Infectious Disorders - Drug Targets 2008, 8, 119-128 119

New Approaches in Drug Delivery Systems: Application for Diabetes

Treatment

Jorge F. J. Coelho1,*, Paula Ferreira2,3 and Maria H. Gil2

1
Centre of Ophthalmology, Biomedical Institute for Research in Light and Image (IBILI), Faculty of Medicine,
University of Coimbra, 3000-354 Coimbra, Portugal. 2Department of Chemical Engineering, University of Coimbra,
3030-290 Coimbra, Portugal. 3Department of Health Sciences, Portuguese Catholic University, 3504-505, Viseu,
Portugal.

Abstract: Advanced drug delivery systems present indubitable advantages for drug administration. During the past three
decades, new approaches for the development of new carriers for this topic have been suggested. This led to explosion of
publication activity in the area. This article reviews briefly the history of the topic and focuses on general concepts in the
issue.
One of the most crucial properties of advanced delivery systems is their ability to be well controlled in terms of a carrier
structure which is responsible for an optimal drug release. Here we describe new polymerization technologies which
consider this particular aspect. A special attention is paid to the preparation of materials by LRP (Living Radical
Polymerization) and perspectives of its practical application to the treatment of single diseases.
Due to the epidemic scale of Diabetes mellitus, novel drug delivery systems play an important role in and are highly
relevant for improved treatment of worldwide permanently growing sub-population of diabetic patients. Type 1 is the
insulin-dependent diabetes which accounts for 5 till 10 percent of the whole pool of diabetic cases and currently attracts
main attention in research activity devoted to the development of advanced drug delivery systems. Minimal invasive
insulin administration approaches and/or improvement of pancreatic activity in own insulin production is the main goal of
novel drug delivery systems highly desirable for advanced treatment of diabetic patients with both type 1 and type 2 of the
disease.
Keywords: Living radical polymerization, drug delivery systems, cells encapsulation, Diabetes mellitus.

INTRODUCTION degradation during the whole process. The development of a

Pharmaceutical treatments started plenty of decades or
even centuries ago (e.g. aspirin since 1828) with the oral
administration of solid pills (and liquids), or injectables that
had fast acting active chemical drugs. Despite the effecti-
veness of these treatments, the impossibility of controlling
the drug level over a long period of time constituted an
important drawback. During the last two decades, new
approaches and strategies have been developed to control
several parameters considered essential for enhancing the
treatment performance, such as: the rate, period of time and
targeting of delivery. The first two features were addressed
by using the manipulation of the drug carriers that typically
were polymers. The latter aroused the interest of the scien-
tific community and it has witnessed tremendous develop-
ments over the last decade. The drug targeting involves the
conjunction of different areas related to drugs design, drug
carriers, biological systems, genetic approaches and precise
design of new molecules.
In order to improve the effectiveness of the actual
methods for drug delivery, several steps need to be
accomplished. The main goal is generically related to deliver
a suitable drug at a desired target without any sign of
*Address correspondence to this author at the Biomedical Institute for
Research in Light and Image, Azinhaga Santa Comba, Celas, 3004-548
Coimbra, Portugal; Tel: +351-239 480-220; Fax: +351-239-480-280;
E-mail: jcoelho3@gmail.com
drug delivery system that can dose orally, being less
expensive and less painful for the patients and at the same
time is extremely effective considering a specific disease
represents a final target for the research community. For this
purpose, the drug delivery systems have to possess some
features. The system should be recognized by the specific
target tissues. The polymeric carrier itself, once in the
targeting area should be able to control the drug adminis-
tration by means of either a physiological or chemical
trigger. The design of a delivery system should be done in
such a way that it will be suitable for specific areas of the
body where it could be damaged by environmental condi-
tions e.g. pH of the stomach. The need to deliver a drug in a
specific area of the body is also extremely important in terms
of lowering possible side effects of the active compounds
when enter non-targeted organs and tissues.
A significant number of carriers have been studied to
deliver the active compounds, mostly based on polymeric
materials. Among the major important ones, we can stress
the use of: nanostructures that can diffuse over small barrier
and enlarge the surface areas available to drug release. In this
field, the microspheres and nanocapsules are of particular
interest. Also, pH and temperature sensitive hydrogels, as
well as dendrimers offer indubitable advantages in terms of
structure and targeting. Once the effectiveness of these
approaches was proved, the research effort has been focused
in the development of strategies that can fine tune the
properties of the molecules used to prepare the drug carrier.

1871-5265/08 $55.00+.00 © 2008 Bentham Science Publishers Ltd.

