The document discusses using nanoparticles for targeted drug delivery to the central nervous system (CNS). It notes that the blood-brain barrier (BBB) prevents many drugs from reaching the CNS. Nanoparticles can overcome this barrier and precisely deliver drugs for conditions like Alzheimer's and brain tumors. The document outlines various types of nanoparticles used, including solid lipid nanoparticles, polymeric nanoparticles, nanocrystals, and carbon nanotubes. It also discusses properties needed for effective CNS delivery and mechanisms nanoparticles can use to cross the BBB, such as receptor-mediated transport. While promising, the document notes more research is still needed to optimize nanoparticle delivery and ensure safety before clinical use.

1. Targeted Drug Delivery to
CNS using Nanoparticles
By
K.Gautham Reddy
2011A8PS364G

2. Introduction
 The delivery of drugs to the CNS is of prime importance for treating
various degenerative diseases such as Alzheimer, Parkinson’s and
tumors such as Glioblastoma.
 The major problem in treating such CNS disorders is due to their
inability to surpass the natural CNS protective barriers, mainly the
Blood Brain Barrier (BBB) and the Blood Cerebro Spinal fluid barrier
 The BBB is a structure formed by a complex system of endothelial
cells, astroglia, pericytes, and perivascular mast cells , preventing
the passage of most circulating cells and molecules . The tightness
of the BBB is attributed mainly to of brain capillary endothelial
cells which are interconnected side-by-side by tight junctions.
 BBB regulates the movement of ions of small molecules from the
blood to the brain, protecting it from injuries and diseases.
However, the BBB also significantly precludes the delivery of drugs
to the brain, thus, preventing the therapy of a number of
neurological disorders.

3.  It should also be mentioned that a further obstacle for drugs
crossing the cerebral capillary endothelium and entering the brain
is represented by the presence of the P-glycoprotein pump in the
BBB, allowing the recognition of molecules necessary for the brain
to enter the brain and the expulsion of other molecules,
pharmaceuticals included.
 Given such premises, different approaches have been tried to allow
pharmaceuticals to overcome the BBB. These explorative strategies
have been ranging from invasive techniques, for example, through
osmotic opening of the BBB, to chemical modifications of drugs , or
exploiting the so-called “Trojan horse” technology, coupling BBB-
impermeant pharmaceutical to molecules able to cross the barrier
taking advantage of receptor-mediated transport systems

4. Advantages of nanoparticles for
CNS targeted drug delivery
 Nanoparticles protect drugs against chemical and enzymatic
degradation.
 Site-specific targeting can be achieved by attaching targeting
ligands to surface of particles or use of magnetic guidance
 Imaging or sensing agents might additionally be incorporated into a
nanodelivery system to generate multifunctionality (e.g., drug-
loaded quantum dots).
 Sustained drug release at the targeted site after injection over a
period of days or even weeks.
 Due to their small size nanoparticles penetrate into even small
capillaries and are taken up within cells, allowing an efficient drug
accumulation at the targeted sites in the body.

5. Ideal properties of nanoparticles
for CNS drug delivery
 The nanoparticles should be nontoxic, biodegradable, and
biocompatible.
 Should be physically stable in blood
(No aggregation).
 Nanoparticles should avoid opsonization, thereby prolonged
blood circulation time.
 Amenable to small molecules, peptides,
proteins, or nucleic acids.

6. Use of nanoparticles for CNS
targeted drug delivery
 Neutral nanoparticles and low concentrations of anionic
nanoparticles have no effect on BBB integrity
 The extent of brain uptake of anionic nanoparticles at lower
concentrations was superior to neutral or cationic formulations at
the same concentrations.
 High concentrations of anionic nanoparticles and cationic
nanoparticles were toxic for the BBB
 So, nanoparticle surface charges must be considered for toxicity
and brain distribution profiles.

