Brain Targeting Drug Delivery System: A Review

 

Pooja M. Nikam1*, S.B. Gondkar2, R.B. Saudagar3

1Department of Pharmaceutics, R.G. Sapkal College of Pharmacy, Anjaneri, Nasik- 422003

2Department of Pharmaceutics, R.G. Sapkal College of Pharmacy, Anjaneri, Nasik- 422003

*Corresponding Author E-mail: poojanik93@gmail.com

 

ABSTRACT:

The Overall prevalence rate for CNS pathology has demonstrated that approximately 1.5 billion people under going from disorders of central nervous system. The most distressing fact about delivery of drugs to the CNS is the presence of blood brain barrier that have a tendency to impair the drug distribution and denotes the major impediment for the development of CNS drugs. Neuropeptides and many drugs which are hydrophilic in nature, possibly will encompass the intricacy while passing the blood brain barrier. The net amount of delivered drug (medicinal agent) and its capability to gain access to the pertinent target sites are the main considering points for CNS drug development. In order to distribute the drugs into the CNS via passing the blood brain barrier, many new emerging approaches have been developed for example Magnetic drug targeting, chemical delivery Systems, Drug carrier systems (antibodies, liposomes or Nanoparticles). Among drug carrier system, Nanoparticles exhibit an impressive attention in the field of targeted drug delivery system because of possessing solid colloidal particles with a size range between 1- 1000nm. Gradual drug release reduced peripheral toxicity and potential totarget specific brain sites by crossing the blood brain barrier are major benefits contributed by Nanoparticles. In this review we will discuss the methodologies for targeting the brain site.

 

KEYWORDS: Brain barrier, Drug delivery to brain, Nanotechnology, Colloidal drug carriers.

 

 

INTRODUCTION:

The central nervous system is protected by BBB, BCF, and BTB which control the entry of compounds into the brain, thereby regulating brain homeostasis. Barrier restricts access to brain cells of blood–borne compounds and facilitates nutrients essential for normal metabolism to reach brain cells. This regulation of the brain homeostasis results in the inability of some small and large therapeutic compounds to cross the blood–brain barrier (BBB). Therefore, various strategies have been developed to enhance the amount and concentration of therapeutic compounds in the brain [1].

 

 

The brain is shielded against potentially toxic substances by the presence of two barrier systems: the blood brain barrier (BBB) and the blood cerebrospinal fluid barrier (BCSFB).

 

It is estimated that more than 98% of small molecular weight drugs and practically 100% of large molecular weight drugs (mainly peptides and proteins) developed for CNS pathologies do not readily cross the BBB and discovery of new modalities allowing for effective delivery of drugs and bio macromolecules to the central nervous system (CNS) is of great need and importance for treatment of neurodegenerative disorders (Alzheimer’s disease, Epilepsy) [2].

 

This manuscript focuses on three relatively new strategies. The first strategy involves inhibition of the drug efflux transporters expressed in BBB by Pluronic® block copolymers, which allow for the increased transport of the substrates of these transporters to the brain. The second strategy involves around the design of nanoparticles conjugated with specific ligands that can target receptors in the brain microvasculature and carry the drugs to the brain through the receptor mediated transcytosis. The third strategy involves artificial hydrophobization of peptides and proteins that facilitate the delivery of these peptides and proteins across BBB [3].

 

The parameters considered optimum for a compound to transport across the BBB are:

●     Compound should be unionized.

●     Approximately logP value must be 2.

●     Its molecular weight must be less than 400 Da.

●     Cumulative number of hydrogen bonds must not go beyond 8 to 10.

 

It is estimated only 2% of small molecular weight drug will across BBB.

 

Barriers to CNS drug delivery:

The failure of systemically delivered drugs to effectively treat many CNS diseases can be rationalized by considering a number of barriers that inhibits drug delivery to the CNS.

 

Blood-Brain Barrier (BBB):

Basal membrane and brain cells, such as pericytes and astrocytes, surrounding the endothelial cells further form and maintain an enzymatic and physical barrier known as the blood–brain barrier (BBB). BBB tight junctions are formed between endothelial cells in brain capillaries, thus preventing paracellular transport of molecules into the brain.

