Vignesh Pernati

October 10, 2016

Period 1
Annotated Source List
American Society for Clinical Pharmacology and Therapeutics. American Society of Clinical
Pharmacology and Therapeutics, www.ascpt.org. Accessed 10 Oct.2016.
The American Society for Clinical Pharmacology and Therapeutics provides
information on the advancements occurring in clinical pharmacology and medicine for
therapeutic benefit of patients. The source contains information about current advancements,
meetings, membership policies and access to the Journal of Clinical Pharmacology and
Therapeutics. Their main page displays recent achievements of scientists, annual meetings,
online seminars and other content. This includes podcasts, journal blogs, journal submissions and
the latest news and events. The website is organized into 9 separate webpages. They are About
ASCPT, Membership, Knowledge Center, Meetings, CPT, CPT PSP, CTS, Career Center, and
Donate. About ASCPT explains the goal of the society and that it focuses on improving the
understanding of existing drug therapies and developing more effective treatments. The
membership page explains the benefit of being a member and news recognizing outstanding
members. The knowledge center provides student resources, tools, and online education. The
Meetings tab gives the dates and locations of meetings occurring in the area. The CPT, CPT PSP,
CTS are the tabs related to the journal and provide an international forum for scientists in the
pharmacology space. The CPT tab includes the history of Clinical Pharmacology and
Therapeutics, also journal statistics and an abstract index. CPT:PSP is an online only involved in
publishing advances in quantitative methods in pharmacology. CTS(Clinical and Translation
Science) highlights original research that bridge laboratory discoveries with diagnosis of human
disease. The career center gives links to applications for those who are searching for jobs in the
field.
The source is useful and provides valuable information about clinical pharmacology and
therapeutics. This source provides student resources that can be accessed easily through the
website and may help those who do not understand the content. The website provides very
accurate information and has multiple references to valid journals. The information is also up to
date and new information is always being uploaded on to the website. The CPT journal has
around 33,000 subscribers and around 60,000 downloads yearly. The homepage provides the
latest news articles and there are webinars for members of the organization. The user can also
access journal submissions with their account and access podcasts and blogs to learn more about
topics. The information is oriented towards scientists in the field who may want to reference the
articles in their own article. The information focuses on multiple areas such as infectious diseases
, administration of drugs, proteins and all topics accompanied in pharmacology. The journals are
the most helpful resource and provides information on pharmacology. I can use this reference as
way to research articles and find articles associated to the topic that I am researching.

Azima, H. (1959). Imipramine (Tofranil ): A New Drug for the Depressed .Canadian Medical
Association Journal, 80(7), 535540.
The properties of Imipramine in treatment are discussed and the depressive effects they
have. Imipramine inhibits and reduces the serotonin levels in the brain. This drug has
considerable value in the treatment of depression and help patients with multiple disorders. There
were biochemical tests upon patients and included testing of urine, blood pressure and
temperature. The toxicity of the drugs were tested on mice and the isolated animal organs were
tested upon. The drugs were administered orally to the patients and many were given less then
200mg of the drug daily. The patients continued to have follow ups on the drugs. The therapeutic
results showed that depression seem to form continuous states. The differences between neurotic
and psychotic states were discussed and severity was tested. The depressive symptoms of the
patients was looked at, 3 out of 6 showed improvements and the others did not show any. It
showed improvement in alcoholics who lost their desire to drink. The dosage of the imipramine
have the bearing on the efficacy of the antidepressant therapy. The optimal initial dose was 75mg
daily up to 200 mg daily. 70% of the patients showed therapeutic response and all the patients
may need to take the drug for long periods. The dosage varied in patients from high to low. There
were also many side effects that occurred if the dosage decreased which included agitation,
nausea, respiration, insomnia, and decrease in appetite. There was also muscle weakness that
occurred. Others also experienced bladder problems. The results show that imipramine has a
direct effect on the central nervous system and results became capable of self-assertion.
The source explained well the reason for the use of imipramine and the effects that it has
on the human body. The experiment shows the sample space and the number of people being
tested upon. The administration of the drug into the body and how the toxicity of the drug was
measured. The patients actions and results were taken into account after in taking the drug. The
results showed the withdrawal symptoms from the drugs which explains the side effects that may
occur. Also the calculations of the mgs of drugs is shown and the therapeutic response to the
drug. This allows the reader to refer the information to make a conclusion the effectivity of the
drug. The muscle weakness that occurred can be accounted for and also the effects on the types
of patients. The research shows the patients who were treated by the imipramine. This is shown
using the extended period from around 3 month to 6 months which accurately displays the data.
The anti-depressant therapy showed success in some patients which varied on the admistration of
the drug. The actions of the patients that occurred as a result of taking the drug was accounted
for. This includes aggressiveness, self-destructiveness, guilt feelings, and the involuntary nature
of the patient. The table in the beginning displays the improvement that had taken place and the
number of patients being tested.
Calderon, A. J., Muzykantov, V., Muro, S., & Eckmann, D. M. (2009). Flow dynamics, binding
and detachment of spherical carriers targeted to ICAM-1 on endothelial
cells. Biorheology, 46(4), 323341. http://doi.org/10.3233/BIR-2009-0544
This source refers to the methods involved in attaching nanocarriers to ICAM-1 particles
to the endothelial cells. The use of targeted delivery and therapeutic agents to diseased tissues to
reduce the toxicity. The pathways of administration are discussed and also the optimal carrier
targeting. The administration of NCs are carried through the vesicles and ICAM-1 is used to