120 Infectious Disorders - Drug Targets 2008, Vol. 8, No. 2
The polymers are responsible for the most important
breakthroughs in the field of drug delivery systems. These
materials have great potential due to several features, such as
the large variety of different synthetic materials available,
simplicity in processing, possibility to control the chemical
and physical properties through well-known synthetic
methods. On this matter, during the last decade the
remarkable development of the living radical polymerization
methods brought an effective and powerful tool to synthesize
new polymeric macrostructures with controlled morpho-
logies, architectures and topologies. In this review, a special
attention is focused on living radical polymerization (LRP)
field. LRP processes join the advantages resulting from the
nature of the living and radical methods (see Table 1).
By using LRP, now it is possible to synthesize most of
the polymerizable monomers due to a very high tolerance to
different functional groups. Nevertheless, an importance of
other approaches should be stressed, such as the poly-
merization by using step-growth reactions. Several contri-
butions have proposed this approach to obtain polymeric
matrixes presenting a very fast degrading behaviour. The
reason is the introduction of low-weight molecules con-
taining heteroatoms in the main backbone with amorphous
structures and hydrophilic nature.
Historically, the development of the polymeric field
improved new concepts in the drug delivery area. In this
area, the lactic acid based polymers, were pioneers in the
1970s. Nowadays, the polymeric materials are also
synthesized with the purpose to obtain controlled reservoirs
(mainly microspheres [1, 2], nanocapsules and more recently
nanotubes). Apart from the systems where the active drug is
retained within a polymer shell, there are also other systems
that involve the entrapment of the drug within a polymer
network, which normally constitutes a membrane or a film
[2]. The research field focused on conjunction of biological
entities with synthetic polymers is one of the central topics in
the pharmaceutical chemistry during the last decade [3 - 5].
In this review, a recent technology of polymeric
synthesis, living radical polymerization, is described. Also,
some possible applications of polymers obtained by this
technology are considered. Special attention is paid to the
development of drug delivery systems as well as to living
cells encapsulation. As an example, drug delivery systems
Table 1. Advantages and Disadvantages of the Living and Free Radical Processes
Living Ionic
Control of chain length
Advantages
Narrow polydispersity
Block copolymers
Telechelics
Disadvantages
Poor functionality tolerance
Not easy to scale up
Poor functionality tolerance
Coelho et al.
are demonstrated for diabetes treatments. Diabetes mellitus
is used as a particular example of a chronic disease the
treatment of which can certainly benefit from advanced
technologies in drug delivery.
LIVING POLYMERIZATION - BRIEF HISTORY
The work on living polymers began in the middle of the
1960s under the supervision of Szwarc [6-8]. The final result
was published in a one page communication entitled
“Polymerization initiated by electron transfer to monomer -
A new method for formation of block copolymers” [8]. The
outstanding achievement of this work was the demonstration
of the possibility of polymerizing a monomer without termi-
nation reactions. In this way, the term “living polymeri-
zation” was introduced. The block copolymerization concept
allowed a discovery of the thermoplastic elastomers such as
the styrene-butadiene-styrene (SBS) as well as different
materials with particular properties.
Since this discovery, the living polymerization has been
studied very extensively. As a result several types of living
polymerizations were proposed: anionic systems [9], cationic
systems [10-11], ring-opening systems [12, 13] and radical
systems [14-17]. In these methods, the living chain ends are
protected from termination by a variety of strategies based
either in complexation or steric hindrance. This reaction
operation is normally designed on the basis of the correct
choice of reagents, solvents and temperature. All the
strategies that allow a synthesis of living polymers have
witnessed important developments. Among those, Living
Radical Polymerization (LRP) has attracted remarkable
scientific interest as well as an interest in its practical
application [18]. Behind the explosive interest reported, was
an intention to prepare new well-defined structures (blocks,
stars, comb-like, networks, end-functionalized and other
materials without traditional problems) by means of radical
processes [18]. This change in mechanism led to a
development of processes carried out under mild conditions
typically used by industry for a large scale production. The
LRP approaches join the advantages of the living ionic and
radical methods (see Table 1). Further advantage of it is a
big range of monomers that can be polymerized with living
features, compared to ionic polymerizations.
Free - Radical
Easy procedure
Water-friendly
Functional monomers
Industrial processes
No control
Block Copolymers
Telechelics
New Drug Delivery Systems - Diabetes
LRP - INTRODUCTION
From the theoretical standpoint, this strategy allows the
synthesis of living polymers under radical mechanisms with
all the associated advantages. Moreover, even at the very
beginning of its development, the possibility of imple-
menting such reactions in aqueous environment, due to
radical nature of the reaction was predicted. Environmental
and economic issues involving the use of aqueous media are
very interesting. Two decades ago the possibility of
establishing methods for the preparation of tailored made
polymers by a living and radical mechanism, was considered
an impossibility. The basis for this assumption was the fact
that the radical termination reactions occur under diffusion-
controlled rates [18]. Whereas termination is second-order
with respect to the growing radical, the propagation is first-
order, keeping the concentration of radicals at a very low
level that allows avoiding the termination reactions and
preparing a product with the desired molecular weight
characteristics.
The LRP process provides the possibility of controlling
the parameters that can influence the material performance.
This allows for the creation of polymers that can improve the
properties of composite materials used nowadays. The use of
the same raw materials and the functionalization of polymers
with the appropriate chemical groups allows/increases the
possibility of interaction with other materials [19].
One of the major advantages of LRP systems is the
predictability of the degree of polymerization, determined by
the ratio of the consumed monomer and the initiator (DP =
[M]/[I]0). Also, for an ideal system, the polydispersity
should be close to the Poisson distribution (Mw/Mn
1+
1/Mn) [18] (when Mn 
, Mw/Mn 1) and the chain ends
are active (alive).
Experimentally, the most appropriate way to determine
the living character of the reactions is by assessing their
polymerization kinetics in what concerns the evolution of the
molecular weights, the polydispersities and the functio-
nalities with conversion [18]. There are various features that
could be expected from a living system: 1. linear evolution
of the molecular weight with the conversion, 2. linear kinetic
relationship for the semi logarithmic coordinates (ln[M]
0/[M] versus time), 3. low polydispersity [20]; functional
groups allow for further re-initiation. These features are a
direct consequence of the lack of a chain-breaking reaction.
The presence of active chains is a characteristic which allows
the preparation of copolymers. The continuous addition of
different monomers leads to the preparation of block
copolymers using different monomers. The composition can
be controlled by the amounts of the monomers added. The
proof of living character results from a re-initiation test by a
macro-initiator; thereby the complete movement of the
macro-initiator towards high-weight molecules should be
clearly visible. Potentially failed re-initiation may arise from
procedural problems and not necessarily by the lack of active
chain ends. Normally, such evaluations are carried out using
a low molecular weight macro-initiator and leads to a high
molecular weight copolymer. The difference between Mn
