Targeted Drug Delivery to CNS using Nanoparticles

ByK.Gautham Reddy2011A8PS364G

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.

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

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.

Ideal properties of nanoparticlesfor 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.

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.

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 BreakdownBBB breakdown occurs in neuroinflammatory diseases . NPs can reversibly open the tight junctions located at the BBB and other sites, thus, increasing their paracellular permeability

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 .

Different types of nanoparticles used forCNS targeted drug delivery Solid Lipid NanoparticlesSolid 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 NanoparticlesPolymeric 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.

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.

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.

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.

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