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RESEARCH

DRUG
DELIVERY
INNOVATIONS
As things  stand today, for most
medications, only a small
portion reaches the organ to be
affected.

One of the challenges of the
drug  industry is to increase that
portion,  particularly inside the
cell.
In traditional drug delivery
systems such as oral ingestion
or intravascular injection, the
medication is distributed
throughout the body through
the blood circulation.

Targeted drug delivery seeks to
concentrate the medication in
the tissues of interest while
reducing the relative
concentration of the medication
in the remaining tissues.

ELECTROPORATION

This new technique punches
holes in cells, and it could treat
tumors.
In the early 1970s  it was
reported that the application to
cells of very fast electrical
pulses - in the microsecond and
millisecond range - creates an
electrical field that causes
nanoscale pores to open in the
cell membrane. This is called
electroporation.
Research since then has mainly
focused on reversible
electroporation, which uses
voltages low enough to
temporarily increase the cell
membrane's permeability. The
holes in the cell membrane
created by reversible
electroporation close up shortly
after treatment, allowing the cell
to survive.
This concept has  really caught
on in modern biotechnology,
especially over the last decade.
It is used primarily to help get
genes and drugs into cells.

The field of irreversible
electroporation was pretty much
forgotten.

Irreversible electroporation
(IRE)  uses electrical pulses that
are slightly longer and stronger
than reversible electroporation.
With IRE, the holes in the cell
membrane do not reseal,
causing the cell to lose its ability
to maintain homeostasis and die.
In a way  IRE overcomes the
limitations of current minimally
invasive surgical techniques
that use extreme heat, such as
hyperthermia or radiofrequency,
or extreme cold, such as
cryosurgery, to destroy cells.
Advocates of these modern
techniques claim that they focus
on the cancerous part and
nothing bad happens to the
sorrounding tissue.

This is not entirely true.
Temperature damage to cells
also causes structural damage
to proteins and the surrounding
connective tissue. For liver
cancer, the bile duct is at risk for
damage. For prostate cancer,
the urethra and surrounding
nerve tissue is often affected.

Electroporation, on the other
hand, acts just on the cell
membrane, leaving collagen
fibers and other vascular tissue
structures intact. Leaving the
tissue's "scaffolding" in place
allows healthy cells to regrow
far more quickly than if
everything in the region was
destroyed.

Another chronic drawback of
heat or cryo treatments for
cancer is the difficulty in treating
cells that are immediately
adjacent to the blood vessels.
Because blood maintains a
relatively stable temperature, it
actually transfers heat or cold
away from a treatment area in an
attempt to return the region to a
normal temperature range. That
means some cancerous cells
might actually survive treatment.
That counts for a lot of failures
when treating liver cancers.  
With IRE, you can destroy
cancerous cells right next to the
blood vessels. It's a more
complete treatment. In clinical
practice this is about as good as
it gets.


To commercialize this
technology, Drs Rubinsky and  
Onik founded Oncobionic which
was later  sold to
AngioDynamics, a New York-
based manufacturer of medical
devices.

The FDA  granted approval to
market irreversible
electroporation technology for
soft tissue ablation, which uses
needles and image guidance to
target cells. The process is
similar to existing thermal
ablation technologies, but
instead of "cooking" or
"freezing" the targeted tissue, it
disrupts the cell membrane,
thereby destroying the targeted
cells.
The impaired cells are then left
in the body to be removed by
the immune system.
AngioDynamics calls their
technique the  "NanoKnife
System" as the  next generation
in minimally-invasive tissue
ablation technology.

The NanoKnife System includes
an energy generator, footswitch
and single-use disposable
electrodes. The System uses
electrode probes to transmit
active energy from its generator
to a targeted area.

During treatment, the unique
action opens permanent nano-
sized pores in the cell
membrane, causing irreversible
damage which rapidly induces a
natural cell death. After IRE
treatment, cells that form the
nerves, blood vessels, and
other collagenous tissues in the
treated area remain viable,
reducing the risk of damage to
these structures. Microscopic
imaging after treatment reveals
a sharply delineated separation
between affected and
unaffected cells.