improve disease treatment. The selected particle is known as platelet endothelial cell adhesion
molecule (PECAM). The endothelial cells are internalized then transported to lysosomes. The
conjugation of drugs with antibodies used them to bind at the endothelial cells. The antibodies
deliver drug carriers to certain cellular destination and is key to delivery. Drug delivery using
polymer carriers are targeted to platelet endothelial cell adhesion. PECAM-1 is expressed well
with endothelium types and is stable. These particles must have parameters that match the
endothelial surface and can bind. Furthermore, the flow of the blood must be accounted for to
prevent collisions of the particles in the bloodstream. The force can also remove the carriers
bonded to the endothelial surface. Therefore, the adhesion with the endothelial surface must be
strong. PECAM-1 can be with drug delivery and the epitopes (part of an antigen molecule to
which an antibody attaches to) were tested. The Anti-PECAM carriers were prepared and were
then bonded to the endothelial cells. The binding of Anit-PECAM was intracellularly
transported. The results show that they bind efficiently to endothelial cells.
The source provides a problem that need to be solved and reveals the particles that may
be used to solve the problem. Through extensive testing the particle are chosen based on the
experiments done. The source is organized into the material and methods and also the testing
procedures. Furthermore, there also formulas that are present that show the calculation that were
made to show they got their results. There is also analysis that breaks down the information
gathered from the results and tells the importance of the carriers. The diagrams also explain the
flow stress upon the particles and the number of bonds that would be required to prevent carrier
detachments. The source explores the flow parameters of the carriers that are targeted to ICAM1. The use of endothelial cells allows for transport of the NCs. The binding of the cells are useful
in transport and they are able to deliver the drugs. Binding is important in drug delivery and
allows the attachment of proteins to the nanocarriers. This allows the testing of the properties to
see the valid situations. Additionally, we are able to use the correct drug delivery methods
accompanied with the proteins that are used. These particles are biocompatible allowing for the
safe and controllable environment inside of the body. Having controlled substances means there
are less side effects and better treatment plans.
Garnacho, C., Serrano, D., & Muro, S. (2012). A Fibrinogen-Derived Peptide Provides
Intercellular Adhesion Molecule-1-Specific Targeting and Intraendothelial Transport of
Polymer Nanocarriers in Human Cell Cultures and Mice. The Journal of Pharmacology
and Experimental Therapeutics, 340(3), 638647. http://doi.org/10.1124/jpet.111.185579
This source discussed drug delivery plans using ICAM-1 particle and ways to effectively
reach the desired target tissue. In order to achieve this a peptide must be associated with the
ICAM-1 particle. This article discusses the protein being paired and analyzes the effects of the
pairing. Furthermore, the source discusses the needs of the peptide and how the particles should
be transported using cell cultures. ICAM-1 is a transmembrane protein that is expressed on
endothelium and is a suitable target for drug delivery. However, these particles can be attacked
by antibodies which poses a threat to the organisms. Additionally, the nanoparticles are
internalized by the cells and are transported through endocytosis. ICAM- 1 affects endothelial
cells which line the intestines of the body. Antibodies are paired with ICAM particles which
allows them to be undetected in an organism. The antibodies allows for enhanced delivery of
therapeutics. This may result in side effects such as inflammatory reasons and to get rid of

them a peptide known as y3 was used. ICAM strengthens interaction during inflammation. There
were two types of internalization such as clathrin-mediated pathways which are vesicles
completely made of complex proteins and they are found in almost all cells. The other type
includes caveolae are non clathrin coated and consists of a bilayer enriched in cholesterol and is
smaller in diameters. The nanocarriers were bonded to ICAM-1 which were binded to the cells
in culture. The results showed that y3 peptide bonded well with the ICAM. The nanocarriers with
y3 were bounded to the endothelial cells which shows that they are compatible to the Human
cells. The binding of nanocarriers to the human cells were tested. The results support the
targeting utility of y3 NCs.
This source provided information on the internalization and the benefits with the use of
Anti ICAM. There are also visual representation of the effectiveness of the particles. It compares
the internalization of the lysosomes and the bar graphs show the application upon at the liver and
lungs. The source explains the differences between the usages of the particles and is evident
through the visual representations. Furthermore, the material and methods of the show the
culture of the cells and the application in the experiment. This allows scientists to refer to the
methods and use them the sources in their own papers. Finally, the papers are done
professionally and are meant to be read by others studying drug delivery.ICAM Particles paired
with y3 is effective in intracellular transport of drugs throughout the body. he particles can be
used alongside ICAM particles which means that they are compatible. Additionally if y3 serves
as an antibody then the body will not reject it and it will allow the particles to reach the target
tissue. This is valuable because treatment will be much easier and side effects such as
inflammation will not occur. Furthermore, intracellular treatment is most effective with this
method.
Garnacho, C., Shuvaev, V., Thomas, A., McKenna, L., Sun, J., Koval, M., Muro, S. (2008).
RhoA activation and actin reorganization involved in endothelial CAM-mediated
endocytosis of anti-PECAM carriers: critical role for tyrosine 686 in the cytoplasmic tail
of PECAM-1. Blood, 111(6), 30243033. http://doi.org/10.1182/blood-2007-06-098657
Platelet endothelial cell adhesion molecule are involved in leukocyte transmigration, and
represents a good target for endothelial drug delivery. The endothelial cells do not internalize
PECAM antibodies and the nanocarriers causes endocytosis at nonclassic CAM-mediated
pathway. The endothelial uptake of multivalent anti-PECAM complexes is associated with
PECAM-1 phosphorylation. The model REN cells express a series of PECAM which required at
the binding sites. PECAM-1 signal with the cytoskeleton and is required for CAM- endocytosis.
Endothelial cell adhesion molecules play an important role in blood tissue transport and
represent target determinants for drug delivery to the endothelium. The endothelial cells
internalize anti-PECAM protein conjugates and the anti-PECAM. The mechanisms of clathrin
and caveolar endocytosis allow operation in the endothelial cells. This permits intracellular drug
delivery and therapeutic agents. The functions of the PECAM-1 are associated with the
rearrangements of the cellular cytoskeleton. This approach is safe for endothelial drug delivery
purposes. The endothelial cells were cultured and are seeded for experiments and the AntiPECAM complexes were prepared by crosslinking and the multivalent carriers were prepared by
coating anti-PECAM. The effects of anti-PECAM/NCs on endothelial integrity and permeability
was tested along with the pulmonary targeting and effects of the anti-PECAM. The mice were

