Download III. challenges in drug delivery

BME 1450 Midterm Paper by Sawitri Mardyani
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Rational Development of Drug Delivery Systems
through Systems Biology
Sawitri Mardyani, Member, IEEE

Abstract—Up to now, many drug delivery strategies have been
developed through hit and miss methods. A move towards rational
design requires an understanding of how the components in the
human body work together as a system. Using systems biology,
drug delivery strategies may be simulated, existing strategies may
be optimized, and new strategies may be developed that take
advantage of existing structures in the body in order to deliver the
right amount of drug to the right place at the right time.
Index Terms—drug delivery systems,
strategy, simulation, systems biology
mechanism-based
I. INTRODUCTION
I
N the process of developing drugs to treat human diseases, it
is not sufficient to merely develop a molecule that would act
to produce a desired response. There must also be an effective
method for delivering the drug to the target tissue.
Ideally, the drug delivery strategy should safely transport the
drug molecule through the body to reach the target tissue.
Through this transport route, the drug should be protected so as
not to lose its effectiveness and so that healthy tissues that are
passed en route to the sick tissue are not adversely affected by
the drug. Once the drug reaches its target site, it should be
released in just the right quantity to produce the desired healing
effects. This ideal drug delivery situation would optimize the
effectiveness of the drug and minimize its side effects.
Many past advancements towards the ideal drug delivery
strategy have come out of serendipitous discoveries and
hit-and-miss research methods [1]. In order to develop a more
rational, systematic approach, it is necessary to have an
understanding of how the human body works as a whole. Along
with providing a better process for creating better drug delivery
strategies, this holistic understanding of a biological system may
inspire entirely new methods for administering drugs to
unhealthy cells or tissue.
This paper will discuss the relevance of systems biology to
drug delivery research, outline some of the challenges faced in
drug delivery and how a systems biology understanding can be
used to overcome those challenges. It will also discuss some
current drug delivery methods that were developed using
knowledge from systems biology.
Manuscript submitted October 28, 2003. This work was supported in part
by NSERC.
S. Mardyani is with the University of Toronto, Toronto, ON M5S 1A1,
CANADA (email: [email protected])
II. SYSTEMS BIOLOGY
A. A holistic approach
Systems biology studies how the components of a biological
system work together [2]. It tries to model the interactions of
different components in a biological system and then use that
model to predict how the system would respond to stimuli [2].
Whereas traditional biology often focused on only one
particular component of a system, systems biology aims to study
how they all work together [3]. It is this dynamic understanding
that is necessary to design effective drug delivery strategies.
The immediate appeal of such an approach from a drug
delivery standpoint lies in the fact that the drug delivery process
involves the interaction between many biological components.
In its journey to a target tissue or cell, a drug molecule may pass
by several organs and many different types of cells, receptors
and proteins. In order to develop effective drug delivery
methods, we need to look at the big picture of how these
components interact with each other.
Putting together this big picture requires an interdisciplinary
effort [3]. The information collected by the biologists is
compiled to produce a computer model. In this model, equations
and algorithms describe the behavior of each component [3].
The complexity of biological system limits the effectiveness of a
simple intuitive understanding when it comes to predicting
results [2]. Thus, computers are needed to produce accurate
simulations of biological systems. Through the combined
efforts of biologists, mathematicians, computer scientists, and
control systems experts, computer models are made that
simulate the behaviors of the biological systems [3].
B. Computer simulation
Computer simulation has important applications in drug
delivery. A computer model of a biological system can be used
to test the effectiveness of a drug delivery strategy in simulation
before they are tested in vitro or in vivo. Although in silico
testing cannot replace the wet lab altogether, it can provide
valuable insights into what strategies work best. It can be used
to optimize delivery methods and develop new ones.
C. Working with the system
Besides the use of computer simulations for research, one of
the most valuable fruits gained from using systems biology for
development of drug delivery strategies simply comes from the
new way of looking at things. By studying the system and
BME 1450 Midterm Paper by Sawitri Mardyani
understanding how it works, we can develop delivery methods
that work with the system by capitalizing on existing structures
and pathways.
Mechanism based approaches can be designed to more
effectively use the existing biological structures to transport
drug molecules to their target. Such approaches have been used
in the development of cancer treatments that are now starting to
appear on the market [5]. Essentially, these new cancer
treatments are designed to halt a specific cancer-causing
mechanism. The difference in applying this design strategy to
drug delivery is that we are not looking for ways to disable an
existing mechanism but to take advantage of it. We can use the
human body and its pathways of operation as a blueprint for our
drug delivery strategies.