Inovio is another company
who's  electroporation-based
DNA delivery system can
increase the cellular uptake of
an agent by 1,000 times or more.
When used to deliver DNA
vaccines, Inovio's systems can
increase  levels of gene
expression (i.e. production of
the coded protein) by 100 times
or more compared to plasmid
DNA delivered without other
delivery enhancements.

STAPLED PEPTIDES


There are hundreds of
thousands of proteins in the
human body, many of them with
links to human disease.
However, only a tiny fraction —
about 20 percent — of these
proteins is considered
"druggable."
"The entire pharmaceutical
industry has been working on
drug-design platforms that
focus on this little sliver of
human drug targets and this
limits the drug arsenal available
to doctors," says Gregory
Verdine, Ph.D, a chemical
biologist at Harvard University.  
"What's required is an entirely
new class of drugs that
overcome the shortcomings of
drugs of the past."
Thanks to a new generation of
drug discovery technologies,
that tiny fraction is now
expanding.

After decades of dreaming the
drug developer's impossible
dream, scientists finally are
making drugs that target the
"untouchables":   the hundreds
of thousands of proteins
against which   previous efforts
had failed  to develop a drug.

Peptide molecular medicine is a
very hot area.
So-called "stapled peptides,"
get their name from chemical
"braces" that hold the peptides,
or protein fragments, in a
compact shape that gives them
high stability in comparison to
their unfolded versions.
The three-dimensional shape is
critical for the peptide to
function normally and help
orchestrate body processes.
The chemical stapling allows
them to resist destruction by
enzymes.


The Swiss pharmaceutical giant
Roche is throwing its weight
behind the  experimental
technology of Aileron
Therapeutics.

Roche has agreed to pay $25
million now and up to $1.1
billion later to Aileron
Therapeutics of Cambridge,
Mass., for developing the  
"stapled peptides" technology.

Aileron, which holds patent
rights from Harvard and the
Dana-Farber Cancer Institute,
hopes to start clinical trials in
2010.

Synthetic peptides can deliver
particularly potent doses of
drugs at the cellular level. They
are stabilized in a helical shape
that stays active longer in the
body. They have been
successfully tested in animals.
In human trials they are
planning  to deliver medicine
inside cells for a variety of
medical conditions, including
Roche's priorities like
treatments for cancer and
inflammation.


Professor DiMarchi co-founded
Marcadia Biotech in 2005 and
signed a licensing deal with
Merck in 2008 to pursue other
forms of stabilized peptides to
treat diabetes and obesity.

Such new technologies are
fraught with possible setbacks,
however, on the path from
laboratory bench to bedside.
Monoclonal antibodies, for
instance, another hyped field a
few years beack,  have yet to
live up to expectations.


THE "SUPERBOWL PILL"
Scientists from ANU ( Australian
National University)   have
developed a 'Superbowl' drug
delivery system that promises
more accurate drug dose
delivery.

The researchers, led by
Associate Professor Michael
Sherburn, have created a
molecule which can capture,
hold and deliver drugs.

"Excitingly, unlike conventional
capsules, we can control the
rate at which a drug is released
from our superbowl container
molecule," said Sherburn. "This
has the potential to allow lower
drug doses, hence leading to
fewer side-effects."

The group have already
successfully put aspirin inside
the superbowl and are now
working on incorporating drugs
to treat other diseases,
including cancers, arthritis and
heart disease.


PATCH OF MICRONEEDLES

University of  Purdue developed
a patch that can  painlessly
deliver drugs to a patient's
bloodstream with the touch of a
finger.

Babak Ziaie, a professor of
electrical and computer
engineering, and his research
team have fabricated a "patch"
composed of a new type of
pump and an array of
"microneedles."

The patch is  powered by liquid
fluorocarbon, a substance
similar to those used in
refrigerators, that has very low
boiling point. The user simply
places his or her finger on the
pump, which causes the liquid
to rise in temperature and boil.
This reaction activates the
pump which puts enough
pressure on the medication to
force it through the skin.

