Journal of Biomaterials and Nanobiotechnology, 2011, 2, 614-621
doi:10.4236/jbnb.2011.225073 Published Online December 2011 (
Copyright © 2011 SciRes. JBNB
Drug Delivery: Plant Lectins as Bioadhesive Drug
Delivery Systems
Marija Gavrovic-Jankulovic, Radivoje Prodanovic
Department of Biochemistry, Faculty of Chemistry, University of Belgrade, Belgarde, Serbia.
Received September 17th, 2011; revised October 9th, 2011; accepted November 11th, 2011.
Selective targeting of drugs to the proposed site of action provides therapeutic advantages such as reduced toxicity and
smaller dose levels. Despite a huge progress made in drug design and delivery systems, many challen g es still ha ve to b e
solved. Small therapeutic drugs always have the potential to pass into the kidneys and be excreted from the body. The
use of macromolecular constructs (carriers) that allow longer circulation times, contribute to improved chemical func-
tionality and more precise drug delivery is an attractive alternative option. Bioadhesive systems which will utilize in-
tense contact to increase the drug concentration gradient could be an attractive approach. Because of their specific
carbohydrate-binding, lectins can in teract with g lycoco n jugates presen t o n the ep ith elial cells th a t line all o f th e organs
exposed to the external environm ent. The unique carboh ydrate specificitie s of plant lectins can facilitate mucoadh esion
and cytoadhesion of drugs. As immunostimulatory molecules with an adjuvant effect plant lectins can also be employed
in vaccine development.
Keywords: Drug Delivery, Epithelium, Plant Lectin, Polymers, Vaccine
1. Introduction
The traditional routes of drug administration are nasal,
oral, subcutaneous, intramuscular, intravenous, topical,
ophthalmic and rectal. A wide variety of polymeric bio-
materials are compounds of various formulations and
devices which are routinely used for delivering drug to
the body. However, these medication delivery systems
may not always achieve optimal drug concentration at
the appropriate site, nor do they necessarily minimize
local or systemic toxicity [1]. Therefore, there has been
enormous interest in developing controlled-release for-
mulations and devices that can maintain a desired blood
plasma level of the drug for longer periods of time with-
out reaching a toxic level or dropping below the mini-
mum effective level [2].
This paper will give an overview of the systems that
have been used for drug delivery via mucosal surfaces
and will showcase recent employment of plant-derived
lectins in creation of drug delivery vehicles, but also their
immunomodulatory p ot ential.
2. Mucoadhesive Polymer Drug Delivery
Mucoadhesive drug delivery systems are vehicles which
utilize the property of bioadhesion of certain polymers
that become adhesive on hydration [3] and can be used
for targeting a drug to the particular region of the body
for an extended period of time [4]. In the case of a
polymer attached to the mucin layer of a mucosal tissue
the term “mucoadhesion” is employed [5].
The polymeric properties which are relevant for high
retention via mucoadhesive interactions at particular
targeted sites include hydrophobicity, negative charge
potential and the presence of hydrogen bond forming
groups [6]. In add ition, the polymer should p ossess suffi-
cient flexibility to penetrate the mucus network and be
biocompatible, non-toxic and economically favorable [7].
According to Park and Robinson, [8] polymers com-
monly employed in the manufacturing of mucoadhesive
drug delivery platforms that adhere to mucinepithelial
surfaces are categorized as follows:
Polymers that are bioadhesive due to their stickiness,
Polymers that adhere through nonspecific, noncovalent,
primarily electrostatic interactions,
Polymers that bind to a specific receptor on the cell
2.1. First-Generation Mucoadhesive Polymers
According to the net overall charge, mucoadhesive poly-
Drug Delivery: Plant Lec ti ns a s B ioad hesi ve Drug Delivery Syste ms615
mers have been divided into three categories: anionic
polymers, cationic polymers, and non-ionic polymers,
with the first two groups exhibiting the highest mucoad-
hesive strength [9]. Due to their high mucoadhesive po-
tential and low toxicity anionic polymers are the most
widely employed mucoadhesive vehicles in pharmaceu-
tical formulations. Anionic polymers contain carboxyl
and sulphate functional groups that give rise to a net
overall negative charge. Examples include poly-acrylic
acid (PAA), its weakly cross-linked derivatives and so-
dium carboxymethylcellulose (NaCMC). Both polymers
possess excellent mucoadhesive characteristics because
of the formation of hydrogen bonding interactions with
mucin from porcine stomach [10].