should be significant, in order to allow the complete shift of
the peak towards high-weight molecules (Fig. (1)).
Infectious Disorders - Drug Targets 2008, Vol. 8, No. 2 121
Fig. (1). Schematic representation of the molecular movement
towards high molecular weights resulting from the preparation of a
block copolymer initiated from a macroinitiator.
LRP - A BRIEF DESCRIPTION OF THE METHODS
AVAILABLE IN THE LITERATURE
The scientific progress achieved over the last decade in
the LRP research field has few prior precedents. Two
reasons can be given to explain this evolution. Firstly, the
experience gained over the past 60 years in different fields
related to LRP, was highly beneficial for further branch-
related progress: atom transfer radical addition; persistent
radical effect; living anionic and cationic polymerization and
free radical polymerization. Secondly, the extraordinary
interest towards this technology gave rise to a number of
excellent projects resulted in extensive publication activity:
more than 1,000 issue-related articles have been published
alone in 2004 [19].
Otsu et al. were responsible for a pioneer work on the
LRP methods during the 1980s [21-22]. These were followed
by hundreds of studies from the middle of the 1990s. Several
methods have been developed and proposed for controlling
living radical polymerizations in recent years. In 2001,
Kamigaito with co-authors identified 9 different reaction
mechanisms [23]. Among these strategies, four based on
either a reversible termination or a reversible transfer
mechanism, attracted special attention and represent more
than 90 % of the publications on this field. In spite of having
different mechanisms and reagents involved in the reactions,
all the strategies are unified by reduction of radical
concentration. The relative reduction of active species
(radicals) to the dormant species allows the chains to grow
slowly and simultaneously without bimolecular irreversible
terminations [24].
More strict control over the polymerization and reaction
conditions may be considered as beneficial for its wide-
spread exploitation. Reversible termination mechanisms,
such as Atom Transfer Radical Polymerization (ATRP) [25]
and Stable Free Radical Polymerization (SFRP also known
as Nitroxide Mediated Polymerization, NMP), both are based
on the reversible reaction between a controlling agent and
the propagating polymeric radical to yield a dormant chain.
The equilibrium is shifted strongly towards the dormant
122 Infectious Disorders - Drug Targets 2008, Vol. 8, No. 2
species, resulting in a lower concentration of active propa-
gating radicals compared to those obtained in the con-
ventional process.
Whereas the propagation reaction is of first order with
respect to the monomer, the termination is of second order,
i.e. the reduction of active radicals support termination
reactions. However, some irreversible bi-radical terminations
are expected to occur, leading to dead chain ends and broad
spectrum of molecular weight [26]. Due to irreversible bi-
molecular termination, increased controlling agent is
available to react with further radicals. Consequently, the
equilibrium is driven to the dormant state decreasing the
reaction rate.
The experimental conditions for SFRP and ATRP should
be accurately chosen which enable chains to be quickly
initiated [26]. The SFRP [27] uses stable radicals which
reversibly react with active radicals together forming dor-
mant covalent species. Several stable radicals have been
successfully used: nitroxides [28], benzhydryl derivatives
[29], triazolinyl radicals [30], dithiocarbamates [21] and
organometallic species [31].
Based on a different mechanism, both Reversible Addi-
tion-Fragmentation Transfer (RAFT) [32] and Degenerative
Chain Transfer (also known as Degenerative Transfer) [33]
use a chain transfer agent that reacts reversibly with the
propagation macro-radical. This reaction between the dor-
mant species and the active radicals results in the transfer of
an end-group from the transfer agent to the radical. For the
DT process, this transfer directly involves, for example, an
iodine atom. In the RAFT process, an addition-fragmentation
process is used to exchange a moiety (for example, a
dithioester) between the two chains [26]. The Macromole-
cular Architecture Design by Interchange of Xanthates
(MADIX) process is similar to the RAFT process but uses
xanthates as transfer agents [26, 34, 35]. For the RAFT
approach, generically the conventional initiators are used as
radical source. The transfer involves the radicals formed
during the decomposition of the initiator. To maximize the
“livingness” of the polymerization, the transfer-agent should
be used in excess. On the other hand, low DPs (DP =
[monomer]/[transfer-agent]) are more desirable.
The basic principle behind the different methods relies on
the capacity for reduction of the number of radicals in a
reversible process, being the difference among those strate-
gies on the way to accomplish it. For radical polymeri-
zations, the termination reaction rate (Rt) is a function of the
power square law of the radical concentration [P](Rt =
Kt)[P]2. The propagation radical concentration is propor-
tional to [P](Rp =Kp [P][M]). Because of this, a half
decreasing of [P] will result in a half decrease of the reaction
Fig. (2). Atom Transfer Radical Polymerization [37].
Coelho et al.
rate but the termination rate decreases two fold. Moreover, in
the FRP process all of the chains are terminated, whereas, in
the LRP process, only 1-10 % of the total chains are
terminated irreversibly [36]. The other fraction involves
dormant species that can be re-initiated and functionalized.
Due to its intrinsic properties, the specific target is an
important aspect to be considered in the decision as to which
LRP strategy should be used. The ATRP is unquestionable
the most studied and applied method [23, 37].
The mechanism presented in Fig. (2) consists of the
formation of active radicals through a redox process
catalyzed by a transition metal complex. The Pn
are known
as propagation radicals, while the Pn–X are definedn as
dormant species. The transition-metal complex (M t -
Y/Ligand) plays an indispensable role in this system, since it
provides the activation processes and the deactivation
processes, which keep the concentration of radicals to be
very low. These processes are related to a one-electron
oxidation with concomitant abstraction of a (pseudo) halogen
atom X from the dormant specie (Pn–X) [37] (n= 0,
initiator). The radicals (Pn
) are able to react reversibly with
the oxidized metal complex (X–Mtn+1 /ligand) to form again
the dormant species and the activator. The ligand is essential
to the solubilization of the transition metal salt in the organic
medium and to the adjustment of the redox potential of the
metal centre, which defines the reactivity and the dynamics
of the atom transfer process [37]. Once the radicals are
active, the polymer chain growing process is similar to the
FRP process. The equilibrium between the active species and
dormant species is shifted towards the dormant species via
an excess of the higher oxidation state of the catalyst that is
generated by a small amount of radical dimerization, during
the initial steps of polymerization [38]. This effect is known
as the persistent radical effect (PRE) [39, 40]. Several metal
catalysts have been proposed as mediators of the ATRP
process. Among these are the copper based catalysts that
were extensively [23] studied due to their potential, low cost
and large availability. New ligands for several transition
metals have been developed with outstanding results
achieved, related to the increase of the catalyst activity
(10,000 fold when compared to the initial systems [36, 37,
41]. The accomplished developments, with respect to the
capacity to polymerize different monomers and the smoo-
thing of reaction conditions for living radical polymerization
methods, are remarkable in the last decade.
Details about each polymerization system may be found
in the literature. In order to develop a broad understanding of
this technology, several reviews can be recommended:
mainly about LRP [22, 26, 27, 42], ATRP [23, 37], NMP
[43] and macromolecular engineering [44]. There is no any
review which would exclusively deal with DT processes.
New Drug Delivery Systems - Diabetes Infectious Disorders - Drug Targets 2008, Vol. 8, No. 2 123

