodistribution of liposomes containing synthetic galactose-terminated diacylglyceryl-poly(ethyleneglycol)s

    Biochim. Biophys. Acta

    (1997)
  • T Hara et al.

    Receptor-mediated transfer of pSV2CAT DNA to a human hepatoblastoma cell line HepG2 using asialofetuin-labeled cationic liposomes

    Gene

    (1995)
  • H. Stillmark, R. Über, ein giftiges Ferment aus den Samen von Ricinus comm. L. und einigen anderen Euphorbiaceen...
  • W.C Boyd et al.

    Specific precipitating activity of plant agglutinins (lectins)

    Science

    (1954)
  • N Sharon et al.

    Lectins: cell-agglutinating and sugar-specific proteins

    Science

    (1972)
  • J.F Woodley et al.

    The potential of lectins for delaying the intestinal transit of drugs

    Proc. Int. Symp. Control Rel. Bioact. Mater.

    (1988)
  • M.R Jiménez-Catelanos et al.

    Mucoadhesive drug delivery systems

    Drug Dev. Ind. Pharm.

    (1993)
  • D.C Kilpatrick

    Purification and some properties of a lectin from the fruit juice of the tomato (Lycopersicon esculentum)

    Biochem. J.

    (1980)
  • N Naisbett et al.

    The potential use of tomato lectin for oral drug delivery: 3. Bioadhesion in vivo

    Int. J. Pharm.

    (1995)
  • C.M Lehr et al.

    Bioadhesion by means of specific binding of tomato lectin

    Pharm. Res.

    (1992)
  • J.M Irache et al.

    Bioadhesion of lectin–latex conjugates to rat intestinal mucosa

    Pharm. Res.

    (1996)

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