Due to its good biocompatibility, biodegradability and
favorable toxicological properties [11] chitosan is among
the most extensively investigated cationic polysaccha-
rides, produced by the deacetylation of chitin [12]. Chi-
tosan binds to mucin via ionic interactions between pri-
mary amino functional groups and sialic and sulphonic
acid of mucins [13,14]. The hydroxyl and amino groups
may also interact with mucus via hydrogen bonding.
The major benefit of using chitosan within pharma-
ceutical applications has been its chemical reactivity and
the easiness of addition of various chemical groups, in
particular to the C-2 position, allowing the formation of
novel polymers with improved functionality. Using such
modifications, the properties of chitosan may be tailored
to the requirements of specific pharmaceutical-techno-
logical challenges [15].
2.2. Second-Generation Mucoadhesives
The major disadvantage in using traditional, non-specific
mucoadhesive systems is that adhesion may occur at sites
different than those intended, i.e. delivery of the drug
may occur nonspecifically to any region of the 10-meter
long gastrointestinal tract. Unlike first-generation non-
specific polymers, certain second-generation polymers
are less susceptible to mucus turnover rates, with a po-
tential to bind directly to mucosal surfaces via the proc-
ess of “cytoadhesion”. Taking into consideration differ-
ent surface topogr aphy of poten tial target sites, this could
be an advantage for the creation of more accurate drug
delivery ve hi cles.
3. Mucus Structure
In order to improve bioadhesive properties of drug deliv-
ery vehicles it is necessary to reveal structural features of
epithelial surfaces for which the drug is targeted to. Mu-
cus is a complex viscous secretion synthesized by spe-
cialized goblet cells in the columnar epithelium that lines
all of the organs exposed to the external environment.
This includes the respiratory tract, the gastrointestinal
tract, the reproductive tract, and the oculo-rhino-oto-
laryngeal tract [16]. Its physiological functions at these
locations include maintaining a hydrated layer over the
epithelium, shielding the epithelial surfaces against phy-
sical and chemical damage, posing a barrier to pathogens
and nontoxic substances and acting as a permeable gel
layer for the exchange of gases and nutrients with the
underlying epithelium [17,18]. Mucus is the first barrier
with which nutrients and enteric drugs must interact and
pass through, in order to be absorbed and to reach the
circulatory system and respective target organs. The
mucus blanket is highly hydrated (95% water), with the
main component of this extracellular epithelial layer re-
sponsible for its viscosity and gel-like properties being
the glycoprotein mucin.
Mucins are large (0.5 to 20 MDa) membrane bound
and extracellular glycoproteins. They are highly glycol-
sylated and consist of about 80% of carbohydrates, pri-
marily N-acetyl-D-galactosamine, N-acetyl-D-glucosa-
mine, fucose, galactose, and sialic acid (N-acetylneura-
minic acid), with traces of mannose and sulfate.
The oligosaccharide chains, consisting of 5 - 15 mono-
mers, exhibit moderate branching and are attached to the
protein core by O-glycoside bonds via the hydroxyl side
chains of serine and threonine and arranged in a “bottle
brush” configuration around the protein core. NMR
studies of MUC1 secondary structure revealed very little
alpha helixes, a small amount of beta sheets and mostly
random coil [19,20]. Currently, approximately 19 human
mucin (designated MUC) genes have been identified,
cloned and partially sequenced, and homologs of many
of these have been identified in mice and rats [21].