Like human-made systems, biological systems exhibit
patterns in the way their parts work [4]. Rather than completely
re-inventing the wheel, we can mimic pre-existing systems in
our attempts to deliver drug molecules to specific tissue. By
understanding and then adopting existing biological systems,
patterns of operation or ‘motif’, we will be able to deliver drugs
by working in cooperation with the human body’s own systems
and components [4].
D. A knowledge-based approach
Much of the difficulty in developing effective drug delivery
methods arises out of our limited understanding about how the
human body works. Rational design of drug delivery methods
cannot proceed without first trying to fill this knowledge gap.
Because drug delivery involves the interaction between many
different biological components, it is necessary to develop a
holistic understanding of how the body works as a system. This
knowledge-based approach can be used to tackle many of the
challenges seen in drug delivery today.
III. CHALLENGES IN DRUG DELIVERY
A. The gastrointestinal tract
Oral drug delivery is one of the simplest methods to bring a
drug molecule into the body. It is especially important in
developing countries where clean syringes and medical
professionals may be hard to find [6]. However, especially in
the case of protein-based drugs, the low pH of the gastro
intestinal tract may degrade a drug molecule so that it loses its
function [7]. Thus, in order to preserve its effectiveness a drug
must be protected from the acid in the stomach.
Once it passes through the stomach, the drug must be
absorbed in the intestine. Despite numerous animal studies,
there remains controversy about the efficiency and the site of
intestinal absorption [7]. Many of these studies use microscopy
techniques where the sample preparation process may introduce
artifacts into the measurements [7]. Further study must be done
to develop a better understanding of this process. A
comprehensive study of absorption through the intestine can be
done using a systems biology approach.
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First, data from previous studies would be collected, keeping
in mind the context in which these studies were performed [2].
Data from studies about the intestine as a whole, and individual
cells in the intestine as well as components inside those cells
would be put together to make a computer model of the
intestinal absorption process. Predictions from this computer
model would be compared to experimental results. Where
predictions do not match the results, the assumptions made by
the model must be examined and new experiments can be
conducted to ascertain the validity of such assumptions [2].
Through this iterative process, the computer model of the
intestine is refined and a predictive model can be developed [2].
With this predictive model, new oral drug delivery strategies
may be tested in silico before they are tested in vivo.
A similar strategy has been used to model drug delivery for
cystic fibrosis. Using a supercomputer model of the lungs and
fluid dynamic equations to describe the trajectory of inhaled
drug particles, this model offered new insight into the
deposition patterns of inhaled drugs for patients with cystic
fibrosis [8]. Using the model, inhaled drugs can be designed for
optimal deposition in affected areas of the lung [8]. A similar
model of the intestine could provide valuable insight into what
forms of drug delivery vehicles would provide the most efficient
transfer of a drug into the blood stream.
B. The Blood Stream
The blood stream is another challenge met by drug
molecules. As the drug molecule travels through the blood
stream, it must be able to find its destination tissue. The blood
stream poses many hazards to an unprotected drug molecule.
Foreign molecules do not stay very long in the blood stream as
the body is designed to identify these molecules, disable them,
and excrete them. The natural defense mechanisms are
particularly problematic for drugs such as anti-coagulants
whose targets are in the blood stream.
One recent strategy to overcome this problem was to attach
the drug molecule to red blood cells and then inject these cells
back into the blood stream. The Muzykantov research group
from the University of Pennsylvania used this strategy to deliver
a drug that destroys blood clots in the heart. By disguising the
drug under the cover of a red blood cell, the research group was
able to increase its effectiveness. Using this Trojan horse
strategy, the drug attached to the red blood cell stayed in
circulation more than ten times longer than unattached red
blood cells and was thus able to eliminate more clots. This
delivery method also reduced side effects by keeping the drug in
the vascular system away from other tissues where it may have
caused excess bleeding. [9]
This novel drug delivery strategy is an excellent example of
rational design. By using the body’s existing vascular system to
their advantage, the group was able to increase the effectiveness
of the drug while reducing side-effects. Through increased
understanding gained from studies in systems biology, similar
solutions in even more complex environments may be designed.
BME 1450 Midterm Paper by Sawitri Mardyani
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Fig. 2. Implantable self-regulation responsive drug delivery system under
development by ChipRx. [13]
This kind of thinking, where known biological processes are
used to inspire new delivery strategies, will only increase with
the increased knowledge from systems biology.
Fig. 1. Receptor-mediated endocytosis [10]
C. Traversing the cell membrane
The cell membrane poses a difficult challenge for a drug
molecule to overcome. Its function is to protect the cell from
foreign invaders while allowing cell nutrients to enter and cell
waste to exit [1]. Unfortunately, because the drug molecule is a
foreign invader, it has a difficult time crossing this membrane.