injected and anesthetized. The PECAM-1 expression levels were determined from cell lysates
and were transferred to difluoride membranes. Furthermore, the RhoA testing of the GTPase
protein was tested with the PECAM-1. The cells were able to internalize multivalent antiPECAM complexes using CAM mediated endocytosis. However, using just the PECAM
antibodies internalization does not occur in the CD cells and REN cells. They PECAM is able to
activate the RhoA in these cells.
The source explains the two methods being used for internalization which includes
PECAM antibodies and anti PECAM complexes for mediated endocytosis. This was used on the
cells to test the activation of RhoA in these cells and were successful in doing so. The source has
multiple figures explaining the expression of the cells and the effect PECAM upon the cells. The
internalization of anti-PECAM is also displayed and is a bar graph explaining the data. It
comparres the internalization between a control cell and a CD cell. There are also figures
showing the incubation period of the cells and also the activity of Rho inside of the cells affected
by PECAM. The models that the source provide allows for a visual representation and it is easier
to understand the data. The biodistribution of the anti-PECAM Ncs is shown using a chart. It is
conclusive that PECAM is suitable for drug delivery and provides therapeutic effects in cell
culture. The discussion portion explains the results that were gained from the experimentation
and summarizes the methods involved. It explains the use of Rho at binding sites of the
endothelium and other particles The article also has footnotes explaining the details and the
references provide more articles related to the topic. The source also provides acknowledgements
to labs and the imaging process involved.
Ghaffarian R, Bhowmick T, Muro S. Transport of Nanocarriers Across Gastrointestinal Epithelial
Cells by a New Transcellular Route Induced by Targeting ICAM-1. Journal of controlled
release: official journal of the Controlled Release Society. 2012;163(1):25-33.
doi:10.1016/j.jconrel.2012.06.007.
The journal of controlled release publishes public research involving the controlled
release and delivery of drugs and other active agents. Controlled release and drug delivery refers
to the passage of drugs and the utilization of biological processes. There is a large spectrum that
include multiple aspects of controlled release and drug delivery. It also involves the use of
polymers, nanoparticles and other particles used in the experiments. The journal has full length
papers and experiments. Nanocarriers are used to transport drugs using a transcellular route
across Epithelial cells. Epithelial cells line the insides of the lungs, the gastrointestinal tract, the
reproductive and urinary tracts. In order to do so they are coated in an ICAM protein. ICAM
stands for intracellular adhesion molecule and they are paired with proteins which serve as a
surface markers. The ICAM targeting provides delivery of therapeutics to the affected area.
Circulation serves as a way of transport known as transcytosis and oral administration is another
way of transporting the drug. The ICAM NCs are engulfed in circulation by macrophages
through endocytosis. Engulfing the NCs allows them to be trafficked throughout the body. In the
experiment, fluorescent polystyrene microspheres were used for tracking particles and cells. In
the experimental phase the required cells were cultured and the ICAM NCs were binded to the
epithelial cells. The ICAM NCs were transported through epithelial layer. The cells used for
intracellular transport were Ca2Co and they were bonded with the ICAM particles. The results
showed that the cells had high levels of ICAM. There endocytosis of Anti-ICAM NCs and can be
used to enhance drug transport