The well-know tendency of other substances to adhere
to mucin, known as mucoadhesivity, is not surprising
given that this glycoprotein exhibits electrostatic, hydro-
phobic, and hydrogen bonding interactions [22]. Mucus
covers all the organs that are exposed to the external en-
vironment and therefore those locations are targets for
bioadhesi ve dr ug deli ve ry vehicles.
4. Mucosal Membrane Delivery
4.1. Intranasal Delivery
Intranasal formulation is regarded as a patient-friendly
route of drug administration. In terms of pharmacokinet-
ics, the absorption rate is rapid and followed by a faster
onset of action compared with oral and intramuscular
administration. Due to the high total area which is sur-
rounded by a dense vascular network the nasal mucosa is
regarded as an excellent absorptive surface [23]. In addi-
tion, the advantage of this route lies in the fact that the
hepatic first-pass metabolism is avoided, compared to
oral drug administration, in which a clinically significant
Copyright © 2011 SciRes. JBNB
Drug Delivery: Plant Lectins as Bioadhesive Drug Deliv ery Systems
portion of the drug taken is degraded during first-pass
metabolism, requiring a higher oral dose for the given
effect. Intranasal drugs can be delivered in a variety of
formulations that include powders, drops, topical gels,
and sprays.
The most commonly employed intranasal pharmaceu-
ticals are solutions of sympathomimetic vasoconstrictors
as nasal decongestants. Apart from local effects, the in-
tranasal route of drug administration is often employed
for induction of systemic effects [24]. For example, the
synthetic hormone desmopressin exerts its action on the
kidneys by reducing urine production. It is formulated for
intranasal application, frequently prescribed for treatment
of Diabetes insipidus.
Another systemic effect achieved by intranasal drug
administration is used in the treatment of patients with
vitamin B12 deficiency. After normalization with intra-
muscular vitamin B12 therapy, maintenance of vitamin
B12 concentration is achievable with CaloMist (cyano-
cobalamin) nasal spray that is used on a daily base [25].
4.2. Gastrointestinal Tract Delivery
Despite the tremendous advances in drug delivery the
oral route still remains the preferred route for the ad-
ministration of therapeu tic agen ts due to low cost, ease of
administration and high levels of patient compliance
However, the delivery of therapeutic agents to, or via
the oral cavity is limited by the efficient removal mecha-
nisms that exist in this area. The oral cavity is employed
as a site for local and systemic drug delivery [27]. He-
patic first pass metabolism and drug degradation within
the gastrointestinal tract are additional obstacles in the
oral administration of certain classes of drugs, such as
peptides and proteins.
It is generally believed that mucoadhesive drug deliv-
ery systems have not reached their full potential within
oral drug delivery, since their lack of sufficient adhesion
onto the GI tract does not provide prolonged residence
time [28]. Targeted drug delivery systems have mainly
been focused on mucoadhesive patches and microparti-
cles using first-generation polymers [29]. The problem
with mucoadhesive solid formula tions, such as tablets, is
their poor adherence to mucosal surfaces, combined with
their vigorous movement to the GI tract [6]. However,
second-generation vehicles have attracted more attention
to drug delivery via the GI tract. In an animal model, a
thiolated chitosan tablet has been employed for the oral
delivery of insulin in rats [30]. In non-diabetic rats a
more decreased glucose level was achieved with thio-
lated chitosan insulin tablets than with unmodified poly-
mer insulin tablets. The explanation for this was that
chitosan and the thiol group s showed an inhib itory effect
on proteolytic enzymes, together with the penetration
enhancing effect of the polymer system, and its improved
mucoadhesi ve potential.
