Dear Professor Dr. Andrew Charles Gomes
Thank you for your question soliciting my coments on this
website:
I am not an expert in this area of medicine – nano-medicine,
or in nano-pharmacodynamics or its kinetics.
But still, I shall attempt in a
simple, non-technical way to answer your question by explaining its mechanisms as a potential
drug-delivery system especially in hard-to-access target areas such as the
brain where concentrated drug dosage need to be delivered without compromising
toxicity exceeding therapeutic index / therapeutic windows to the rest of the body especially for
cytotoxic agents in cancer treatment.
Brief Introduction:
The application of nanotechnology as a drug delivery system
especially in cancer research and in other therapeutics is considered as nanomedicine.
This discipline is one of the most
active and exciting areas of medicine scientists are actively working on today.
It applies nanotechnology to highly specific medical and pharmacological interventions for the
prevention, diagnosis and treatment of diseases. The haste in nanomedicine
research over the past few decades is
now recognized as part of translational medicine that may result in considerable marketing efforts by
bio-pharmaceutical companies throughout the world.
There are at present a significant number of products using
nanotechnology such as cosmetics on the
market and an increasing numbers are in
the pipeline. Presently, nanomedicine is restrained to drug delivery systems, and
the results of R & D in this areas has exceeded 75% of total nanotechnology sales.
However, the application of nanotechnology as an emerging drug
delivery systems would depend on their safety and efficacy data, but I believe would
fail to reach clinical development for other therapeutic regimens because of their
poor biopharmacological properties, such as modest solubility or poor
permeability across the brain-blood barrier or even through the intestinal
epithelium, circumstances that translates into poor bioavailability and undesirable
pharmacokinetic end-points.
Currently there exist various nanoforms that have been attempted
as drug delivery systems. They vary from metallic-organic conjugates, biological compounds, such as albumin,
gelatin and phospholipids in liposomes complexes, to chemical compounds such as various polymers and solid metal-congugated
complexes.
Polymer–drug conjugates, which have high-small size spectrum
are normally not considered as nanoparticles(NPs). But since their size can still be structured within
100 nm, they have been integrated into
these nanodelivery systems.
These nanodelivery systems can be designed to have
drugs absorbed or conjugated onto the particle surface, encapsulated inside the
polymer/lipid bonds or dissolved within the particle matrix including perhaps magnetic
–sensitive NPs which is the question Professor Dr. Andrew Charles Gomes, a Senior Consultant ENT
Surgeon associated with Johns Hopkins Hospital was asking me to comment
Brain-Blood Barrier:
First, we must consider the existence of blood–brain barrier (BBB) which is a highly
selective permeability barrier that disconnects the circulating blood from the
brain extracellular fluid in the central nervous system (CNS).
This blood–brain barrier is shaped out by the brain
endothelial cells, which are then linked by tight junctions with an extremely
high electrical resistivity.
Neurophysiologists know that the blood–brain barrier allows only the passage of water, some gases
like oxygen and carbon dioxide, and lipid-soluble molecules into the brain. These molecules are transported by passive
diffusion, as well as the selective transport of compounds such as glucose and
amino acids that are critical for neurological function.
On the other end of the blood–brain barrier it may prevent
the entry of lipophilic, potential neurotoxins by way of an active transport
mechanism mediated by P-glycoprotein.
Astrocytes are essential in this barrier mechanism to create
the blood–brain barricade. A small number of regions in the brain, including
the circumventricular organs (CVOs), do not have a blood–brain barrier such as
what Prof Dr. Andrew Gomes emailed me on the above website.
However, there are regions in the brain where there is an open
gate, and where certain “thermo-gates”
are temporary opened at certain
temperatures. It is here scientists take
an advantage when the gates are opened and / or subjected to a magnetic field
for drug-laced nanoparticles to gain entry.
Normally, the blood–brain barrier exists along all
capillaries and consists of tight junctions around the capillaries, but do not exist
in normal circulation. Endothelial cells restrict the diffusion of microscopic
objects such as bacteria and pathogens, and large or hydrophilic molecules into
the cerebrospinal fluid (CSF), but allowing the diffusion of small or hydrophobic
molecules such as oxygen, carbon dioxide and hormones.
It is in these regions of the brain t that actively
transports nutrients such as glucose and specific range of proteins across the barricade
which encompasses a thick basement membrane and astrocytic sheet.
This "bio-barricade” results from the selectivity of
the tight junctions between endothelial cells in CNS vessels restricts the
passage of even solutes which generally are not magnetic-sensitive
At the interface between blood and the brain, endothelial
cells are sewed together by these tight junctions. These junctions are composed
of smaller subunits, frequently biochemical dimers, that are trans-membrane
proteins such as occludin, claudins, junctional adhesion molecules.