Some articles deal with the interpretation of the DT
mechanism and its applications [24, 33, 42, 45-53]. On the
other side, the main difference is the nature of the steady
state concentration of radicals that in FRP results from ratio
of the rate of the initiation and the rate of termination. For
LRP it is the balance between the activation process and the
deactivation process that is of relevance. Since the rates of
initiation, activation and deactivation are much larger than
termination [18] control over the polymerization becomes
possible.
The contribution of several research groups allowed the
adjustment of the equilibrium reactions between the active
and dormant species leading to improvement of the LRP
reaction conditions. For some of these methods, a production
of new materials in large scale is thinkable [54].
The LRP methods involved a control over the relation
structure-properties for polymer materials in terms of
particular drug-carrier properties. Novel technologies for a
synthesis of materials with desirable properties are now
available for a large range of monomers. The radical poly-
merization is currently the only process that demonstrates a
great tolerance to the incorporation of biological segments
[55]. Simple design of well-controlled reactions represents a
tremendous potential for the practical application and
products commercialization.
DISADVANTAGES OF CURRENT DIABETES
TREATMENT
Diabetes mellitus has been recognized as a particular
disorder at least 3,500 years ago. However, its origin was a
mystery until early 20th century (Table 2). Type 2 diabetes is
treated in the first years following diagnosis in a stepwise
manner. Patients are encouraged to initiate some lifestyle
changes, which may include nutritional advising as well as
some form of exercise [56]. Usually these adaptations in
patients’ routine are also accompanied by oral administration
of some anti-diabetic drugs that stimulate insulin secretion
from beta-cells and increase insulin sensitivity in target cells
[57]. However, about 50 % of type 2 diabetes patients
eventually require exogenous insulin namely in the case of
failure of an oral therapy [57]. Type 1 diabetes usually must
be treated by frequent injection of insulin under permanent
surveillance of blood glucose levels. Consequently, stable
blood glucose values are not achievable by insulin injections
and episodes of hypo/hyperglycaemia are not avoidable [58].
These limitations and disadvantages are accompanied with
the injection-associated discomfort, pain, increased risk for
infectious disorders, psychological stress for patients and
their families. Therefore, alternative insulin delivery
methods should be developed that allow achieving optimum
glycaemic control and avoiding above mentioned limitations
/ disadvantages [59]. Here we summarize advanced insulin
delivery systems and novel techniques aimed at replacement