It  all takes about 30 seconds.

The drug is delivered through
microneedles at the bottom of
the patch which barely
penetrates the skin. The patch
contains an array of needles,
each about one-fourth the width
of a human hair. Applying the
patch feels like rough paper.

Most medications have
molecules that are too large to
be absorbed through the skin.
This technology could allow
easier distribution of medication
like painkillers, hormones,
insulin and cancer treatments.

Ziaie and his team created the
patch to be practical and
disposable. The idea is that it
will be used once and thrown
away. All components used to
make it are fairly common and
can be manufactured easily and
cheaply.


NANO-PARTICLE TECHNOLOGY

Nano-particle technology
enables drugs to be made into
very tiny particles so they are
able to be readily delivered to
the site of action. Generally this
enables a higher dose to be
delivered without compromising
safety and tolerability.
ABRAXANE ( a cancer drug)  
trials showed that nab
technology allowed for a 49%  
higher dose of paclitaxel to be
delivered, significantly
improving efficacy compared to
conventional solvent-based
paclitaxel.
Nab technology is Abraxis
BioScience's   proprietary
nanoparticle technique which
leverages albumin
nanoparticles for the active and
targeted delivery of
chemotherapeutics to the
tumor. This nab-driven
chemotherapy provides a new
paradigm for penetrating the
blood-stroma barrier to reach
the tumor cell.
The company said: "We believe
ABRAXANE exploits the
albumin-binding protein
receptor, Gp60, to penetrate the
blood-stroma barrier in essence
opening a portal to the tumor
micro-environment, enabling the
delivery of targeted cytotoxic
agents leading to stromal
collapse and tumor penetration."

NANODIAMONDS
Nanodiamonds Show Promise
As Safe Chemo Boosters For
Breast And Liver Cancer

Finding ways to make
chemotherapy drugs more
efficient is a continual
challenge, particularly for the
treatment of cancers that are
resistant to chemotherapy, such
as recurring breast and liver
tumors.

One way to do this, is through
the use of nanoparticles to
deliver the drugs. One example
that researchers have been
looking at recently is the
nanodiamond, a particle of
carbon that is between 2 and 8
microns thick; about 10,000
times thinner than a human hair.

The advantage of using such
tiny particles is that you can get
the drug to stick to their
surfaces, use them to enter
cancerous cells and release the
drug slowly over time, exit the
cell when they are finished, then
leave the body altogether.

Using nanodiamonds, tiny
particles of carbon, as a drug
delivery system, researchers
have developed a promising
approach to treating breast and
liver cancer tumors that are
resistant to chemotherapy.

Led by Dr Dean Ho, an
associate professor of
biomedical engineering at
Northwestern University in
Evanston, Illinois, US, the
researchers used lab mice to
test how effectively and safely
the nanodiamonds released the
cancer drugs over time.

Ho told the press that in this
study, they were able to boost
the efficiency of the cancer drug
they tested 70 times while still
maintaining safety.

"It's the best of both worlds," he
said.

If you could see a nanodiamond
you would understand why it
has that name, it looks like a
diamond, and it is not just its
size that makes it useful, but
also its shape.

"They're called truncated
octahedrons," explained Ho.

"They're shaped like a soccer
ball but the faces are more
angled."

It's the faces of the
nanodiamonds that allow the
drugs to bind tightly to their
surface and release slowly.

Ho said sustained release was
an important feature because by
their very nature, chemotherapy
drugs are toxic.

Sustained release over time also
reduces side effects of very
toxic chemotherapies.

"The surface chemistry,
coupled with the architecture of
the surface, allows for a very
sustained interaction with
drugs," said Ho.

The drugs can be bound tightly
to the surface with a chemical
bond, or temporarily with an
electrostatic bond. It is useful to
have these options because
some drugs can do their job
without letting go of the surface,
while others have to come away
to be effective.

Another advantage of
nanoparticles as drug delivery
systems is that you can make
them seek out particular
molecules or tumor sites by
attaching a unique chemical
compound or antibody to one
end.

