Biomedical Engineering Reference
In-Depth Information
breakthroughs in nanotechnology-based medical approaches. Thus, targeting of
drugs to the CNS remains for the future success and development of nanotech-
nology-based diagnostics and therapeutics in neurology. The global market for
drugs that target the CNS would have to grow by over 500% to come close to
the global market for cardiovascular diseases.
201
The efficient delivery of potentially therapeutic and diagnostic compounds
to specific areas of the brain are hindered by the BBB, the blood cerebrospinal
fluid barrier, or other specialized CNS barriers which restrict the passage of
foreign particles into the brain. Thus, because of these barriers, the efficient
design of noninvasive nanocarrier systems that can facilitate controlled and tar-
geted drug delivery to the specific regions of the brain is a major challenge for
neurological diseases.
101,202
The BBB acts as a neuroprotective shield by selecting the passage of sub-
stances from the blood, supplying the brain with nutrients, and disposing harmful
compounds from the brain back to the bloodstream.
203
The BBB composed of
the brain endothelial cells that make up the cerebral microvascular endothelium
together with astrocytes, pericytes, neurons, and the extracellular matrix con-
stitute a “neurovascular unit” that is essential for the health and function of the
CNS.
204
This maintains the transport of substances including drugs in and out of
the brain, leukocyte migration, and regulates the brain microenvironment that is
crucial for neuronal activity and proper functioning of CNS. The unique environ-
ment in the CNS makes the treatment of neurological diseases such as inborn
metabolic errors (e.g. lysosomal storage diseases), brain tumors, infectious dis-
eases, and aging and is a unnerving challenge.
205,206
Transport across the BBB
is strictly constrained through the physical TJs and adherent junctions as well as
metabolic barriers (enzymes, diverse transport systems) that excludes very small,
electrically neutral, and lipid-soluble molecules.
207
The CNS also has a lack of
fenestrations (perforations) and a lack of pinocytotic vesicles.
208,209,210
Combined
with an intricate complex of transmembrane proteins [junctional adhesion mol-
ecule-1 (JAM-1), occludin, and claudins], it allows drugs with cytoplasmic acces-
sory proteins, zonula drugs, or small molecules, with high lipid solubility and low
molecular mass of <400-500
Daltons. On top of this intricate structure, there are
other CNS barriers, such as the blood tumor barrier and the blood retina barrier
shielding the brain which may play a role in drug transport.
211
Thus, conventional
pharmacological drugs or chemotherapeutic agents are unable to pass through the
barrier.
NMs have emerged as potential drug delivery carriers to various tissues
throughout the body including the brain owing to their small size, solubility
in aqueous solutions, adaptable surface, targeted drug delivery, and multifunc-
tionality.
1
However, because entry through the almost impermeable BBB is
extremely selective, the proper design of these engineered nanocarriers become
extremely important to facilitate drug delivery. In addition, it is also necessary
to retain the integrity and stability of the drug to prevent untimely degradation
of the drugs in the NMs-drug complex. Multiple factors such as size, shape,