4.3. Ocular Drug Delivery
The delivery of aqueous ophthalmic drug solutions shows
limitations due to the efficient removal mechanisms that
exist within the precorneal area. Ocular drug absorption
requires good corneal penetration, along with a pro-
longed contact ti me with the corneal tissue [31]. Various
approaches have been considered to extend the residen ce
time of topically applied medications in the precorneal
region and various formulations such as suspensions,
inserts, and aqueous gels have been investigated [32]. It
is estimated that almost 95% of medication delivered by
eye drops is lost as the medication mixes with tears and
drains into the nasal canal [33]. The first report on the
use of soft contact lenses in drug deliv er y was reported in
1965 for effective treatment of ocular conditions [34]. A
drug delivery smart lens has been an ticipated to be useful
in the control of infection during wound healing follow-
ing trauma and surgery. Several research groups have
been working on strategies for smart lenses that will
release medications more evenly over extended periods
[35]. One approach in the smart lens technology is based
on the suspension of the pharmaceutical in a layer of
biodegradable polymer (poly-lactic-co-glycolic acid,
PLGA). The relative amount of PLGA to the pharma-
ceutical will regulate the amount that passes through the
lens over time. The more PLGA, the slower the drug is
released. In lab tests, these multilayer lenses demon-
strated ability to release ciprofloxacin for up to 100 days
4.4. Buccal Drug Delivery
The buccal cavity is an attractive target for drug delivery
formulations as it is easily accessible. Delivery systems
used include mouthwashes, aerosol sprays, chewing
gums, bioadhesive tablets, gels and patches [37]. The
obstacles associated with drug therapy within the oral
cavity are the rapid elimination of drugs due to the
flushing effect of saliva, the non-uniform distribution of
drug release from a solid or semisolid delivery system
within saliva, and the taste and “mouth discomfort” [38-
41]. In case of side reactions and toxicity buccal drug
delivery can be promptly terminated, and therefore this
route is considered safe and easy for drug utilization [42].
Due to its unique structural and physiological properties
the oral mucosa offers several opportunities for drug de-
livery. As the mucosa is highly vascularised, any drug
diffusing across the oral mucosa membranes has direct
access to the systemic circulation and will bypass hepatic
circulation. The rate of blood flow through the oral mu-
Copyright © 2011 SciRes. JBNB
Drug Delivery: Plant Lec ti ns a s B ioad hesi ve Drug Delivery Syste ms617
cosa is substantial, and is not considered to be the rate-
limiting factor in the drug absorption [43]. In addition,
saliva a relatively mobile fluid with less mucin and lim-
ited enzymatic activity [44], is favorable for protein and
peptide delivery.
The first-generation mucoadhesives, such as carboxy-
methylcellulose [45] have been extensively evaluated
mostly for the treatment of periodontal disease [46], and
resent research has been mainly focused on the con-
trolled delivery of therapeutic reagents such as peptides,
and proteins [47].
4.5. Vaginal Drug Delivery Systems
Drug delivery via the vaginal rout is an attractive option
due to the avoidance of hepatic first-pass metabolism and
a reduction in the incidence of gastrointestinal side ef-
fects. The advantages for systemic drug delivery are the
large surface area, rich blood supply and high permeabil-
ity, while low retention time is a disadvantage because of
the self-cleansing effect of the vaginal tract [48]. Data
from literature demonstrated the superiority of vaginal
placement over the oral route regarding minimization of
general and gastrointestinal side effects [49]. A very at-
tractive issue concern ing the vaginal drug delivery refers
to prevention and treatment of sexually transmitted dis-
eases. Some of these approaches will be discussed later.
5. Lectins as Specific Site Directed
Due to the lack of specificity, the first generation of mu-
coadhesive polymers provides nonspecific binding to
mucosal surfaces in the body. Therefore, their employ-
ment in the creation of mucoadhesive drug delivery sys-
tems for a particular tissue is limited. Creation of poly-
mers and microspheres with attached mucus or cell-spe-
cific ligands have increased therapeutic benefits and
made site-specific drug delivery possible. In contrast to
classical mucoadhesion, which relies on nonspecific in-
teractions of polymer chains and mucins, the lectin in-
teractions with mucins are very specific.