For this study, Ho and
colleagues tested the
nanodiamonds as a delivery
system for doxorubicin, a
common chemotherapy drug
that is very efficient at killing
cancer cells but as Ho
explained, "it is also very
effective at killing everything
else".


RNA INTERFERENCE
"Just as all roads lead to Rome,
all roads lead to cellular
delivery," says Steven F.
Dowdy, Howard Hughes
Medical Institute investigator."
Today, everybody in the field
recognizes that delivery is the
problem to solve, and all other
problems, of which there will be
numerous ones, pale in
comparison."
Scientists trying to deliver
siRNA need to engineer around
several troublesome properties.

RNA has a molecular weight
that is 10 to 20 times that of a
traditional small-molecule drug.
And because the molecule is
highly negatively charged, it
typically can't cross the similarly
negatively charged plasma
membranes to enter the cell.

Delivery systems for siRNA
must overcome three major
obstacles: getting the drug to its
target in the body, coaxing it
inside the cell, and releasing it.
Even after all that is
accomplished,companies still  
need to worry about safety, a
major concern given the power
of siRNA to turn off cellular
processes.
Lipid- and polymer-based
systems are the most
established approaches for
systemic delivery of RNAi.

In the clinic, lipid nanoparticles
(LNPs) have advanced the most.
Alnylam Pharmaceuticals,
widely acknowledged as the
leader in the RNAi arena, has a
liver cancer drug in Phase I
trials that applies Tekmira
Pharmaceuticals' stable nucleic
acid lipid particle technology.

DELCATH

Delcath Systems Inc expects to
apply for U.S. review of its
cancer drug delivery system in
the fourth quarter of 2010, which
would put it on track for
approval by mid-2011.
Delcath in June 2010  presented
trial results showing that
melanoma patients whose
cancer had spread to their liver
survived for an average of 398
days before dying or having
their cancer get worse after
treatment with the company's
"Percutaneous Hepatic
Perfusion" system.
Patients treated with standard
drugs survived for an average
of 124 days before they died or
their tumor growth restarted.
Delcath's system is designed to
deliver high doses of the
generic chemotherapy drug
melphalan directly to the liver
via the hepatic artery.
The system aims to minimize
side effects by filtering the
highly toxic drug out of the
blood stream as it leaves the
liver, but some of the drug leaks  
out.
Two of the 93 patients in the
pivotal trial died as a result of
the treatment. A third death was
attributed to the fact that the
patient had such advanced liver
metastases that he should not
have been enrolled in the trial.
Delcath's pivotal trial, in which
patients were allowed to cross
over from standard treatment to
the Delcath system, was
designed in concert with the
FDA.
He estimated that around 15,000
U.S. melanoma patients would
be eligible for treatment with the
Delcath system.
Delcath is also studying use of
the system in other types of
cancer.
-----------------------------------





NEW DESIGN
IDEAS  FOR
CLINICAL
TRIALS

In September 2010 the New York
Times ran a dramatic story
concerning melanoma.

Two young men, friends, both
had it. One managed to get into
a clinical trial of  a promising
drug, PLX4032 made by Roche,
the other one , due to the
random nature of the trials, was
rejected.  

The man in the trial survived, the
other died.

Some of the doctors involved,
according to the story, bitterly
complained about the system:
that if a drug is promising early
on, why do they have to wait for
years to prove survival
advantage and not give it to all
neeedy patients right away.

Well, the story has  several
problems.

It does not mention some
innovating ideas in trial design
in the works. And it  does  not
mention that there are several
locations where the trial of this
drug is not random, not to
mention  several other trials
ongoing against the same BRAF
mutant.

There are currently 13 non-
randomized trials for BRAF-
mutant, advanced melanoma
listed in the National Cancer
Institute's clinical trials
database. These are phase I and
II trials, with either PLX4032 (the
drug in the Times story) or for
GlaxoSmithKline's version of
the drug, and they are actively
recruiting patients with
advanced disease; previous
treatment is okay for most of
them.

