Conference Session A2
6057
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USING TRANSCYTOSIS AND DIRECT NOSE-TO-BRAIN DRUG DELIVERY
TO OVERCOME THE BLOOD-BRAIN BARRIER
Christine Heisler, cnh27@pitt.edu, Mahboobin 10:00, Danielle Stark, das 241@pitt.edu, Mahboobin 10:00
Revised Proposal — The blood-brain barrier is an obstacle
for bioengineers and medical researchers in multiple areas of
disease treatment. It creates a physical line of defense against
foreign particles in the bloodstream, preventing their access
to the brain. This poses a problem when treating
neurodegenerative diseases and psychological disorders with
current oral medications because few molecules make it
across the selectively-permeable barrier. As a result, previous
methods of treatment have relied heavily on surgical incisions
and injections to physically break through the blood-brain
barrier, but this use of brute force causes damage to the brain
capillaries and has severe effects on patient health. Finding a
way to penetrate the barrier biologically, or bypass it
altogether, will increase the efficiency of drug deliverance to
the brain without causing more damage. This development
increases the probability of success and minimizes negative
side effects of the medication, making it significant to patients
and their loved ones in addition to the field of bioengineering
as a whole. In this paper, we will discuss two methods of
overcoming the blood-brain barrier: receptor-mediated
transcytosis, which involves crossing the barrier, and direct
nose to brain delivery, which bypasses the barrier. This type
of transcytosis exploits the function of receptors bound to the
endothelial cell membranes, as they allow passage of
nutrients and other critical molecules into the brain.
Meanwhile,
direct
nose-to-brain
delivery
offers
straightforward access to the brain through two main nerve
pathways in the nasal cavity. Both of these methods address
the challenge that the blood-brain barrier presents and make
advances in treatment of neurodegenerative diseases and
psychological disorders. We will continue to consult online
scientific and medical journals, such as the National Center
for Biotechnology Information, and related articles to extend
our understanding of these methods and further demonstrate
their importance in the medical field. Simultaneously, we will
consult sources of neuro- and bio- ethics to address the social
and cultural issues that may arise with use of these
treatments. With further exploration, we will determine the
concrete effects of current research, and discover the larger
implications these techniques will have on future medical
practice.
ANNOTATED BIBLIOGRAPHY
University of Pittsburgh Swanson School of Engineering 1
2016/01/29
“The blood-brain barrier and CNS drug development.”
(2008). D. Stanimirovic, National Research Council of
Canada,
Canada.
(video
lecture).
https://hstalks.com/t/770/the-blood-brain-barrier-andcns-drug-development/?biosci
As a member of a national research council, Dr.
Danica Stanimirovic possesses extensive knowledge of
the brain’s transport mechanisms. In this lecture, she
explains multiple drug delivery strategies, but
emphasizes that they must be “tailored” to specific
diseases in accordance with factors such as target area
location and timing of barrier disruption. With this
information, we will assess the situations in which
receptor-mediated transcytosis is most applicable as a
transport method.
“Breaking through the Blood-Brain Barrier.” (2014).
Genetic Engineering & Biotechnology News. (online
article).
http://www.genengnews.com/gen-newshighlights/breaking-through-the-blood-brainbarrier/81249872/
This article, from a premier biotech publication,
highlights the discovery of a transcytosis-suppressing
gene, Mfsd2a, by researchers at Harvard Medical School.
The article explains that the gene’s removal may allow
targeted drug delivery to the brain and it advocates for
further research on Mfsd2a counteraction to promote
transcytosis. As a result, we will use this source to
analyze possible limitations of receptor-mediated
transcytosis because the gene presents an obstacle.
P. Brey ‘Biomedical Engineering Ethics.’ (2009). A
Companion to Philosophy of Technology. Blackwell.
The ethical overview of biomedical engineering in
this article contemplates crucial issues facing the medical
field, including patient autonomy, confidentiality, human
enhancement, brain imaging, and alteration of
neurological imbalances. By taking these issues into
consideration, we will be able to think critically about the
methods of drug delivery we research and decide if they
are are truly viable options in the process of treating
neurological and mental disorders.
Christine Heisler
Danielle Stark
overall discussion of the challenges associated with these
molecular procedures.
T.Fuchs. (2006). “Ethical Issues in Neuroscience.”
NCBI.
(online
article).
http://www.ncbi.nlm.nih.gov/pubmed/17012939
This scholarly article published on a database that is
supported by the National Institute of Health provides an
analysis of neuroethics. In this article, Fuchs raises
several important questions, allowing the readers to
understand that neurological alteration or treatment could
imply a change to the human condition. This article with
help us consider all the potential consequences of direct
drug delivery to the brain.
J. Laterra, R. Keep, L. Betz, G. Goldstein. (1999). Basic
Neurochemistry: Molecular, Cellular and Medical
Aspects. 6th Edition. University of Michigan, Ann Arbor,
MI.
(book).
http://www.ncbi.nlm.nih.gov/books/NBK28180/
In this excerpt from their book, faculty from the
University of Michigan provide background information
on the blood-brain barrier and the types of molecules that
can penetrate it. The passage also argues that the
“barrier” character of the brain endothelium is inducible
and repressible in other tissue. Thus, we will use this
source to examine the opposite perspective of most
treatment research: changing the barrier rather than the
drug.
D. Hoekstra, I. Zuhorn, J. Georgieva. (2014).
“Smuggling Drugs into the Brain: An Overview of
Ligands Targeting Transcytosis for Drug Delivery across
the Blood-Brain Barrier.” pharmaceutics. (online
article).
