Current Drug Targets, 2004, 5, 449-455 449

Drug Delivery Systems: Past, Present, and Future

Rubiana M. Mainardes1 and Luciano P. Silva2,*

1
Pós-Graduação em Ciências Farmacêuticas, Faculdade de Ciências Farmacêuticas, Universidade Estadual Paulista
“Júlio de Mesquita Filho”, Araraquara, 14802-902, Brazil and 2Pós-Graduação em Biologia Animal, Instituto de
Biologia, Universidade de Brasília, Campus Universitário Darcy Ribeiro, Brasília, 70910-900, Brazil

Abstract: Drug delivery systems are essential components of drugs controlled release. In the last decades, several drug
delivery technologies have emerged including capsules, liposomes, microparticles, nanoparticles, and polymers. These
components must be biocompatible, biodegradable, and display a desired biodistribution providing a long-term
availability of the therapeutic at specific target over time.

Key Words: Drug design, microtechnology, nanotechnology, nanospheres, nanocapsules, antibody-based drug delivery.

INTRODUCTION the first known people to actually carry out chemical

The applicability of drugs is almost always a delicate
compromise between their therapeutic roles and side effects.
Current advances are aiding the discovery and rationale
design of many new classes of drugs. It is clear that to turn
these new advances into clinical effectiveness is crucial to
improve specific drug delivery methods opening novel
therapeutic horizons.
Controlled drug delivery technology represents one of the
most intriguing frontier areas of science, which involves
multidisciplinary fields. Biology, pharmacy, chemistry,
physics, and medicine work together to provide rapid and
consistent advances in this vanguard area.
Therefore, the development of techniques that could
selectively deliver drugs to the pathological site is currently
one of the most important areas of drug research. This
review focuses on the fundamental concepts and approaches
of drug delivery systems with particular emphasis on recent
and perspective advances on this area.
HISTORICAL PERSPECTIVE OF DRUG DELIVERY
SYSTEMS
The drug delivery system concept is not new despite
great progress has recently been made in this area. Modern
drug delivery systems have been modeled for centuries and
their development appear parallel that of Humanity. The
history of drug delivery technology can be didactically
divided in three parts. From Pharmacy origin to Industrial
Revolution, macroscopic delivery systems were developed.
It is impossible to put an exact date when drug delivery
approaches originated since people were practicing Phar-
macy before the word even existed. The Ancient Populations
of Mesopotamia, Egypt, China, and indigenous peoples of
the Western Hemisphere (Aztecs, Mayans, and Incas) were
*Address correspondence to this author at the Pós-Graduação em Biologia
Animal, Instituto de Biologia, Universidade de Brasília, Campus
Universitário Darcy Ribeiro, Brasília, 70910-900, Brazil;
E-mail: paulinoluciano@unb.br
processes to therapeutic. A number of systems containing
polymers existed and commonly waxes were added with the
drugs to extend their action mechanisms or improve some
feature like site specificity. From Industrial Revolution to
1970 different drug delivery technologies were developed.
The Industrial Revolution had a major effect on how Phar-
macy was practiced. The advent of the machines allowed the
large scale production of important systems commonly used
nowadays, including capsules and microparticles. After
1970, site directed drug delivery systems developed very
rapidly and such strategies have been constantly “updated”
including liposomes (immunoliposomes, magnetoliposomes),
nanoparticles (magnetic nanoparticles, polymeric nanopar-
ticles), high technology polymers (dendrimers), and virus.
For proper perspective, a simple literature search with the
keywords "drug" and "delivery"; "drug" and "target"; and
"drug" and "design" for the last 13 years is shown in Fig. (1)
revealing the crescent academic importance of these area.
DRUG DELIVERY VEHICLES ON A PERSPECTIVE
VIEW
Finding solutions to deliver drugs at specific sites is not a
contemporary issue but remains as a crucial biomedical
aspect. The constant development and design of optimized
strategies involving polymers, nanoparticles, liposomes, and
others active or passive delivery systems has been a
revolution on the way that the drugs exert their actions and
several novel strategies are developed and tested all years.