One way to bring a drug into the cell is to hijack the cell’s
own transporters. Exploiting receptor-mediated endocytosis is
one example of this strategy. Fig. 1 shows a schematic of
receptor-mediated endocytosis. Here, a drug carrier takes
advantage of protein transport systems built into the cell
membrane. Receptors in the cell membrane produce vesicles
that ferry large molecules into the cell. These receptors are able
to recognize different molecules and will only give passage to
molecules that the cell needs. By disguising itself as one of
these needed molecules, a drug molecule carrier can hijack this
transport system and penetrate through the cell membrane. [1]
In order to exploit receptor-mediated endocytosis for drug
delivery, we must know what sorts of molecules the cell is
looking for. The capsule carrying the drug can then be
conjugated with that molecule so when the cell takes in its
molecule of interest, it will bring the drug molecule in with it.
This strategy has been successfully exploited for some new
nano-particle delivery systems that are still in experimental
stages [11].
A further development to this delivery scheme could be to
take advantage of the changes in the environment of the drug
capsule as it enters the cell through endocytosis. For example, it
is known that the interior of the vesicle produced through
endocytosis experiences a decrease in the pH as it enters the cell
[11]. This is the effect of a proton pump on the vesicle
membrane [11]. This decrease in the pH can be exploited as a
mechanism to release the drug from its transportation capsule.
One way to implement this would be to use polymer-based drug
carriers that mimic the body’s secretory granules [12]. If these
carriers are made small enough, they may be able to enter the
cell through endocytosis and carry drugs to the cell.
D. Regulated drug delivery
Bringing the drug to the target tissue is just one aspect of drug
delivery. Administering the right amount of drug to the target
tissue is another challenge. This involves a feedback loop where
the response of the patient to the administered drug dosage will
control the subsequent dosage [14]. This feedback loop can
exist on many levels. Usually, the physician will monitor the
status of the patient and administer medication accordingly. In
some cases, especially in the administration of analgesics, the
patient may request or even administer additional doses based
on the presence of pain [14].
One drawback of these systems is the delay between the body
producing a signal and the administered medication taking
effect in response to that signal. It takes time for a patient to
detect a signal and communicate it to the physician. Then the
physician must make a decision, decide what drug at what dose
to deliver and then deliver the drug. In addition, more time is
then taken for the drug to enter the system, find the target tissue
and then take effect. Another drawback of these feedback loops
is the cost of monitoring the system for responses and the tests
required to measure those responses. By bringing the
administration control directly to the site of the drug release,
this delay and cost can be significantly reduced.
The tissue and the drug could act together in a feedback loop.
If the drug delivery vehicle can sense when the tissue needs
more drugs, it could respond by increasing the dose.
Conversely, if the tissue has healed and is no longer in need of
these drug molecules, the drug delivery system should stop
administering them.
Through understanding the biological system, we can find
what biochemical signals a drug vehicle can monitor and use as
controls for determining the dose to administer. Using a
computer simulation we can find the optimal dose that will
provide the desired response.
An implantable self regulating drug delivery chip is currently
being developed by ChipRx, a biotech company in Utah [13].
Fig. 2 shows a schematic of their implant. It uses biosensors to
determine the correct amount of drug to administer and artificial
muscles control the administration of the drugs.
BME 1450 Midterm Paper by Sawitri Mardyani
IV. DRUG DELIVERY MODELS
As well as providing the inspiration for new methods of drug
delivery, a systems biology approach can also be used to
analyze existing drug delivery strategies. Baxter et al used a
model to study the effects of physiological and antibody-related
variables on their antibody mediated therapy. Their model
included compartments representing organs of interest,
connected in an anatomical fashion. Mass balance equations
were used to represent the intra and extravascular spaces in each
organ. Variables including organ volumes, blood flow rates,
vascular permeability, and binding affinity of the drug molecule
were included in the simulation. This model was found to be
useful in determining what factors affect antibody uptake in
target tissue, optimizing treatment parameters and suggesting
experiments to gather data on important parameters. [15]
More recently, a computer model was used to test the delivery
of asthma medication. Data from MRI images was used to
create a three dimensional computer model of the lung.
Predicted drug deposition patterns were compared with SPECT
(single photon emission computed tomography) images from
human subjects. Results from the model agree with the results
from human tests. [16]
This model can be customized for individual patients.
Because asthma is a disease with many forms and variations, a
generic treatment regime may not be effective for many patients.
The ability to model each patient’s lungs is important for
tailoring the prescription to his or her needs. [16]
V. CONCLUSION
Systems biology has the potential to make many
contributions in drug delivery. Using an understanding of the
human body as a system, mechanism-based delivery strategies
may be developed. Computer simulation may also be used to
gain a better understanding of the dynamics of a system, to test
delivery strategies in silico and to tailor prescriptions to
individual patients according to their needs.
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