Lectins are a highly heterogeneous group of proteins
and glycoproteins of non-immune origin that bind to
carbohydrates specifically and noncovalentlly. The term
“lectin” derives from the Latin verb legere—to select or
choose. Lectins were first discovered in plants; however,
their presence was confirmed in most living organisms
(bacteria, animals and humans). Lectins are involved in
various biological processes: cell-to-cell recognition and
communication, particularly in the mammalian immune
system (transendothelial migration), adhesion and attack
of infectious agents on host cells, clearance of glycopro-
teins from the blood circulation, etc. [50,51]. The asso-
cia- tion constant Ka of lectins with monosaccharides is
usu- ally in the range of 103 - 104 [52]. As carbohydr ate-
binding proteins lectins can increase the adherence of
drug delivery vehicles to the mucose surfaces.
The utilization of lectin-mediated drug targeting is
based on the fact that most cell surface proteins, and
many lipids in the plasma membrane, are glycosylated,
and these glycans represent ligands for lectins. Different
cell types express various glycan patterns, particularly in
pathological states, such as transformed or cancerous
cells, where completely different glycans are expressed
compared with their healthy counterpar ts [53]. Th eref or e,
lectins are regarded as potential carrier molecules to tar-
get drugs specifically to various cells and tissues. Selec-
tion from natural biological material or creation by re-
combinant DNA technology of a specific lectin, and its
coupling to macromolecular drugs or particular drug car-
riers may lead to efficient cellular uptake and subsequent
intracellular routing of such delivery systems. Russel-
Jones and coworkers were able to demonstrate transloca-
tion of nanoparticles which had been conjugated to
lectins, such as wheat germ agglutinin (WGA), concana-
valin A (Con A) and LBT, the binding subunit of heat-
labile toxin from E. coli, [54] across the cell layer in an
in vitro model of intestinal epithelial cells, whereas A.
aurantia lectin, from the edible orange cup mushroom,
was able to mediate antigen delivery to M cells [55].
Jain and Jangdey [56] reported on the development of
a ConA conjugated gastroretentive multiparticulate de-
livery system of clarithromycin for the effective treat-
ment of colonization of Helicobacter pylori. Attachment
of Con A lectin to ethylcellulose microspheres signifi-
cantly increased the mucoadhesiveness and also con-
trolled the release of clarithromycin in simulated gastric
fluid. Prolonged gastric residence time of over 6 h was
achieved in rabbits for Con A-conjugated microspheres
of clarithromycin.
For the patient, the gastrointestinal route is the most
convenient and attractive method for systemic delivery of
drugs. However it is one of the most challenging routes
of administration. The acidity of the gastric juice, as well
as the gastric and intestinal enzymes and brush border
hydrolases can degrade the drug. Also the viscous mucus
blanket overlying the epithelium can limit the absorptive
capacity of the cell layer, therefore successful mucosal
absorption of drugs requires drug formulations which
prolong the residence time at the site of absorption and
provide an intimate contact to the absorptive tissue [49].
Among reagents available to direct drugs specifically to
the gut epithelium, plant lectins are prime candidates,
due to their stability in low pH conditions and their abil-
ity to bind specifically to epithelial cells [50,57]. It has
been shown that recombinant banana lectin (rBanLec),
preserved structural stability and its carbohydrate-bind-
Copyright © 2011 SciRes. JBNB
Drug Delivery: Plant Lectins as Bioadhesive Drug Deliv ery Systems
ing potential under the conditions of simulated gastric
fluid and simulated intestinal fluid. In this regard it can
be considered as a candidate for the novel bioadhesive
lectin-based drug delivery systems to the gastrointestinal
tract [58].