POLYMERS IN DRUG DELIVERY
One of the enduring features of drug delivery techno-
logies is the central role that polymers play in control of drug
release, and fabrication of drug delivery devices. The need
for polymers with desired biological and physical properties
has generated continuing interest in novel polymer synthesis.
Classification of polymers in drug delivery applications
can be difficult due to the inherent diversity of chemical
structures. In broad terms, polymers may be classified as
either biodegradable or nonbiodegradable. Biodegradable

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450 Current Drug Targets, 2004, Vol. 5, No. 5
Fig. (1). Occurrences in the Institute for Scientific Information - ISI database, including all journals of the Science Citation Index - SCI to
"drug and delivery", "drug and target", and "drug and design". Per year search results for the last 13 years of the used words. Results are
shown for abstract, keyword, and title searches.
devices have garnered much of the recent attention and
development in drug delivery systems because they do not
require retrieval or further manipulation after introduction
into the body [1]. In the realm of degradable polymers, there
exists another level of classification based upon the mechan-
ism of erosion. It is essential recognize that degradation is a
chemical process, whereas erosion is a physical phenomena
dependent on dissolution and diffusion processes. Two
mechanisms of polymer erosion can be identified: surface
and bulk erosion. For most biodegradable polymers both
mechanisms occur, but the relative extent of surface or bulk
erosion varies radically with the chemical structure of the
polymer backbone [1, 2].
A wide array of natural and synthetic biodegradable
polymers has been investigated for prolonged drug release or
drug targeting. However, only a few of them are actually
considered biocompatible. Biodegradable polymers are
degraded in vivo, either enzimatically or non-enzimatically
to produce biocompatible, toxicology safe by-products which
are further removed by the normal metabolic pathways.
Drugs formulated in polymeric devices are released either by
diffusion through the polymer barrier, or by erosion of the
polymer material, or by a combination of both diffusion and
erosion mechanisms [3-5]. Both of these mechanisms are
influenced by the degradation rate of polymer [6, 7]. The
polymers selected for the parenteral administration must
meet several requirements like biocompatibility, drug com-
patibility, suitable biodegradation kinetics and mechanical
properties, and ease of processing [3].
Mainardes and Silva
Polyester-based polymers are the best characterized and
the most widely studied biodegradable systems. Polylactic
acid (PLA), polyglycolic acid (PGA) and their copolymers
polylactic-co-glycolic acid (PLGA) are some of the most
well-characterized biomaterials with regard to design and
performance for drug-delivery applications based on
diffusive and/or erosive biodegradative aspects [1, 3, 8-13].
It is possible to modify the mechanical, thermal and
biological properties of PLA by altering its stereochemistry.
Further biodegradability can be tuned by changing the
proportion of PLA and PGA in the copolymer [1, 2]. The
lactide/glycolide polymers chains are cleaved by hydrolysis
to form naturally occurring metabolites (lactic and glycolic
acids), which are eliminated from the body by the citric acid
cycle [1, 3, 7, 14-17].
The need to develop biodegradable polymers that inhibit
drug release by diffusion mechanisms and allow drug release
only after the hydrolysis of polymer chains at the surface of
the device was the motivation for designing the polyor-
toesters for drug delivery [1]. Polyorthoesters have been
under development since the 1970. To date four polymer
families have been developed and they have singular features
among all biodegradable polymers, as mechanical properties
can be readily varied by choosing appropriate diols or
mixture of diols used in their synthesis [2, 18].
Polyanhydrides have been investigated as an important
biomaterial used for short-term release of drugs for more
than two decades [19]. Polyanhydrides are characterized by
their rapid degradation followed by fast erosion of material,
Drug Delivery Systems
but at the same time can be designed to release drugs that
last from days to weeks by suitable choice of monomers [2].
The more hydrophobic the monomer, the more stable the
anhydride bond is to hydrolysis. Aliphatic polyanhydrides
degrade within days whereas aromatic polyanhydrides
degrade over several years [1, 20].