This source was useful in providing valuable information on the transportation of NCs in
the body. The article was organized well and included all the steps taken to produce results. The
experiment replicated functions of the body to get accurate results. Additionally, the article
included multiple citations from other articles to allow easy access to the information. The article
is split into the methods and results to allow the reader to browse through information. The
article describes the transport of the of the ICAM nanocarriers, the mechanisms involved,
targeting of the nanocarriers and the discussion of the results. There are also supplementary
diagrams which give visuals and chart values to help the reader understand the material. The
importance of nanocarriers is that they are used to treat diseases in the body and effectively treat
them in low doses. ICAM NCs will reach the target tissue and there are multiple types of
administration that will allow for diverse treatment for an individual. The protein that are paired
with the ICAM Particles has various effects on the body and they must be tested with the ICAM.
These types of administration favors reduced costs and they help to enhance drugs for
transportation.
Hsu, J., Serrano, D., Bhowmick, T., Kumar, K., Shen, Y., Kuo, Y. C., Muro, S. (2011).
Enhanced Endothelial Delivery and Biochemical Effects of -Galactosidase by ICAM-1Targeted Nanocarriers for Fabry Disease. Journal of Controlled Release: Official
Journal of the Controlled Release Society, 149(3), 323331.
http://doi.org/10.1016/j.jconrel.2010.10.031
The fabry disease occurs due to deficiency of (a-Gal) causes lysosomal accumulation in
multiple tissues. Strategies were developed to enhance delivery of (a-Gal) to organs and other
endothelial cells. A protein was expressed on the endothelial cells and the enzyme on the
nanocarriers were coated with the anti-ICAM. Fluorescence proved targeting and lysosomal
transport of anti ICAM. Fabry disease is lysosomal storage disorder is caused by a genetic
deficiency. ERT using recombinant galactosidases and binds to receptors on the surface of the
cells. They are injected in the circulation and the enzymes accumulate on the tissues. Receptors
in the cells are affected (BBB) the LSD and limit ERT outcome. ICAM-1 targets antibodies and
affinity peptides for delivery of protein conjugates. ERT of Fabry diseases benefits from
strategies enhancing enzyme delivery to organs. Lysosomal enzymes are delivered to
microvascular ECs and was not tested. The enzymes are released in response to lysosome
environmental conditions. There were also multiple antibodies and reagents, he prepares anti
ICAM nanocarriers and enzyme release. There was also cell culture models created for the
endothelial cells and the cells were incubated and found concentrations of sustainable growth.
The anti-ICAM nanocarriers have a intracellular destination and have the functional activity of
the carriers are tested. The characterization shows the nanocarriers assisted targeting of enzymes
for treatment of Fabry diseases. The nanocarriers are accumulated NCs in the lungs. This was
tested upon mice in the experiments and the Vascular ECs were the main target in the
experiment. The Anti ICAMs were internalized with different chemicals and the ECS were
treated with them. The enzyme therapies for Fabry disease is the lysosome and there was
intracellular trafficking of anti-ICAM Ncs were examined. The method provides of intracellular
enzymatic activity. The successful strategies are available for treatment of the disease.
The source explains how ERT allows the Fabry disease to be treated and the strategies
that were put in place to determine the correct way in transporting nanocarriers. The

characterization of the anti-ICAM were shown and the properties required to treat the disease. It
explains the current treatment and how lysosomal storage disorder is affected. The source also
explains how ERT benefits from enhancing enzyme delivery to organs and how this can be
accomplished. The source explains the efficacy patterns of the carriers which are imposed by
biochemical properties of the enzyme. The lysosomal enzymes to microvascular ECs and the
internalization of the nanocarriers to the lysosome was tested. The localizations of the particles
are tested and the nanocarrier assisted enzyme for treatment of Fabry disease. The source
explains the figures that includes the release of a Gal from anti ICAM nanocarriers. There are
also figures explaining the circulation of anit ICAM nanocarriers vs a Gal in the mice. It also
explains the internalization of anti ICAM in lysosomes and compares a gal to anti ICAMs. The
relative distribution across the organs such as the lungs. The source also includes the
supplementary material which shows the tests upon the mice. This shows the incubation of the
chemicals and methods used to treat the chemicals.
Muzykantov, V., & Muro, S. (2011). Targeting delivery of drugs in the vascular
system. International Journal of Transport Phenomena, 12(1-2), 4149.
Biotherapeutics include enzymes and genetic materials which requires sub-cellular
addressing. Endothelials line the surface of blood vessel and are a major therapeutic target in
diseases. The delivery of therapeutics across endothelium requires carriers and cell adhesion
molecules are attractive targets of delivery. Drug delivery system provide control of the
parameters of drugs such as pharmokinetics,blood circulation and internalization into the
endothelium. The protein therapeutics require localization at the cell surface, endosomes,
lysosomes, and other cellular vacuoles. The carriers are introduced into the body in multiple
pharmacological routes and oral delivery of therapeutics is limited by their degradation in the
intestines. However, the blood brain barrier is an obstacle to drug transport, the carriers circulate
through capillaries in which nanocarriers are most useful. The drug carriers include protection of
therapeutics and are optimized for blood clearance. The carrier parameters include stability, and
features that influence targeting. The carriers are coated with glycol and the liposomes. The
carriers encounter multiple interactions with several types of blood cells including phagocytes in
tissues. The endothelium separates the blood from the extravascular tissues and this barrier is
hard to permeate at the brain. In order to achieve targeting the drugs must include antibodies and
other affinity molecules must be coupled to the carrier surface. Therefore, the endothelium acts
as a barrier when trying to treat diseases and tumors in those areas. Epitopes are bonded on the
target surface molecule and must be accessible to nanocarriers and should not cause side effects.
The epitopes initiate carrier endocytosis using clarathin and caveoli mediated mechanisms. The
pulmonary system is target for carriers and contains a large portion of the endothelial surface and
can be used for intravenous administration. Materials entering must travel through a series of
intracellular vesicular compartments.
The sources provides information on the methods of drug delivery and treatment
affecting the endothelial surface. The first section effectively explains how the properties of the
particles may affect the drug delivery. It also includes the routes the drugs must take inside the
body and how the routes may be used. The article also displays the parameters of the carriers
which need to be taken into account when delivering the drugs inside the body. Therefore, the
source introduces the topic of drug barriers well and then transitions to targeting drugs to the