Table 2. Brief History of Diabetes Discovery and Treatment

1552 BC Egyptian physician Hesy-Ra of the 3rd Dynasty makes the first known mention of diabetes – found on the Ebers Papyrus – and lists
remedies to combat the 'passing of too much urine.'

1869 German medical student Paul Langerhans discovers the islet cells of the pancreas but is unable to explain their function. The find is
dubbed as the 'islets of Langerhans.'

1889 Scientists Oskar Minkowski and Joseph von Mering of the University of Strasbourg, demonstrate how removing a dog's pancreas
produces diabetes.

Oct. 1920 Banting conceives the idea of insulin and continues research using a variety of different extracts on depancreatized dogs.

Nov. 1921 Banting and Best discover that extract from cattle foetal pancreas lowers blood sugar levels of depancreatized dogs. Experiments begin to
test the long-term effectiveness of insulin treatment.

Jan. 1922 Leonard Thompson, 14, a ‘charity patient’ at the Toronto General Hospital, becomes the first person to receive an injection of insulin to
treat diabetes.

Oct. 1923 Insulin is made commercially available in the United States and Canada.

1940s Link is made between diabetes and long-term complications (kidney and eye disease).

1944 Standard insulin syringe is developed, helping to make diabetes management more uniform.

1955 Oral drugs are introduced to help lower blood glucose levels.

1959 Researchers identify type 1 diabetes (insulin dependent) and type 2 diabetes (non-insulin dependent).

1960s The purity of insulin is improved. Home testing for sugar levels in urine increases level of control for people with diabetes. First pancreas
transplant performed at the University of Manitoba

1970 Blood glucose meters and insulin pumps are developed. Laser therapy is used to help slow or prevent blindness in some people with
diabetes.