Since poly-amino acids are chemically and structurally
related to natural proteins, the synthesis of amino acid-based
polymers has been explored as a potential source of new
biomaterials. Starting from about 1970, the use of both homo
and copolymers of amino acids was studied for a variety of
biomedical applications [21-25]. Poly-amino acids that have
good biocompatibility have been investigated to deliver low-
molecular-weight compounds. However, amino acid-based
drug delivery approaches are limited by their antigenic
potentials and poor controlled release due to the dependence
on enzymes for biodegradation. So far, only a small number
of polyglutamic acid and copolymers have been identified as
promising candidate materials for drug delivery [26, 27].
A relatively novel class of biodegradable polymers
belonging to polyphosphoesters has a single backbone
consisting of phosphorous atoms attached to either carbon or
oxygen. The uniqueness of this class of polymers lies in the
chemical reactivity of phosphorous, which enables a wide
range of potential side-chains to be attached for manipulating
the molecular weight, biodistribution, and biodegradation
rates of the polymer [2].
Chitosan is a polysaccharide derived by deacetylation of
chitin, a by-product of the seafood industry. Chitosan meets
the important requirements for excipients in drug delivery,
including biocompatibility and biodegradability. Chitosan
has been investigated as mucoadhesive polymer for years
[28], and more recently as a permeation enhancer for drug
delivery in vitro [29] and at mucosal epithelia [30]. The
degree of deacetylation and derivatization with various side-
chains can be a source of manipulation for site-directed drug
delivery applications [2, 31].
Cyclodextrins (CDs) are potential high-performance
carrier materials that have the ability to alter physical,
chemical, and biological properties of drugs through the
formation of inclusion complexes both in solution and solid
state. The alpha, beta, and gamma CDs are the most common
naturally occurring CDs consisting of six, seven, and eight
D-glucopyranose residues, respectively, linked by alpha-1,4
glycosidic bonds into a macrocycle [2]. Recently, a number
of CD derivatives and polymers have been suggested to
obtain better inclusion abilities. The hydrophilic and hydro-
phobic CDs are useful for the immediate or prolonged release
type formulations, respectively. Commonly, the combination
of CDs and other carrier materials is useful for optimizing
the release rate of drugs [32]. In drug discovery, CDs have
mainly been used to increase the aqueous solubility and
stability of poor hydrophilic drugs. CDs complexation of
lipophilic drugs has also been shown to increase drug bio-
availability [33]. For some years CDs and their hydrophilic
derivatives have been described in the literature as solubi-
lizers capable of enhancing the loading capacity of lipo-
somes and microparticles. Its main purpose was to combine
some advantages of CDs (e.g. increased drug solubility) with
some advantages of liposomes (e.g. targeting of drugs to
Current Drug Targets, 2004, Vol. 5, No. 5 451
their activity site) and microparticles (e.g. slow release) into
a single system circumventing problems associated with
each system [34].
POLYMERIC MICELLES
Block copolymer micelles are promising carriers in drug
delivery systems. Originally, the block copolymer micelles
composed of amphiphilic block copolymers were used as a
carrier of various hydrophobic drugs including anticancer
agents [35]. A polymeric micelle usually consists of several
hundred block copolymers and has a diameter ranging from
20 to 50nm. There are two spherical concentric regions of a
polymeric micelle, a densely packed core consisting of
hydrophobic blocks and a shell consisting of a dense brush
of hydrophilic block. Polyethylene oxide (PEO) is frequently
the hydrophilic block, but others are being studied.
Hydrophobic blocks include poly-alpha-hydroxy acids and
poly-L-amino acids [36, 37]. The molecular weight of the
hydrophobic block is usually less than 2000g per mol [38].
There are a number of reasons why polymeric micelles
are interesting as drug carriers. As a solubilizing agent for
hydrophobic drugs they have a clear advantage over low
molecular weight surfactants in view of the higher stability
of the produced micelles [35, 36]. This higher stability is
reflected in terms of the usually very low critical micelle
concentration of polymeric surfactants. This means that
polymeric micelles are resistant to dilution effects, upon for
example intravenous administration of the drug formulation.
Another important characteristic of micelles, when compared
with other typical delivery methods, is their small and
uniform particle size distribution. In theory, particle sizes
can go down to the order of 10 nm for non-loaded polymeric
micelles. This size is still large enough to accomplish passive
targeting to cancer and inflamed tissues. As said above, the
hydrophilic corona of the micelles may prevent interaction
with blood components. This characteristic and their small
size prevent immune system recognition, and thus long
circulation times in the blood stream may be achieved.