 

Micro-vessels small in diameter and thin walls compared to vessels in other organs make up an estimated 95% of the total surface area of the BBB, and represent the principal route by which chemicals enter the brain. In brain capillaries, intercellular cleft, pinocytosis, and fenestrate are virtually nonexistent; exchange must pass trans-cellularly. Therefore, only lipid-soluble solutes that can freely diffuse through the capillary endothelial membrane may passively cross the BBB [4].

 

Blood–cerebrospinal fluid barrier (BCSFB):

Another barrier between the blood and the brain is the blood–cerebrospinal fluid barrier (BCSFB), which separates the blood from cerebrospinal fluid (CSF). However, this barrier is not considered as a main route for the uptake of drugs since itssurface area is 5000-fold smaller than that of the BBB [5–8]. CSF can exchange molecules with the interstitial fluid of the brain parenchyma; the passage of blood-borne molecules into the CSF is also carefully regulated by the BCB. Physiologically, the BCB is found in the epithelium of the choroids plexus, which is arranged in a manner that limits the passage of molecules and cells into the     CSF[9-11]. The choroid plexus and the arachnoid membrane act together at the barriers between the blood and CSF [12]. The arachnoid membrane is generally impermeable to hydrophilic substances, and its role is formation of the Blood-CSF barrier, is largely passive. The choroid plexus forms the CSF and actively regulates the concentration of molecules in the CSF.

 

Blood-Tumor Barrier:

Intracranial drug delivery becomes even more challenging when the target is a CNS tumor. The presence of the BBB in the microvasculature of CNS tumors has clinical consequences [13]. In CNS malignancies where the BBB is significantly compromised, a variety of physiological barriers common to all the solid tumors inhibit drug delivery via the cardiovascular system. Drug delivery to neoplastic cells in a solid tumor is compromised by a heterogeneous distribution of microvasculature throughout the tumor interstitial, which leads to spatially inconsistent drug delivery.

 

Fig. 1: Schematic representation of the transport of molecules across the BBB

 

Fig. 2: Schematic representation of the drug penetrate and impenetrate across the BBB.

 

Fig. 3: Schematic representation of the factors affecting drug transport across the BBB

 

 

However, as a tumor grows large, the vascular surface area decreases, leading to reduction in trans-vascular exchange of blood-borne molecules. At the same time, intra-capillary distance increases, leading to a greater diffusional requirement for drug delivery to neoplastic cells and due to high interstitial tumor pressure and the associated peri-tumoral edema leads to increase in hydrostatic pressure in the normal brain parenchyma adjacent to the tumor. As a result, the cerebral microvasculature in these tumor adjacent regions of normal brain may be even less permeable to drugs than normal brain endothelium, which leads to exceptionally low extra-tumoral interstitial drug concentrations [14]. Brain tumors may also disrupt BBB, but these are also local and non homogeneous disruptions [15].

 

Approaches to CNS drug delivery:

Basically, two methods have been described in the literature to actively enhance drug delivery to the brain after systemic administration: either opening/disruption of the neuroprotective BBB by osmotic imbalance, ultrasound or vasoactive compounds (e.g., bradykinin or P-glycoprotein inhibitors), or physiological strategies aiming to use endogenous transport mechanisms. While the first method has the disadvantage that those neurons may be damaged (semi)-permanently due to unwanted blood components entering the brain[16-20]. The physiological strategies have a largepotential as discussed in several review papers elsewhere [21]. As a third alternative (using a combination of aspects of both methods), positive charge has also been applied to compounds or drug carriers to quite effectively enhance the absorptive-mediated transport across the BBB [22-23] however, a beneficial therapeutic window of this basically toxic transport mechanism has thus far not been established.

 

To overcome the multitude of barriers restricting CNS drug delivery of potential therapeutic agents, numerous drug delivery strategies have been developed. These strategies generally fall into one or more of the following categories: invasive, non-invasive or miscellaneous techniques [24-26].

 

Brain Targeting Technologies:

A     Non invasive approach: Lapidate the drug molecules e.g transnasalroute[27] .