1983 First biosynthetic human insulin is introduced.

1986 Insulin pen delivery system is introduced.

124 Infectious Disorders - Drug Targets 2008, Vol. 8, No. 2
of damaged beta cells by transplantation of insulin producing
tissue.
INSULIN DELIVERY
Insulin therapy has been introduced for diabetes
treatment by Frederick Banting and Charles Best in 1922
[60, 61]. Currently insulin administration is the universal
treatment for type 1 and majority cases of type 2 diabetes.
Since insulin is inactivated by enzymes along digestive tract,
it can not be taken by oral administration. Consequently,
insulin is administrated by subcutaneous injection either
using a typical syringe/needle system or a pen-like device
[62]. Typical injection sites are abdomen, upper arm or
buttocks, and the outer side of the thighs [63]. However,
subcutaneous insulin administration can not lead to optimal
pharmacodynamic properties of the applied insulin.
In order to overcome this limitation, insulin is commer-
cialized in different forms, each of them presenting
individual acting speed and duration in the organism. There
are five main sorts of insulin: rapid-acting, short-acting,
intermediate-acting, long-acting and, finally, biphasic
insulin. Rapid-acting insulin begins to work less than 15
minutes after injection. It reaches its acting peak about one
hour latter but continues to work for a period between 2 to 4
hours. Short-acting insulin typically reaches the bloodstream
30 minutes after injection, and achieves its action peak 2 to 3
hours later. Its effectiveness is maintained for 3 to 6 hours.
Intermediate-acting insulin needs 2 to 4 hours to get to
bloodstream and its maximum peak is achieved 12 hours
latter. Its action lasts up to 18 hours. Long-acting insulin
presents a continuous action that simulates normal insulin
secretion in the organism. Although this type of insulin has
the potential to mimic natural insulin secretion, its activity
does not present a particular peak of activity. For this reason,
its administration has to be complemented by injections of
rapid-acting or short-acting insulin before all meals to
provide bolus coverage for food intake. Finally, biphasic
insulin represents a mixture of short-acting and intermediate-
acting insulin types which can be combined in different
proportions. These kinds of insulin mixtures are beneficial
for patients with difficulties in combining diverse insulin
types and managing several bottles and doses of different
insulin types. All these insulin forms are usually adminis-
trated in individual regimens. The type of insulin used by a
patient must be adapted individual needs.
Despite the constraints associated with insulin self-
injection, this method is currently the most successful and
popular among diabetics. However, significant progress has
been achieved in insulin delivery systems and corresponding
equipment in last years. The new techniques are mainly
designed to overcome the traditional self-injections. Amon-
gst these alternative insulin delivery methods are included
the insulin pumps and jet injectors. Furthermore, the main
effort in diabetes treatment research considers novel non-
invasive approaches for insulin administration, in particular,
oral, buccal, nasal, pulmonary and transdermal adminis-
tration.
Coelho et al.
INSULIN PENS AND JET INJECTORS
Insulin pens consist of auto delivery devices designed for
subcutaneous self-administration of insulin [64]. These
injection systems have been introduced by Novo Nordisk
Pharmaceuticals Inc. (Princeton, New Jersey; formerly refer-
red as Novo Nordisk) and remain available on the market
since 1985 [65]. Insulin pens use either prefilled or reusable
insulin containing cartridges and disposable needles.
Following the setting of the dose by a dial, the needle is
inserted into the skin and the dose is delivered by a plunger
[66]. This type of insulin administration provides simpler,
more convenient and more accurate dosing; additionally it is
also considered to be more convenient for the patient’s use.
In fact, pen-like devices allow more discreet injection in
social situations, they minimize the fear of self-injection
procedure and consequently they improve patient’s comp-
liance towards multiple injections regimens [67]. On the
other hand, insulin jet injectors are devices that deliver
insulin without the use of needles. Instead, a high-pressure
air mechanism pushes insulin through a small orifice with
enough strength to enter the subcutaneous tissue to a depth
equivalent to standard needle syringe [68]. This sort of
system does not puncture skin, but several local side effects
have been reported. These include bleeding and bruising, as
well as local insulin leakage [66]. Moreover, patients have
reported pain associated with this delivery method to be at
least as significant as needle injection [69]. The combination
of these limitations led the American Diabetes Association to
state that jet injectors “should not be viewed as a routine
option for use in patients with diabetes” [70]. Nevertheless,
these devices may be beneficial to patients with needle
phobia as well as for patients that suffer from severe
lipoatrophy [66]. However, factors such as device high cost
and the fact that a trial period should be considered before
purchase must be considered.
INSULIN PUMPS
Insulin pumps are also called continuous subcutaneous
insulin infusion (CSII) and they are based on the concept of
continuous insulin infusion from portable electromechanical
pumps [71]. They are composed of three main parts: the
pump itself (includes controls); a reservoir filled with insulin
and a disposable diffusion set (includes a cannula for
subcutaneous insertion and the flexible tube connecting it to
the insulin reservoir). The insertion of the cannula is usually
done in the abdomen, hips or even the tights [72]. However,
this injection place should be changed every 3 days in order
to avoid local infections and lipohyperthophy [59]. These
devices have been used since the late 1970s in the treatment
of patients with type 1 diabetes [73]. They are considered a
most reliable way to mimic the physiological secretion
pattern of insulin since they deliver a basal rate of this
molecule that can be programmed and adapted to different
conditions at any time and with no difficulty [74]. This
means that these systems may allow a better blood glucose
control [75]. Also patients report that insulin pumps provide
greater lifestyle flexibility, including meals schedules and
travel which results is a feeling of greater control over the