Active targeting is also possible by modifying the peripheral
chain ends of the polymers with targeting specific ligands.
For the release of the drugs once the micelles have reached
their targets, degradable or stimuli-responsive micelles have
been recently developed [35- 38].
In addition to conventional therapeutic drugs, block
copolymer micelles might play a role in gene delivery.
Several groups have utilized highlight electrostatic binding
to form micelle-like complexes of block copolymers with
oppositely plasmid DNA.
Lastly, block copolymer form unique thermolar sensitive
hydrogels for drug delivery and novel micelles for diagnostic
imaging [39, 40]. The wide breadth of roles in drug delivery
strategies is evident, and owing to their unique ability to
form nanoscopic supramolecular structures, additional
approaches in drug delivery and similar fields such as tissue
engineering will likely emerge next years [35].
POLYMERIC NANOPARTICLES AND MICROPAR-
TICLES
Over the past few decades, there has been considerable
interest in developing biodegradable nanosized particles as
452 Current Drug Targets, 2004, Vol. 5, No. 5
effective drug delivery devices because they have the ability
to deliver a wide range of drugs to varying areas of the body
for sustained periods of time [10-11, 41]. More recently, they
have even been found to be efficient vectors to deliver
synthetic small fragments of DNA into cells [42].
Nanoparticles are roughly defined as submicron-sized
colloidal systems (vary in size from 10 to 1000 nm) biode-
gradable or not. Depending upon the process used for the
preparation of the nanoparticles, nanospheres or nanocap-
sules can be obtained. Nanospheres have a matrix-like struc-
ture, where active compounds can be firmly adsorbed at their
surface, entrapped or dissolved in the matrix. Nanocapsules
have a polymeric shell and an inner core. In this case, the
active substances are usually dissolved in the core, but may
also be adsorbed at their surface. Similarly to nanoparticles,
microparticles are a general name for microcapsules and
microspheres. The above-mentioned differences between
spheres and capsules are similar, but their size ranges from 1
to 1000 µm for these carriers [10, 17, 43-44].
Although, a number of techniques have been developed
to prepare nanoparticles and reported to date, the choice of
the technique depends on the nature of the polymer, the drug,
the intended use, and the duration of the therapy. In general,
the methods can be classified into two main categories
according to whether the formation of nanoparticles requires
a polymerization of dispersed monomers or whether it is
achieved directly from an emulsification of natural macro-
molecules or preformed polymers [42, 45]. Many methods
are currently available for the preparation of polymeric nano-
particles, such as emulsification-evaporation method [46],
salting-out procedure [47], and nanoprecipitation method
[48].
Although various polymers are possible to make
nanoparticles for drug delivery systems in vitro, polymeric
materials used to prepare microspheres and nanoparticles for
administration into the human body are significantly limited
to a few kinds of acceptable polymers. Among them, PLA,
PGA and their copolymers such as PLGA are one of the
most used biodegradable polymers to make micro- or
nanoparticles for controlled delivery systems [3, 8-13, 49].
This is largely due to their biocompatibility and to their
resorbability through natural pathways. Additionally, the
degradation rate and consequently the drug release rate can
be manipulated by varying the ratio of PLA, increasing the
hydrophobicity, to PGA, increasing the hydrophilicity [2, 7,
9, 10-13].
Nanoparticles have been extensively investigated in
biomedical areas and, specially, in drug delivery systems for
drug targeting, because their sizes are also acceptable for
intravenous injection [10-11, 43, 49-50] and their property to
allow ligands binding. The advantages of targeted drug
delivery to the specific site of body are in the therapy of
several disease states such as anticancer treatment, bacterial
infection, gene therapy, and viral disease. Therefore, the
application of nanoparticles for drug targeting in vivo has
attracted considerable interest to achieve these aims [49].