endothelium. The interactions of the endothelial cells with the drugs is well explained. The
source also includes a diagram which displays the nanocarriers acting upon the endothelial cells
of the body. It shows the ICAM particles binding on to the endothelial surface and being
internalized into the cells. Furthermore, the article cites multiple sources from other articles
which are helpful to refer to incase a statement is difficult to understand. The source explains the
uptake of drug carriers by the endothelial surface provides the rate at which the surface is able to
internalize the ICAM particles. The spherical carriers are trafficked and coated antibodies,
displaying a binding pattern. The concept of carrier geometry explains how the size of the
carriers and diameters may affect the internalization process.
Muro, S. (2016, October 28). [Personal interview].
Dr.Muro is currently an associate professor at the Institute for Bioscience and
Biotechnology Research. Her research interests include the endocytic vesicular transport and
their role in physiology and disease. This includes the application for drug delivery of
therapeutics to targets at the subcellular level. He education involves being a PHD student and
postdoctoral researcher at the Universidad Autonoma de Madrid in Madrid, Spain from
September 1995-2000. She then became a postdoctoral fellow and research associate at the
University of Pennsylvania at at the Institute for Environmental Medicine from January 2001September 2005. She then became a research assistant professor at the Department of
Pharmacology, Philadelphia. She has published multiple publications. She has trained 5
postdocs and graduated 4 PHD students and has trained 7 high school students. She also has a
patent for targeted protein replacement for treatment of lysosomal storage disorders.
Furthermore, targeted nanocarriers for intracellular drug delivery and also the peptides for
transport of therapeutics. She has multiple international patents all relating to drug delivery. She
started studying biology and molecular biology in 1995 and studied drug delivery from 2000
onwards. She has experience in managing federal grants and other funds and has supervised
personnel.
Muro, S. (2012). Challenges in design and characterization of ligand-targeted drug delivery
systems. Journal of Controlled Release: Official Journal of the Controlled Release
Society, 164(2), 125137. http://doi.org/10.1016/j.jconrel.2012.05.052
The therapeutic agents attach to molecules. Drugs are targeted to cellular receptors
involved in endocytic transport facilitates intracellular delivery. The mechanisms govern the
interaction of targeted carriers. The features that affect drug efficacy include action of drug, size
of drug, composition, solubility and uptake of cells. The system must deliver drugs to the
affected areas of the body. Drug targeting strategies include passive and active targeting. Passive
targeting is the accumulation of drugs into particular regions of the body. The drug accumulation
occurs in the reticuloendothelial system (RES) which includes the liver and the spleen. They
capture foreign substances and the drugs accumulate passively in these areas. Another type of
passive transport is the EPR effect where small blood vessels can be found in between
endothelial cells where there is drug leakage. Inverse targeting is when sites are blocked in the
body associated to passive targeting so that drugs accumulate in other sections of the body.

Drugs are aimed at the pathological conditions in these tissues. Passive targeting is enhanced by
permeability and retention. Active targeting is when the targeting properties are imposed on the
drug. They can be programmed of drug released based on environment. The drugs are combined
with a ligand that binds to an element at the diseases site. Combined targeting uses EPR effect
and also ligand targeting. It is a combination of active targeting and the passive targeting.
The source describes the differences between drug targeting and also when they should
be used. Furthermore, the source explains the levels of targeting including organs, cellular, sub
cellular and molecular level. The source also explains that the target will influence the specificity
of the drug delivery that will take place. The source gives you all the factors that may affect drug
delivery and the reader will be able to understand the necessary statistics. Drug targeting such as
active and passive transport are valuable. The strategies of drug are based on the complexity and
organization in systems. The types of transport are valuable strategies employed when testing
and experimenting. Both systems have their own benefits, active targeting requires use of a
surface marker and passive targeting occurs much more naturally. The active targeting may result
in side effects but may have better results in the organism. Furthermore, the active targeting can
be used with intracellular transport. The passive targeting is less concentrated and less side
effects occur after administration of the drugs.
Nau, R., Srgel, F., & Eiffert, H. (2010). Penetration of Drugs through the Blood-Cerebrospinal
Fluid/Blood-Brain Barrier for Treatment of Central Nervous System Infections . Clinical
Microbiology Reviews, 23(4), 858883. http://doi.org/10.1128/CMR.00007-10
The entry of particles across the BBB depends on the molecular size, electrical charge,
and active transport at the cerebrospinal fluid (CSF) barrier. The most effective in treating CNS
infections is of small molecular size and a low level of plasma protein binding. These antiinvectives reach the CSF and are valuable in treatment of CNS infections. CNS infections must
be treated with drugs and many of which have reduced sensitivity to the drugs. There can be
strong differences in the drug concentration and entry of drugs into intracranial components is
incomplete. The effective drug concentrations much be reached without inflaming meninges. The
entry of the compound into the CSF depends on the molecular mass and they must be inversely
proportional to the radius of the compound. Lipophilicity refers to the lipid layers that cover the
CNS and the ability to penetrate these membranes. There was a significant relation found
between lipophilicity and diffusion across the BBB of rat. These proteins tend to bind to lipid
membranes. Plasma protein binding also influences the entry of drugs into the CNS and only the
plasma fraction can freely when barrier is intact. The anti-invectives are ligands are responsible
for removal of toxic compounds. Transporter protein is an example of the strong impact of an
active transport system. The treatment of the human endothelial cell line with inhibitors. The
influence of the transport system of weak organic acids in the CNS is moderate. In the
penetration of anti-invectives into the CSF under meningeal inflammation occurs by the opening
of intercellular tight junctions of the vessel walls within the venules. This leads to a rise of CSF
concentrations and hydrophilic antibiotics have increased volume of distribution.
The source shares the various methods of penetrating the CNS under conditions when the
meningeal is inflamed. The factors that are included molecular size, lipophilicity, plasma protein
binding and active transport. The articles states the conditions at which these properties of the
molecules are valid. It also includes how the factors affect penetration across the CSF barrier to