B     Drug conjugates with liposomes and Nanoparticles [28].

C     Intrathecal and intra cerebroventricular delivery of drug molecules in to CNS by using different devices and needles [29].

D     Sustained and controlled release of drugs is considered along with systemic therapy in order to optimize the drug action in to the CNS.

 

Possible systems for drug delivery to brain:

·         Colloidal drug carriers systems for example vesicle, macular solutions, liquid crystal dispersions and liquid crystal dispersions (particle size range 10 to 400 nm)[30].

·         Nanotechnology[31].

 

Nanotechnology:

Improved drug delivery to the brain can be achieved by Nanotechnology, a more competent technology[32]. Materials used to prepare Nanoparticles are Polyacetates, poly(alkylcyanoacrylates), polysaccharides Copolymers, polysorbate-coated nanoparticles etc[33].

 

 

Fig 4. Schematic representation of challenges faced during CNS Drug development[34].

 

 

Mechanisms of Nanoparticle Transport across the blood brain barrier:

There are six enhancing mechanisms for transport of nanopartilces across blood brain barrier.

1.     Adhesion of nanoparticles to brain blood vessel walls[35]

2.     Fluidization of BBB endothelium by surfactants[36]

3.     Opening of tight junctions of endothelium[37]

4.     Transcytosis across the brain endothelial cells[38]

5.     Blockage of the glycoprotein in the brain endothelial cells[39]

6.     Endocytosis by the brain vessel endothelial cells[40]

 

 

Nanoparticulate systems for brain targeted delivery of drugs:

Size range of Nanoparticles is about 10 and 1000 nm and are usually made of various polymers (natural/ artificial)[41]. Nanoparticles have ability to entrap and encapsulate the drug molecules[42].Example of the Nanoparticles drugs are vaccines and anticancer drugs to treat metastatic brain tumors [43]. At the same time, the employing of nanoparticles in the field of ophthalmic and oral delivery was also investigated [44].

 

Future aspects of brain targeting:

Technological challenges need to be addressed are:

·         Attainment of controlled release profile particularly for sensitive drugs [45].

·         Improvement/enhancement of nanoparticles release from implantable devices/ nanochips[46].

·         cytotoxicity of nanoparticles should be reduced to improve the biocompatibility[47].

·         Multifunctional nanoparticles[48].

·         Universal formulation schemes that can be used as I/V, I/M or per oral drugs.

·         Nanoparticles for tissue engineering such as cytokines to restrain the cellular growth, discrimination and promote regeneration[49].

·          Encapsulation of implants by nanoparticles containing biodegradable polymer for  sustained release[50-51].

 

CONCLUSION:

From the above discussion it is found that many delivery systems like polymeric Nanoparticles and liposomes are the promising carriers to deliver drugs beyond the BBB for the scrutiny of the central nervous system. This is even more evident in light of the fact that most of the potentially available drugs for CNS therapies are large hydrophilic molecules, e.g., peptides, proteins and oligonucleotides that do not cross the BBB. Among the several strategies attempted in order to overcome this problem, properly tailored NPs may have a great potential.

 

The large amount of evidence regarding brain drug delivery by means of P80-coated NPs cannot be ignored or considered as single evidence even though its action mechanism is not completely understood. Lipid NPs, e.g. SLN, NLC, LDC NPs, may represent, in fact, promising carriers since their prevalence over other formulations in terms of toxicity, production feasibility and scalability is widely documented in the literature. The ability of engineered liposomes to enter into brain tumors makes them potential delivery systems for brain targeting.

 

A technology of chimeric peptides which are potential BBB transport vectors and have been applied to several peptide pharmaceuticals, nucleic acid therapeutics, and small molecules to make them CNS transportable.

 

It is estimated that the global CNS pharmaceutical market would have to grow by more than 500% just to equal the cardiovascular market.

 

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Received on 01.12.2015          Accepted on 08.12.2015        

© Asian Pharma Press All Right Reserved

Asian J. Res. Pharm. Sci. 5(4): Oct.-Dec. 2015; Page 247-252

DOI: 10.5958/2231-5659.2015.00036.3