MAGNETIC NANOPARTICLES
Magnetically controlled drug targeting is one of the
various recent possibilities of drug delivery. Magnetic-based
Mainardes and Silva
delivery strategies are based on binding drugs with magnetic
fluids (MFs) that concentrate the drug in the site of interest.
MFs are stable colloidal suspensions of magnetic nanopar-
ticles (MNPs) dispersed in organic or inorganic liquid
carriers [51-54]. MNPs are nanometer-sized ferrite- or
magnetite (Fe 3O4)-based spherical particles [55]. In order to
be used for biomedical purposes, MNPs must be pre-coated
with substances enabling them with biostable, biodegradable,
and non-toxic properties. Thus, as biocompatible materials,
MNPs are suitable for drug delivery.
MNPs react to a remote magnetic force enabling them to
be attracted to high magnetic flux density and this feature is
used for drug targeting. The treatment of solid tumors using
drugs associated with MNPs could improve efficacy by
increasing the drug concentration at the tumor. In addition,
hysteresis loss in the alternative magnetic field is an impor-
tant feature of MNPs, because it enables effective thermo-
therapy.
LIPOSOMES AND OTHER LIPID ASSEMBLIES
Liposomes are the major drug carriers that contain lipids
in their functional forms. They are spherical self-closed
structures, composed of well-defined lipid layers which
enclose part of the surrounding solvent into their interior.
Liposomes have diameters ranging from few nanometers to
several micrometers and they can be composed of one or
several concentrically oriented membranes.
They can be classified according to structural features as
large multilamellar liposomes (MLVs), small unilamellar
vesicles (SUVs) or large unilamellar vesicles (LUVs),
depending on their size and the number of lipid bilayers.
Their unique features due to the amphiphilic nature of the
lipids make them suitable for many drug delivery strategies
[56-58]. The hydrophobic bilayer and the hydrophilic inner
core enable solubilization or encapsulation of hydrophobic
and hydrophilic drugs. Liposomal drug delivery systems not
only enable the delivery of higher drug doses, but also a
targeting of specific cells, tissues, or organs. Several studies
based on different drug classes have pointed that harmful
side effects can be reduced or avoided by using liposomes
instead free administration [59]. In addition, liposomes have
been extensively studied as inert carriers for the delivery of
proteins, nucleic acids, and other biologically active agents
into the cells [60].
However, like all other carrier systems, the application of
liposomes in drug delivery has disadvantages. Interactions
with lipoproteins, increased free radicals production, and
complete saturation of the immune system are only some
typical examples of potentially toxic and adverse effects.
Efficient drug delivery systems based on liposomal
approaches need to posses special features. First, good
chemical, coloidal, and biological stability are required.
Second, specific target requires structural and/or chemical
changes related to functional groups incorporation, like
carbohydrates, antibodies, ligands, growth factors, or
magnetic nanoparticles, optimizing drug effects.
The field of liposome targeting has developed rapidly in
the past 25 years to the controlled delivery of molecules. The
primary emphasis of the majority of these efforts focused on
Drug Delivery Systems
strategies for specific liposome targeting. Among the many
schemes devised for controlled drug delivery, three quite
different approaches have proved particularly promising.
1). Ligand-Conjugated Liposomes
Despite of the evident importance of liposome techno-
logy, it is widely held that only a minor fraction of liposomes
fuse with the cell membrane. Liposomes with recognition
molecules adsorb to the cells much more effectively. This
approach involves direct targeting of the drug by conjugation
with a ligand having a distinct affinity for a particular organ,
tissue, cell, or sub-cellular structure. Such ligands typically
include carbohydrates [61], hormones [62], lectins [63],
peptides [64], antibodies [65], and receptor antagonists [66].
Liposomes bounded with antibodies (immunoliposomes)
adsorb to the cells much more effectively than free lipo-
somes. This approach proved to be efficient in delivering
chemotherapeutic [65, 67] and antiviral [68] drugs.
2). Magnetism-Based Liposomes
Magnetically controlled liposomes, so commonly called
magnetoliposomes, are aimed at concentrating drugs at a
specific target site, with the aid of a well-defined magnetic
field [69]. Magnetoliposomes consist of a liposome filled
with nanosized magnetic nanoparticles. A combination of
immunoliposomes and magnetoliposomes has been recently
suggested displaying many advantages over either method
alone, including increased specificity and reduced side
effects [70].