start affecting the infections inside of the CNS. The article well explains each of the factors and
shows a figure. Additionally, there is a graph showing the active transport taking place based on
the ligand being administered. Figure 3 represents effects of inhibitors of drugs on the
penetration of antibiotics into the central nervous system. The visual representation helps prove
the data being provided by the article. The article also differtiates between inflammation of
meningeal and uninflamed of the meningeal. They are separated out and the factors affecting
them are also listed separately. The article also contains the properties of the BBB and the studies
that were involved in coming up with the data. There are multiple references to experiments and
diagrams demonstrating the intracranial fluid components. The article also lists the multiple
types of antibiotics that can be administered into the CNS and also the properties associated with
them.
Papademetriou, J., Garnacho, C., Serrano, D., Bhowmick, T., Schuchman, E. H., & Muro, S.
(2013). Comparative binding, endocytosis, and biodistribution of antibodies and
antibody-coated carriers for targeted delivery of lysosomal enzymes to ICAM-1 versus
transferrin receptor. Journal of Inherited Metabolic Disease, 36(3), 467477.
http://doi.org/10.1007/s10545-012-9534-6
The source is examining treatment methods for Lysosomal storage disorders (LSD)
which are caused from genetic defects affecting lysosomal enzymes. This causes dysfunction in
organs and the central nervous system. However, CNS penetration is difficult and the BBB
prevents cellular transport. Targeting Lysosomal enzymes to receptors are involved in transport
across the cells. They serve as therapies for lysosomal disorders. The receptors are being
explored associated with clathrin-mediated pathways. Bio distribution and delivery uses a model
enzyme which can be used in organs and the brain. The antibodies were compared to antibody
coated carriers. ICAM 1 had enhanced binding to activated endothelium and TFR induced
endocytosis efficiently. Enzyme replacement therapy is used to treat lysosomal disorders.
Endothelial cells limited enzyme transport into the tissue. A way to enhance ERT is
glycolylation-independent targeting for transport across endothelium and into sysomes within
tissue cells. TfR is expressed on the surface of many cells and enables transport across the
cellular barrier through transcytosis. The carriers are transported into the cells by clarthinmediated endocytosis. The pathways is induced by engagement of TfR with ligands such as
antibodies and peptides. TFR and ICAM were compared and Tfr had a increased uptake
compared that of ICAM but required an increased internalization of nanocarriers. There were
more ICAM particles but there was less amount of NCs that could be internalized. Both are
applicable based on the condition of the targeting.
The source compares the usage of both types of particles and uses multiple to diagrams to
convey the information. Furthermore the list the differences between the particles under separate
conditions. The diagrams include bar graphs comparing the internalization of the particles and
the uptake of the drug. The diagrams also have information explaining the graphs and makes it
easy for the reader to understand the material. There are also sources listed next to the
information so it is much easier to refer to. The experiments are well done and use methods
specific to the experiment to test the effectiveness of the particles. ICAM and TfR are
molecules that express their properties differently. ICAM particles can be paired with proteins
and are intracellularly transported within bloodstream. TfR has enhanced brain targeting