A recently published paper on the antiviral activity of
BanLec attracted lots of attention even beyon d the scien-
tific community, as it has been shown that BanLec has
the potential to inhibit genome integration of human
immunodeficiency virus (HIV) in the target cell, and
hence viral replication [59]. Viruses containing high-
mannose glycosylated envelopes, such as human immu-
nodeficiency virus type-1 (HIV-1), are potential targets
for BanLec binding. The entry of human immunodefi-
ciency virus into cells requires th e sequential interaction s
of the viral exterior envelope glycoprotein, gp120, with
the CD4 glycoprotein and a chemokine receptor on the
host cell surface. It has been found that BanLec inhibited
HIV-1 infection by binding to the glycosylated viral en-
velope in a way that blocks cellular entry of the virus.
The relative anti-HIV activity of BanLec compared fa-
vorably to other anti-HIV lectins, such as the snowdrop
lectin and griffithisin, and to T-20 and maraviroc, two
anti-HIV drugs currently in clinical use. Based on these
results, BanLec is a potential component for an anti-viral
microbicide that could be used to prevent the sexual
transmission of HIV-1. Although concerns have been
raised about the potential toxicity of lectins, creation of
recombinant therapeutic protein which can be attached to
polyethylene glycol (PEG) polymer chains to change
bioavailability and reduce toxicity [59].
As ocular drug delivery is limited both by patients’
acceptability and by the limited time that the dosage form
is retained within the precorneal region, Nicholls et al.
[60] tried to identify lectin receptors within the precor-
neal region as potential targets for a lectin containing
ocular dosage form, and thus facilitate prolonged drug
delivery. In an ex-vivo experiment conducted on rat cor-
neal and conjunctival intact (unfixed) epithelia, the
lectins from Solanum tuberosum (potato) and Helix po-
matia (edible snail), with specificity for N-acetyl-D-glu-
cosamine and N-acetyl-D-galactosamine respectively,
were the most promising lectins with binding to ocular
tissues in terms of a 10 s contact [60]. Following this, a
study which explored the potential of these lectins to
cause inflammation and tissue necrosis was performed
with New Zealand white rabbits. The authors concluded
that Solanum tuberosum and Helix pomatia lectins dem-
onstrated minimal acute irritancy, and would be suitable
for formulations and in vivo studies [61].
Beside specific mucoadhesion and cytoadhesion, it has
been shown that certain plant lectins are prone to induc-
tion of immune response upon oral feeding [62]. In this
regard, utilization of novel immunostimulatory mole-
cules having an adjuvant effect to enhance or redirect an
immune response against target immunogens has been an
important issue in vaccine development. Based on its
IgG4-inducing potential, BanLec is regarded as a poten-
tially useful protein carrier for oral antihapten immuniza-
tion in humans suffering from IgE mediated allergic dis-
orders [63]. Resistance to the proteolytic enzymes of the
gastrointestinal tract [64] enables BanLec to pass the
mucosal barrier and interact with the immune system,
inducing a strong IgG4 immune response.
6. Conclusions
In the recent past, new technologies have established
DNA arrays that distinguish different cell types through
the profiling of gene expression. However, cell surface
phenotypes are not only determined by gene expression.
Posttranslational modifications by glycosylation and re-
gulation of protein localization are believed to be essen-
tial in determining the identity of a particular cell type at
a given stage of differentiation. Therefore, it should be
possible to distinguish different cell phenotypes through
the profiling of cell-surface glycans. In this regard, it
seems feasible to design drug delivery vehicles with im-
proved bioadhesive features, and particularly with spe-
cific cytoadhesive properties. A very promising concept,
which can greatly expand the utility of lectins and afford
more accurate and reliable cellular identification and
targeting, is the development of novel lectin libraries
with diverse specificities [65]. Such an approach offers
the possibility of more specific targeting, attachment and
controlled release of no vel lectin-based vehicles. Despite
the promise still lot of investigation has to be conducted
in order to produce improved lectin-based therapeutic
7. Acknowledgements
This work is supported by Grant No. 172049, sponsored
by the Ministry of Education and Science, Republic of
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