3). Photosensitizer-Based Liposomes
Photodynamic therapy is a promising approach for the
treatment of superficial tumors [71-73]. The therapy involves
the systemic administration of a photosensitizer, which after
a predefined time interval is followed by irradiation of the
tumor region with a non-thermal light [74]. The net result is
that malignant cells become photochemically eradicated.
However, like any other anticancer therapy, in photodynamic
therapy, health tissue adjacent to the tumor mass is damaged.
A lower extent of undesired lesions to normal tissues can be
obtained by associating photodynamic agents with passive or
active targeting vehicles, like liposomes [56].
VIRUS
The so called gene therapy relies on nucleic acid carriers.
Viral vectors have been hypothesized and more recently
developed to deliver genes into eukaryotic cells to regulate
cellular functions or to express useful proteins [75]. Syn-
thetic virus-like supramolecular vectors involve genetically
engineered recombinant viruses that carry the therapeutic
gene in their capsid, thus protecting it from enzymatic
degradation. Despite several recent advances in this area, the
rational and safe design of such strategies requires more
studies.
PROTEINS
Proteins-based drug delivery approaches have been
suggested for years [76]. Albumin is a plasma protein and
due to several factors it is the best candidate for drug
Current Drug Targets, 2004, Vol. 5, No. 5 453
delivery approaches [77]. Albumin special features include:
1) abundance and bioavailability; 2) large circulation on the
body; 3) several potential binding sites of different affinities.
DENDRIMERS
Dendrimers are polymeric macromolecular complexes
that comprise a series of well-defined branches around an
inner core [78]. Dendrimers are produced in an iterative
sequence of well-conducted reaction steps, in which each
additional iteration leads to a higher generation dendrimer
(that correspond to the number of layers). Since their
discovery in the early 1980s, dendrimers are the best
examples of controlled hierarchical synthesis allowing the
generation of complex systems. Special features concerning
dendrimers synthesis include the possibility to finely control
the size, composition, and chemical reactivity in a manner
that make it works like a machine.
Virtually any polymer could be used to generate a dendri-
mer. The first structure that was well characterized was the
polyamidoamine dendrimers or PAMAM dendrimers [79]
which are constructed using a reiterative sequence of steps
and products up to generation 10 have been obtained. In the
last 10 years dozens of interesting dendrimer types have
appeared and investigated displaying suitable applicability.
MICROMACHINES AND NANOMACHINES
About four decades ago, the quantum theorist and Nobel
Laureate Richard Feynman became the first individual to
suggest the miniaturization of structures. In his famous
lecture titled “There's Plenty of Room at the Bottom.”
(1959), he examined the infant field of materials nanoscience
speculating at how small a machine could be made and still
be consistent with the known physics laws including quan-
tum mechanics. Despite of intense discussions concerning
this topic, there was no consensus until two decades ago.
Drexler [80] applied the term molecular nanotechnology in a
serious unified form to describe advanced precise capabi-
lities based on molecular assemblers, proposing devices able
to guide chemical reactions by manipulating reactive
molecules with molecular or atomic levels. In addition, he
advanced the proposal that the molecular machinery found in
biological structures demonstrates the feasibility of doing
advanced molecular engineering to produce complex arti-
ficial molecular machines with atomically precise parts of
nanometer dimensions.
In that way, micro or nanomachines could act as
“intelligent” approaches of drug delivery. The importance of
such methodologies in a near future is undoubtedly and
current efforts have been devoted in this area. However,
there is no warranty that all potential risks will be taken into
account.
PHARMACOKINETIC AND PHARMACODYNAMIC
CONSIDERATIONS OF DRUG DELIVERY SYSTEMS
The development of controlled drug delivery is based
practically in to modulate the magnitude and duration of
drug action. To enable optimal design of controlled release
systems, an understanding of the pharmacokinetics and
pharmacodynamics of the drug is essential.
454 Current Drug Targets, 2004, Vol. 5, No. 5 Mainardes and Silva

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Received: March 19, 2004 Accepted: March 23, 2004