New Drug Delivery Systems - Diabetes
pathology and consequently a higher mean satisfaction with
CSII than any other therapy option [76]. Despite the advan-
tages presented by these devices, according to demographic
studies performed in Europe and also in the United States,
showed that the number of patients treated using this strategy
varies considerably among the different countries. In fact,
the acceptance of this technology is much higher in US than
in Europe where the leading countries (France and Germany)
present as little as 10 % of the patients under this type of
treatment. Conversely, in US nearly 20-25 % of the
population with type 1 diabetes is being treated by using
insulin pumps [77]. Among the several factors that may be
responsible for this difference, the poor insurance coverage
over the costs associated with the pumps acquisition that is
verified in some European countries is probably one of the
most important ones. This lack of financial support can hold
back the popularization and the spreading of this technology
among diabetics.
NON-INVASIVE INSULIN ADMINISTRATION
The insulin administration methods described above
represent invasive approaches with all disadvantages asso-
ciated with invasiveness. Therefore, alternative non-invasive
patient-friendly approaches are currently under consideration
[78, 79]. So far, inhaled insulin has been the only system that
was proved to be as effective as the subcutaneously injected
with a pharmacodynamic profile adequate to diabetes
therapy [69]. This inhaled insulin formulation has been
developed by a partnership between Pfizer, Sanofi-Aventis,
and Nektar Therapeutics and has already been approved for
use in the United States and European Union where is
commercialized under the name of Exubera
[80]. This
means that all the other routes that have been considered by
researchers [81] (oral, intranasal, transdermal, ocular, buccal,
rectal, vaginal, and uterine) though promising, haven’t
proved to be feasible in diabetes treatment and are, for that
reason, commercially unavailable. There are some further
highly promising issue-related research directions. One of
these areas is the development of new responsive hydrogels
that can incorporate insulin and “smartly” release it “in situ”
as a function of glucose concentration in its surroundings.
INTELLIGENT HYDROGELS AS INSULIN
DELIVERY SYSTEMS
Hydrogels are three dimensional hydrophilic polymeric
networks that are water insoluble and that absorb large
amounts of water or biological fluids [82]. They have been
considered to be useful in medical applications since, when
hydrated, they present a water content and mechanical
behaviour comparable to the ones of soft tissues. Conse-
quently, they are considered as very biocompatible materials
[58]. Some of these hydrogels present an ability to
considerably change some of their characteristics, such as
volume, in response to environmental stimuli such as the pH,
temperature and ionic strength of the surrounding medium
[83]. These intelligent stimuli-responsive hydrogels have
been intensively studied to be applied as “smart” delivery
systems as the delivery can be triggered upon environmental
changes [27, 84]. As an example, pH sensitive hydrogels
have proved to be useful in oral drug delivery since they can
protect peptide/protein drugs as they travel trough the
Infectious Disorders - Drug Targets 2008, Vol. 8, No. 2 125
digestive track [85]. ‘Intelligent stimuli-responsive’ delivery
systems using glucose sensitive hydrogels have been
investigated in order to release insulin in a pulsatile profile in
response to blood glucose levels [86]. In fact, these systems
can be classified as glucose biosensors. In a biosensor,
volume changes of the hydrogel are usually responsive to
variations in the level of a molecule of interest. This
correlation is normally achieved by incorporating inside the
hydrogel an enzyme or any other agent that can bind to such
molecule [87]. In glucose biosensors, the most common
agent used to identify the glucose molecule is glucose
oxidase, an enzyme that oxidizes glucose to gluconic acid
[88]. Therefore, increases in the external glucose concen-
tration will result in a decrease of the pH value inside the
system. In case of a hydrogel based on a polycation, this pH
decrease will lead to the swelling of the polymer that results
from the ionization process. This phenomenon will be
responsible for a more accentuated insulin release [87].
Another strategy used to achieve controlled insulin
delivery is based on competitive binding of glycosylated
insulin and glucose to a glucose binding protein named
concanavalin. When glucose levels rise, this molecule will
displace insulin from its binding sites and will, as a result, be
released from the system. This can be classified as a self-
regulating insulin delivery system [96]. Although such
systems seem to be highly promising, they demonstrated also
some disadvantages. The main one is probably the risk of
incorporated insulin leakage that may result in hypo-
glycaemia [58].
OUTLOOK
It is expectable the appearance of new materials that meet
necessary requirements to excel outstanding performance.
The continuous development that results from an unpre-
cedented interest about SFRP, ATRP, DT and RAFT
methods will enable the synthesis of new materials with
predictable correlations between the molecular micro-
structures and macroscopic properties. Another important
objective that remains to be accomplished is to carry out the
LRP reactions in heterogeneous conditions. Most of the
reactions procedures reported are designed in homogeneous
conditions being the reaction must easier to be controlled in
terms of mass and heat transfer. These conditions assure the
same growth probability for all chains leading to a high
uniformity of the polymer chains. It is necessary to adapt the
available technologies concerned to dispersed systems,
mainly microemulsions, miniemulsions, emulsions and sus-
pensions. To date, miniemulsions are known to be the most
effective way to conduct LRPs in aqueous systems [89]
regardless the mechanism used (reversible termination or
reversible transfer). These approaches will enable to control
the preparation of new nanoparticles based on tailor-made
materials.
The number of synthetic polymers available is an
important guarantee of chemical and physical diversity with
outstanding properties at very reasonable prices. Therefore, it
is crucial to continue the development of different strategies,
which can be capable to finely tune the properties of new