compared to that of ICAM. These 2 types of molecules can be transported based on the types of
administration. It is important for the research to occur because it allows others to use the
information for their own experiments in the field.
Papademetriou, I. T., Garnacho, C., Schuchman, E. H., & Muro, S. (2013). In Vivo Performance
of Polymer Nanocarriers Dually-Targeted to Epitopes of the Same or Different
Receptors. Biomaterials, 34(13), 34593466.
http://doi.org/10.1016/j.biomaterials.2013.01.069
Drug delivery nanomaterials are associated with affinity molecules which allows for
targeting. These strategies are used to target receptors and the epitopes of the receptors may
influence biodistribution. The epitopes are used with antibodies and nanocarriers are coated with
antibodies which influences the biodistribution. Targeted ICAM nanocarriers enhance enzyme
delivery and have different biodistribution based on the targeting. Nanomaterials must designed
to give active targeting properties and therapeutic agents must reach intended sites in the body.
The targeting enables transport into the cells and will diffuse across the cell barriers. However,
high affinity of the nanocarriers may cause increased accumulation in the areas of the body.
Therefore, targeting nanocarriers to multiple receptors helps modulate bio distribution. The
nanocarriers may be. The PECAM targeted nanocarriers are dependent on the epiotpes being
targeted. The study explores the impact of dual targeting to various epitopes in the body. The
material and methods include cell culture and the antibody coating of the nanocarriers. The test
subjects would be mice and the size of the nanocarriers varied. The nanocarriers were coated
with anti-TfR-8D3 and anti-TfR-R17 and these antibodies show accumulation in the brain, the
lung, the liver. The nanocarriers was dually targeted to two different epitopes. The nanocarriers
had similar sizes and they were bonded to the endothelial cells. This allows the modification of
biodistribution of drug delivery systems. The ASM enzyme can be used for enzyme replacement
therapy through injection of the enzyme. This results in ASM accumulation and corresponds to
the delivery by anti nanocarriers in the brain and the liver. The combination targeting is a
valuable tool for biodistribution of drug delivery and nanocarriers represent a type of ligand.
The source provides information on the targeting on nanocarriers and the antibodies they
are being paired with. The source has an introduction that explains the topic of interest and
explains the testing process that will be required. The introduction demonstrates materials needed
for drug delivery and how this can modify biodistribution. The strategy displays the direction of
the nanocarriers and that each part play a major role in the delivery. The next section involves
materials and methods which shows the the characterization of the nanocarriers and the
antibodies and reagents involved. The binding of the anitbodies or antibody coated nanocarriers
to cells. The source explains the results well which includes biodistribution and the antibody
coated nanocarriers and targeting ICAM particles. The figures explain the localization inside of
the organs and the ratios of the nanocarriers with antibodies. This also shows the specificity
index of the nanocarriers at the lungs, livers and the brain. The article also contains a conclusion
explaining the combination targeting which is a valuable tool to modulate the biodistribution of
drug delivery systems. The effect of nanocarrier dual targeting in different organs results in
modulation of the biodistribuition. The figures the source provides is comparing the areas of
effect. The source provides citations to other resources that the reader can refer to for more
information.

Serrano, D., Bhowmick, T., Chadha, R., Garnacho, C., & Muro, S. (2012). ICAM-1 engagement
modulates sphingomyelinase and ceramide, supporting uptake of drug carriers by the
vascular endothelium. Arteriosclerosis, Thrombosis, and Vascular Biology, 32(5), 1178
1185. http://doi.org/10.1161/ATVBAHA.111.244186
The objective of the article is to find out the regulation of plasmalemma and cytoskeletal
changes that occur when ICAM goes through mediated endocytosis. The experiment requires use
of fluorescence, electron microscopy and cell cultures to test the effects. The CAM-mediated
endocytosis depends on dynamin and involves budding of clathrin and caveolar associated
vesicles. The drug carriers of endothelial carriers require a specialized cytoskeletal structure and
lipid platforms that provide diffusion of involved elements. The CAM mediated endocytosis
remains uncharacterized and there is a regulatory link between plasmalemma and cytoskeletal
elements. The enzyme ASM delivered through transport hydrolyzes sphingomyelin into ceramide
which supports cytoskeletal rearrangement and physical functions. ASM is involved in mediated
endocytosis through ceramide at the site of carrier engulfment. ASM appeared near vesicular
structures and the ceramide became enriched at these sites. The binding of anti-ICAM carriers to
endothelial ICAM-1 leads to intracellular transport of carriers through CAM mediated
endocytosis. The anti-ICAM carriers were co localized with ICAM engulfment structures. ASM
redistributes from regions to plasmalemma sites. The lysosomes carrying ASM requires
increased intracellular which involves CAM-mediated endocytosis.
The source provides indepth information about the regulation and provides figures to
display the properties of the anti ICAM carriers. The first figure describes the enrichment of
molecules at sites of anti-ICAM carrier engulfments. The other figures include the CAMmediated endocytosis in the cell culture and also the distribution of ASM of ICAM-1 and also the
ceramide enrichment. There is also model for the association between CAM endocytosis and the
sphingomylen. The source also provides supplementary material and acknowledges the writers of
the article. Furthermore, there are references to other articles used to create this one. The
methods and results of the article are well explained and gives accurate information for the
testing.
Solomon, M. (2016, October 28). [Personal interview].
Dr. Solomon currently works as research faculty at the Institute of Bioscience and
Biotechnology research. The project she is currently working on is the evaluation of Transcytosis
mechanisms in lysosomal storage disease brains. This involves the examination of the expression
levels of the different pathways of endocytosis in brains of patients affected by the types of
LSDs. It also includes the study of transcytosis of nanocarrires coated with antibodies against the
different endocytic pathways across the human brain endothelial cells. Furthermore, it also
involves the distribution of targeted nanocarriers in the brain of control mice and mice models of
Niemann Pick Disease. She has worked as a teaching assistant of the Massachusetts College of
Pharmacy and Health Sciences,Boston,MA. She taught the lab based part of the course and
conducted reviews for a class of a 100 undergraduate students. She has also been an adjunct
instructor and conducted courses for graduate students. Teaching from 2007-2013 including both

positions.Her dissertation was on the development of three-dimensional tumor spheroid model to