Aside from that  there are
approved treatments that have
shown reasonable success in
cell culture assays such as
Melphalan, Interleukin-2,
ImuVert [Serratia marcescens
microscomes], Interferon,
Temsirolimus + Bevacizumab.
And because they use  "real
life" 3D analysis, that kind of  
profiling predicts  of what willl
happen in the body.
It is called "functional profiling
analysis", which is measuring  
biological signals rather than
DNA indicators,  and  it will
continue to play an important
role in cancer drug selection.
Primary tumors are different for
every patient.

Real-time assessment is already
used in  newly designed  
BATTLE and I-SPY clinical trials.

The functional profiling
approach involves real-time
assessment of "fresh" living
cancer tissue and endothelial
cell behaviors in the presence
or absence of anti-cancer or anti-
angiogenic drugs. This method
accounts not only for the
existence of genes and proteins
but also for their functionality
and for their interaction with
other genes, other proteins, and
other processes occurring
within the cell.

Patients would certainly have a
better chance of success had
their cancer been "chemo-
sensitive" rather than "chemo-
resistant". Identifying the most
effective chemotherapy would
be more likely to improve
survival.

These new trials are using the
so-called adaptive trial design.

The University of Texas M. D.
Anderson Cancer Center runs
the BATTLE for lung cancer.

The study uses an innovative
statistical model to match four
drugs to specific molecular
signatures, or biomarkers, in the
tumors of 255 stage IV non-
small cell lung cancer patients
who had received between one
and nine previous treatments.

Lung cancer is the number one
cause of cancer death in men
and women, but   huge
randomized trials involving  
thousands of patients have
either failed completely or
shown negligible survival
differences.

Until recently, chemotherapy for
lung cancer has been given on
a one-treatment-fits-all basis.
The  BATTLE trial, shows that
treatments tailored for each
patient's particular type of lung
cancer may improve outcomes.

Biopsies of the patients' tumors
are analyzed for mutations in
four different pathways that
affect growth of tumor cells.
Then 255 patients are  randomly
assigned to take one of four
different drugs specifically
targeting the pathways.

The four drugs:  erlotinib  
(Tarceva), sorafenib (Nexavar),
vandetanib (Zactima) and
bexarotene (Targretin). To date
only erlotinib has been
approved by the FDA for use
against lung cancer.

Overall, 46 percent of patients
had their disease in check after
eight weeks of treatment,
meaning that their tumors had
not grown significantly or had
shrunk.
That compares with 30 percent
of late-stage lung cancer
patients with controlled disease
after eight weeks on traditional
chemotherapy.

Each drug was found to do best
against tumors associated with
specific types of mutations.

For instance, sorafenib was
effective for 61 percent of
people who had mutations in
the KRAS gene, but people who
had mutations in the EGFR gene
actually had a worse outcome.

Based on these promising
results, sorafenib in particular is
worthy of further study.

Erlotinib worked best against
tumors with EGFR mutations,
while vandetanib was most
effective for people who had
high levels of VEGFR-2 protein
in their tumors.

A combination of erlotinib  and
bexarotene was most effective
for people with defects in the
Cyclin D1 pathway or who had
extra copies of the EGFR gene
in their tumor cells.

BATTLE has set a precedent for
future clinical trials with the goal
of identifying biomarkers early
on and improving the chance of
successful treatment. This
biological knowledge will shift
the paradigm of how future trials
are done.

Another trial called I-SPY 2 is
unusual because it is
"adaptive," meaning that it uses
information from one set of trial
participants to make changes in
the study for future participants
as it moves forward.

Only drugs that show promise
pass into later stages of the
study, and less-successful
candidates are dropped and not
available for future trial
participants.

The trial design is expected to
greatly speed the process by
which new drugs are tested and
approved for use by cancer
patients.






Stem Cell
Competition
Heating Up

Of the mere 15 publicly traded
biotechnology companies
currently developing stem cell
therapies [see Table 1], more
than half of them have
competing programs in three
major disease areas:

•Cardiovascular
•Gastrointestinal
•Central nervous system [CNS]
Accordingly, the purpose of this
article is to review the key
players in each of these
segments and contrast their
different approaches.

MORE...