drug delivery systems.
126 Infectious Disorders - Drug Targets 2008, Vol. 8, No. 2
The major strategies to prepare advanced drug delivery
systems using LRP approach are based on the synthesis of
smart hydrogels and hybrid materials. The hybrid materials
combine a biopolymer with a synthetic polymers resulting in
a new molecular with synergetic properties, which can
overcome several of their limitations [90]. The use of LRP
methods allows tuning the properties of the synthetic
polymer segment. Using this strategy tailor made polymers
can be prepared with specific set of biological and
degradative properties. Börner [91] reported a method based
on the solution-phase atom transfer radical polymerization
(ATRP) of n-butyl acrylate initiated by the oligopeptide
macroinitiator. The resulting copolymer presented a number-
average molecular weight (Mn) of around 10000 g/mol and a
polydispersity of 1.19. Wooley [92] functionalized a N-
terminated amine group of a peptide with a fluorinated
alkoxyamine derivative used as initiator for NMP leading to
diblock and triblock copolymers, protein transduction
domain (PTD)-poly(tert-butyl acrylate) and (PTD)-poly(tert-
butyl acrylate)-poly(methyl acrylate) respectively. These
approaches revealed the potential of this emerging area
(LRP) in the development of new concepts for drug delivery
systems. The synthesis of hybrid materials is very promising
and may be further extended to the synthesis of block
copolymers made of synthetic polymers typically used in the
drug delivery systems for diabetes. The binding of the
synthetic polymers to the biological materials is an interes-
ting strategy to target the drug devices. Another example of
possible strategies to target the polymeric-based materials
was reported by Wooley [93]. Antigen-decorated shell cross-
linked knedel-like nanoparticles (SCKs) were constructed
from a combination of non-functionalized and chain-end
functionalized amphiphilic diblock copolymers, which were
assembled into micelles and cross-linked throughout the
shell. The amphiphilic diblock copolymer was synthesized
by ATRP of tert-butyl acrylate and methyl acrylate from
either 2,4-dinitriophenyl-functionalized initiator or ethyl 2-
bromopropionate. Washburn [94] reported the ATRP of 2-
hydroxyethylmethacrylate (HEMA) initiated by an oligo-
peptide macroinitiator using a solid-phase supported poly-
merization. The resulting bioconjugate showed properties to
modulate cell adhesion onto polymer coatings.
Richard [95] reported the synthesis of acrylate-based
block copolymers synthesized by ATRP as matrices for
paclitaxel delivery from coronary stents. The polymers
synthesized were multiblock copolymers consisting of
poly(butyl acrylate) or poly(lauryl acrylate) as soft blocks
and poly(methyl methacrylate), poly(isobornyl acrylate) and
poly(styrene). The polymerization allowed the authors to
easily play with the ratios and molecular weights of the hard
and soft segments in way to determine and optimize the
releasing of paclitaxel after coating the block copolymers
onto coronary stents.
Vidts and Prez [96] proposed the synthesis of block
copolymers containing poly(4-Vinylpyridine) P(4VP) by
ATRP from (PEO) macroinitiator. The latter was prepared
from the modification of a hydroxyl end group into an
halogen end group [97]. This work is particular interesting
considering the P(4VP) sensitivity to the pH conditions.
Coelho et al.
Hong and Pan [98] reported the preparation of tailor-
made temperature-responsive polymers, poly(N-isopropyl-
acrylamide) (PNIPAAm) and the water-soluble poly(N-(2-
hydroxypropyl)methacrylamide) (PHPMA), via RAFT poly-
merization using biotinylated trithiocarbonate as the RAFT
agent. The biotin-ended diblock copolymer of PHPMA and
PNIPAAm was also prepared by RAFT polymerization of
NIPAAm using biotinylated PHPMA as macro chain transfer
agent. The biotinylated PHPMA-b-PNIPAAm is able to form
a new kind of coreshell nanostructure with biotin groups on
the surface reversibly induced by temperature. Through the
correct design of thermoresponsive PNIPAM-based mate-
rials it is possible to control the aggregation of conjugates of
streptavidin in aqueous solution [99]. The same authors have
shown improved results by using a biotinylated diblock
copolymer PNIPAM-b-poly (acrylic acid) [100].
The use of tailor-made polymers is nowadays a prime
choice to synthesise self-assembling structures that can
easily encapsulate active compounds. One of the possible
applications of such materials, among many others, is in the
preparation of polymeric semipermeable biocompatible
membranes that can be used to incorporate either drugs or
even living cells. These kind of systems can be applied as
therapeutic agents in the treatment of several diseases.
Diabetes mellitus (DM) is probably one of the diseases in
which more attempts have been made in order to apply this
type of technology trying to achieve an efficient treatment
and most important a possible cure. Although some promi-
sing works have so far been reported in the encapsulation of
cells in DM treatment, most of them have not been
successful because of the failure of the polymeric fraction
involved in the system. New polymerization techniques such
as LRP can most probably be a viable strategy in achieving
new materials that not only are produced under highly
controlled conditions, but also are able to present the desired
properties.
It is expectable a continuous and maybe even more
intense development of the LRP approaches, being fore-
seeable in a close future the polymerization control of
several materials that have proved to be suitable for drug
delivery systems. The modern synthetic methods as the
living radical polymerization have been proven to be
extremely versatile tools for preparing tailor-made polymers
that can be covalently attached to biological entities such as
proteins, oligopeptides, enzymes, viruses and cells. This
polymer/drug or polymer/cells systems can then be applied
as therapeutic agents for the treatment of several diseases,
namely Diabetes mellitus.
ABBREVIATIONS
ATRP = Atom Transfer Radical Polymerization
DM = Diabetes Mellitus
DT = Degenerative Transfer
HEMA = 2-Hydroxyethylmethacrylate
LRP = Living Radical Polymerization
FRP = Free Radical Polymerization
MADIX = Macromolecular Architecture Design by
Interchange of Xanthates
New Drug Delivery Systems - Diabetes Infectious Disorders - Drug Targets 2008, Vol. 8, No. 2 127

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Received: February 28, 2008 Accepted: May 6, 2008