7. How NP can cross BBB
 Crossing the BBB without Functionalization
Although almost all nanomaterials fall into the class of BBB
impermeable, some exceptions have been reported in recent years.
For instance, gold and silica NPs have been shown to reach the brain
and accumulate in neurons even in the absence of any specific
functionalization
 BBB Breakdown
BBB breakdown occurs in neuroinflammatory diseases . NPs can
reversibly open the tight junctions located at the BBB and other sites,
thus, increasing their paracellular permeability

8.  Transferrin Receptor (TfR)
The transferrin receptor (TfR) is the most widely studied
receptor for BBB targeting. TfR is a transmembrane
glycoprotein, consisting of two linked 90-kDa subunits, each
one binding a transferrin molecule.It is expressed on
hepatocytes and endothelial cells of the BBB. The role of the
receptor is the regulation of cellular uptake of iron via
transferrin. Cellular uptake starts with the binding of transferrin
to the transferrin receptor followed by endocytosis .

9. Different types of nanoparticles used for
CNS targeted drug delivery
 Solid Lipid Nanoparticles
Solid lipid nanoparticles (SLN) are a stable lipid-based nanocarrier
with a solid hydrophobic lipid core, in which the drug can be dissolved
or dispersed . They are made with biocompatible lipids such as
triglycerides, fatty acids, or waxes. They are generally of small size
(around 40–200 nm) allowing them to cross tight endothelial cells of
the BBB and escape from the reticuloendothelial system (RES) .
 Polymeric Nanoparticles
Polymeric NPs are composed of a core polymer matrix in which drugs
can be embedded , with sizes usually between 60 and 200 nm. Many
of these materials are designed to degrade within the body. Most
popular ones are polylactides (PLA), polyglycolides (PGA).
poly(lactide-co-glycolides) (PLGA), polyanhydrides,and
polycaprolactone. In spite of development of various synthetic and
semi-synthetic polymers, also natural polymers such as chitosan can
be utilized.

10.  Nanocrystals
Nanocrystals are aggregates of molecules that can be combined
into a crystalline form of the drug surrounded by a thin coating of
surfactant. A nanocrystalline species may be prepared from a
hydrophobic compound and coated with a thin hydrophilic layer. The
biological reaction to nanocrystals depends strongly on the chemical
nature of this hydrophilic coating. These factors combine to increase
the efficiency of overall drug delivery. Both oral and parenteral
deliveries are possible. A drawback however, is that the stability of
nanocrystals is limited. Moreover, this technique requires
crystallization; some therapeutic compounds may not be easily
crystallized.

11.  Quantum dots
QDs are luminescent nanocrystals made of semiconductors used for
imaging in biological systems. They allow specific drugs such as
protein, siRNA, genetic materials, and antisense oligonucleotides to
penetrate targeted cancer cells in the CNS. As semiconductors are
poisonous heavy metals, toxicity is a huge obstacle to clinical
application of QDs for humans.
 Carbon Nanotubes
Carbon nanotubes are used as carriers for drug and represent the
most investigated therapeutic strategies for gene therapy delivery.
They are able to carry small interfering RNA (siRNA) molecules that
exert RNA interference on target gene expression. While they are
potentially promising for pharmaceutical applications, human
tolerance of these compounds remains unknown, and toxicity reports
are conflicting. Extensive research into the biocompatibility and
toxicity of nanotubes remains ongoing.

12. Future prospects
 Several studies demonstrate increased passage of monocytes
across the BBB in various pathological conditions, the synthesis of
NPs mimicking immune cells might be effective in brain-associated
disorders, and it is therefore predictable that the research will
receive a stimulus in this direction in the next years.
 Other possibilities are to exploit the absence or at least the high
permeability of some BBB regions. BBB is present in all brain
regions, with the exception area postrema, median eminence,
neurohypophysis, pineal gland, subfornical organ, and lamina
terminalis . The endothelial cells present in capillaries of these
brain areas have fenestrations that allow diffusion of molecules.

13. Conclusions
 The blood-brain barrier (BBB) is the most important limiting factor
for the development of new drugs for the central nervous system.
 It may possible that most of the future therapeutics against brain
diseases can be delivered through nanovehicles.
 Nanoparticle based drug delivery technology which presently exist
should be improved further, so that it can be safe, effective, target
oriented.
 However, a long way of optimization, standardization and
randomization is needed before actual clinical application takes
into effect.
 Use of Nanotechnology is an innovative and promising approach in
drug delivery to CNS