study disposition and effect of nanocarriers in high-throughput. She has gone to the
Massachusetts College of Pharmacy from 2007-2013. At the John Hopkins University School of
Medicine she has performed 3 projects. Her first project was developing an MS method for the
analysis of psychosine in lipid extracts of cells. Her second project was the Sphingolipid analysis
of brain tissues, neuronal cells and fibroblasts. The third project was the Induction of neuronal
cells from fibroblasts. She has been there from 2013-2015. Her schooling involves going to the
Nirma University, Ahmedabad for 4 years from 2003-2007. She then went to the Massachusetts
college of Pharmacy and Health Sciences from 2007-2013.
Sullivan, D. J., Gluzman, I. Y., Russell, D. G., & Goldberg, D. E. (1996). On the molecular
mechanism of chloroquines antimalarial action. Proceedings of the National Academy of
Sciences of the United States of America, 93(21), 1186511870.
The source discusses the properties of Chloroquine and antimalarial effect it has when
treating infectious diseases. It prevents the polymerization of the toxic heme that is released in
the Plasmodium digestive vacuole. Heme is a non protein and is toxic to cells and parasites are
able to convert this hemozin which protects them from the toxicity. In order to examine the
properties, parasites were tested upon with doses chloroquine which inhibits the function of the
disease. Quinolines are used as a specific antimalarial therapy. The mechanisms include an acidic
digestive vacuole, heme polymerization and also lipids play a major role. Quinolines inhibit
polymerization of the heme that is released during hemoglobin degradation. The quinolone
inhibition is stage specific and generates hemozin. The results of the actions include vacuoler
swelling and pigment clumping. Chloroquine is able to bind heme non covalently and it results
from the direct interaction with a protein. They first bind to the heme which attaches to
elongation sites of hemozin. Hemozin is a disposal product caused by the digestion of the blood
by parasites. The parasite culture were based on the chloroquine resistant and the chloroquine
sensitive. These parasites were incubated under controlled conditions. Infected cultures were
incubated and they had the go through screening. A process called sucrose cushion hemozoin
purification had to occur and the hemozon went through centrifugation. The source extensively
analysis of the experiment and data was gathered. The results showed the chloroquine
distribution after uptake and displayed an increase in the signal. The chloroquine resistant
parasites reduced drug accumulation and there was a reduced amount of chloroquine.The data
suggests the quinolones like chloroquine incorporate drug-heme complex. Without the polymer
elongation the drug cannot associate with the hemozin.
The source is able to present the information effectively. This includes the use of charts
comparting the types of chloroquine distribution based on the type of parasite. The charts show
the analysis of the experimentation and explains it well. Graph B presents the quinolones with
the hemozoin form the cultured parasites. They show the effects of the chemicals upon the
parasites such as lysate, hemoizon and also the heme and the drug. The graphs show the
statistical analysis of the signal distribution of the infected erythrocytes. There is also model that
shows the hemozon and the heme-quinoline complex. The heme complex incorporation at the
elongation sites of the polymers. The graphs also have captions underneath to explain the data
that was gathered from the experiment. The counts per minute were compared to the chemicals
used including the differences between only drug distribution and including the heme. The
overnight incubations of the drugs were shown in the bar graph. They show the binding of

quinolone to hemozoin in the presence of heme in vitro. The material and methods are specific to
the experiment and explains the parasite culture and electron microscopy. The processes such as
ultra-centrifugation were used to get the accurate materials.
User, Super. "Image Analysis Software for Science & Industry - Media Cybernetics." Image
Analysis Software for Science & Industry - Media Cybernetics. Media Cybernetics, n.d.
Web. 25 Oct. 2016
Media cybernetics has developed the Image-Pro Plus 7 which is an analysis software
used by researchers worldwide and makes it easier to automate the work. Accurate analysis
begins with acquisition and the precision of the equipment. Image processing includes
morphology which prepares images for measurements. The pseudo color highlights features of
interest in gray scale images. Count and measure tag objects of interest and sort the sizes. There
are classification methods. The quantifiable data allows you to find the best fit line of data and
detect localization of specimens. The data can be visualized with scattergrams,histograms and
the image Microsoft Excel. Image analysis software calculates 3d objects, ferret size, volumes.
The objects can be quantified in the amount of volume and the touching objects have boundaries.
The intensity of the 3d objects and optical density may also be determined using the data. The
data can also be color coded and objects split and merged. The objects appearance provides
accurate visualization and parameters are edited. The source also includes multiple products such
as the premier version that is able to segment and add object markers to identify samples of the
regions. Additionally, uneven backgrounds are accounted for and will account for differences in
illumination with the background. Also the objects are based on their color and characterize the
data collection. The data can be gathered from multiple experiments and will be compiled into
data collector. They can be set up to collect all images automatically as they are measured.
The sources discusses the different uses and products that are available. They provide a
description on the differences between the products and the soft wares that are used to analyze
the data. The 3d imaging system is designed for research professionals and is directed toward
those working in a lab environment. Furthermore, the features and specifications are listed of
each of the programs. The website also provides tutorials and resources to use for further
information about the products. The source provides applications of these tools and the
environment in which they are useful. The in-depth tutorials are helpful to those starting off
using the program and can learn a lot information from them and be able to apply the
information. The website also has assistance for the program and will help incase you do not
understand a topic. The resources shows the applications in life sciences,manufacturing,materials
research, and security related topics. Image pro products has enabled researches to capture,
communicate, and process image data and involves a robust line of applications. Each product
has its own properties listed under their description and it is very specific to the researchers. The
source also provides contact information in case the program has faults and the company support
includes feedback, product updates, community, and product registration. Furthermore, the
source provides more publications and a library that provides videos to the users.