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4279133
In this article from a peer-reviewed pharmaceutical
journal, the authors comprehensively identify biological
pathways into the brain and the vectors able to traverse
them. The article states there is no current “ideal vector”,
but argues that using enhanced in vitro models of the
blood-brain barrier and imaging that tracks both drug and
vector presence, one may be determined. We intend to
integrate the specifics of Angiopep-2 and Transferrin
vectors in our mechanism explanation.
J. Lochhead, R. Thorne. (2011). “Intranasal delivery of
biologics to the central nervous systems”. Science Direct:
Advanced Drug Delivery Reviews. (online article).
http://ac.els-cdn.com/S0169409X11002791/1-s2.0S0169409X11002791-main.pdf?_tid=942b7ba8-c05611e5-86cb00000aab0f6b&acdnat=1453391559_7a30ba2b75b63b9
8dd7bf6639ff95ff7
This scientific article, published on a reputable
database, provides in-depth information on the intranasal
route of drug administration through the trigeminal and
olfactory nerves in the nasal cavity. It defends the use of
this non-invasive method of bypassing the barrier by
providing proof of its clinical success. This information
will aid in our explanation of the direct nose-to-brain
drug delivery process and the validity of this technique in
clinical settings.
T. Insel. “Toward a new understanding of mental
illness.”
TEDxCaltech.
(2013).
(Video).
https://www.ted.com/talks/thomas_insel_toward_a_new
_understanding_of_mental_illness?language=en#t763765
This TED talk, given by the Director of the National
Institute of Mental Health, offers a vitally important
perception of mental disorders. By discussing the
traumatic impact of disorders such as depression and
schizophrenia, the speaker provides an inspirational
reminder of our initial purpose in writing this paper: to
investigate more efficient treatments of neurological and
mental disorders. This video will allow us to demonstrate
the patient’s perspective in our paper.
Overcoming the (BB)Barrier: Strategies for Delivering
Drugs into the Brain- BrainTech. Israel Brain
Technologies.
(2015).
(Video
lecture).
https://www.youtube.com/watch?v=n4y-JWUejR0
This lecture was presented last year at the
International Brain Technology Conference in Tel Aviv,
Israel. It describes research about a gene that hinders
transcytosis through brain capillaries. Later in the lecture,
the speaker strongly advocates for a new nasal drug
delivery device. These topics directly relate to the subject
of our paper, and will allow us to discuss the real-world
application of transcytosis and direct nose-to-brain drug
delivery.
E. Kerns. (2014). “Blood-Brain Barrier in Drug
Discovery: Optimizing Brain Exposure of CNS Drugs
and Minimizing Brain Side Effects for Peripheral
Drugs.” ProQuest ebrary. (online book).
This book, written by biomedical and pharmaceutical
researchers, discusses drug interactions in the brain by
outlining a variety of techniques, including nanoparticle
targeted delivery, receptor-mediated transcytosis, and
receptor ligand delivery systems. Interaction strength
between receptors and ligands and the dependence of
nanoparticles on the medium in which they travel pose
obstacles to these methods. This information will aid our
C. Pardeshi, V. Belglamwar. (2013). “Direct nose to
brain drug delivery via integrated nerve pathways
bypassing the blood-brain barrier: An excellent platform
for brain targeting.” Research Gate. (online
article).DOI:10.1517/17425247.2013.790887
2
Christine Heisler
Danielle Stark
This research article, written by representatives of the
Patel Institute of Pharmaceutical Education and
Research, provides background information on the noseto-brain drug delivery method. Along with extensive
discussion of the olfactory and trigeminal nerve
pathways, intranasal administration in practice, and
potential treatment of disease, this article discusses both
the advantages and limitations of nose-to-brain drug
delivery systems, providing us with the ability to discuss
all aspects of these systems.
M. Scudellari. (2013). “Penetrating the Brain”. The
Scientist. (online article).
This magazine article briefly discusses different
methods of breaking the blood-brain barrier, including
transferrin receptor mechanisms, receptor-mediated
transcytosis, liposome alteration, ultrasound, and direct
nose-to-brain drug delivery. Through insights from
several experienced individuals, including a Johns
Hopkins nanomedical researcher and a pharmaceutical
company founder, this article provides a concise
overview that sparked our interest in the blood brain
barrier and will help us discuss different techniques that
address biological barricade.
G. Xiao, L. Gan. (2013). “Receptor-Mediated
Endocytosis and Brain Delivery of Therapeutic
Biologics.” International Journal of Cell Biology. (online
article).
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3693099
Coming from a peer-reviewed international journal,
this article explains the process of receptor-mediated
transcytosis and how it is used for drug delivery. It clearly
outlines that Angiopep-2 conjugated systems and
molecular Trojan horses are the most successful
mechanisms of transport and it challenges researchers to
address the issue of receptor saturation. We will utilize
this information to provide background on our topic, and
explain positives and negatives of this method.
(2005). “Zomig/Zolmitriptan Tablets”. FDA.gov.
(Online
briefing
memo).
http://www.fda.gov/ohrms/dockets/ac/05/briefing/20054152b1_05_05_Zomig%20label%20FDA%2011-1604.pdf
This Federal Drug Administration briefing contains
information on the usage, active ingredient, and
molecular mechanisms of zolmitriptan, a migraine
headache medication. The medication binds with 5HT1D receptors to restrict capillaries in the brain, and
through nasal administration, has the potential to act
much faster than an oral tablet. This information helped
explain the mechanism of nasal administration and will
aid our discussion of the benefits of direct nose-to-brain
drug delivery.
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