The units of these trans-membrane proteins are fastened into
the endothelial cells by another protein complex that includes other associated
proteins. None of these molecules to the best of my understanding can be
subjected to magnetic induction.
As I have already explained, the blood-brain barrier is a
highly selective semipermeable barrier running inside the majority of all the vessels
in the brain, and they only that lets through water, some gases and a few other
select molecules, while inhibiting potentially toxic elements in the blood from
entering the brain.
It is almost improbable
for most drugs to get through excepts perhaps Levodopa, the drug used in the management of Parkinson’s disease.
Levodopa is probably the best
drug that mimic dopamine, the natural
neurochemical in the brain
No Entry:
Scientists currently tell us 98 percent of therapeutic
molecules are also blocked by the brain-blood barrier.
However medical researchers have developed a technique using
magnetic nanoparticles to open the door
for such molecules, and in so doing opening the gates to new therapeutics regimen for brain diseases.
"At the present time, surgery is the only way to treat
patients with brain disorders," says Anne-Sophie Carret, a study senior
author in this area of magnetic nano-therapeutics
Currently surgery is the only option to remove certain kinds
of tumors. But some disorders are
located in the brain stem, amongst nerves; making surgery impossible says Anne-Sophie
Carret.
By opening the blood-brain barrier to these therapeutic
molecules, the researchers feel that would provide an alternative to surgery for
treating various brain diseases.
According to researchers the technique involves sending
magnetic nanoparticles to the surface of the blood-brain barrier at the desired
location in the brain. The researchers say this could be achieved using
magnetic resonance imaging (MRI) technology, albeit a different method was used
for their study.
Scientists in the study say that the drug-laced
nanoparticles are directed to the desired location, the nanoparticles are then
exposed to a radio-frequency field that caused them to dissipate heat.
This causes a small rise in temperature which in turn places
mechanical stress on the barrier, thus opening
a localized gate which allows
therapeutic molecules to pass through. The opening is only temporary, remaining
open for around two hours the researchers claimed.
"While other techniques have been developed for
delivering drugs to the blood-brain barrier, they either open it too wide,
exposing the brain to great risks, or they are not precise enough, leading to
scattering of the drugs and possible unwanted side effect," says principal
investigator Sylvain Martel.
Currently technique is experimental, and was developed using
murine (rats and mice) models. It is yet to be tested on humans, but the
researchers are optimistic that one day it
can be used on humans.
"Although our current results are only proof of
concept, we are on the way to achieving our goal of developing a local drug
delivery mechanism that will be able to treat oncologic, psychiatric,
neurological and neurodegenerative disorders, amongst others," says
Carret.
To the best of my understanding at the time of writing this comment,
this is a novel approach in breaking into the brain-blood barrier using
magnetically-induced nano therapeutic molecules, but the question I would like to ask the researchers is, how then would these
drug-tagged nanoparticles get out from the brain parenchyma once it has
delivered its therapeutic molecules to the target region. Surely, the brain-blood
barrier is only a one-way street.
One-Way Entry:
Drugs, especially metallic complexes and large molecules
with high molecular weights cannot find their way into the general blood circulation or cerebrospinal fluid (CSF) flow even via active transport mechanisms, let alone by diffusion especially if a one-way
gate is closed once the nanoparticles get lodged inside the brain This is the dilemma I need to ask my
scientific-medical counterparts . I wonder what their answers would be as much
as I like to direct this same question to Professor Andrew Charles Gomez.
A Neuro-Scientist Opnion:
I had a discussion with Professor Dr. Ong Wei Yi, who is my
nephew and a neuroscientist at Yong Loo Lin School of Medicine, National
University of Singapore (NUS) at a family dinner on September 3, 2016.
I was talking about the use of nano-delivery cream in cosmetic
application such as in sun screens, and my
nephew cautioned me about the use of nanoparticles,
depending on their size as they can lodge in the brain even by inhalation, but
not by injection, probably because of this
brain-blood-barrier mechanisms, and they can cause extensive neurodegeneration
and wide spread tissue and organ damage according to Professor Ong Wei Yi.
This is my nephew’s professional opinion as a neuroscience
expert at NUS.
Many Questions:
I too have many questions to ask on their biosafety that
requires extensive and long-term toxicological evaluation and long-term
clinical trials with safety and dose data clearly demonstrated - right to the end of Phase Four of drug trials before
magnetic nano therapeutic molecules can
find their way into clinical applications
Comments by ju boo lim (lim ju boo)
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