INTRODUCTION:

The brain is the most sensitive and complex organ in the human body and is protected by a very efficient barrier known as the blood brain barrier (BBB).Despites the decades of research in the development of drugs for brain diseases, crossing of the BBB remains a key obstacle. Although the BBB is a life supporting that protects the brain against the toxic substances that circumulate in the blood stream, its existence is a severe limitation to the delivery of the most of the drugs to the brain because they do not cross the BBB in sufficient amounts. To reach the therapeutic drug level in the brain, a novel delivery system such as nanoparticulate system as drug carriers with high loading capacity and small particle size, which bypasses the reticulo endothelial system (RES), are considered as suitable delivery systems. [1-4]

USE OF NANOPARTICLES FOR CNS TARGETED DRUG DELIEVERY:

Nanoparticles with different surface characteristics when evaluated, it was found that neutral nanoparticles and low concentrations of anionic nanoparticles have no effect on BBB integrity, whereas high concentrations of anionic nanoparticles and cationic nanoparticles were toxic for the BBB. The extent of brain uptake of anionic nanoparticles at lower concentrations was superior to neutral or cationic formulations at the same concentrations. So, nanoparticle surface charges must be considered for toxicity and brain distribution profiles. Especially coating of the nanoparticles with the polysorbate (Tween) surfactants resulted in transport of drugs across the blood brain barrier. The mechanism for transport was suggested to be endocytosis via the Low Density Lipoprotein (LDL) receptor of the endothelial cells after adsorption of lipoproteins form blood plasma to the nanoparticles. Investigations revealed the role of apolipoprotein-E for transport of drugs across the BBB. It is suggested that the recognition and interaction with lipoprotein receptors on brain capillary endothelial cells is responsible for the brain uptake of the drug.[5] Passage of the BBB may also be achieved by masking certain drug characteristics preventing or limiting binding to cellular efflux systems like p-glycoprotein, a cellular transporter associated with drug removal from cells. P-glycoprotein is one of the ATP dependent efflux transporters that has an important physiological role in limiting drug entry into the brain. Other routes for reaching the brain, circumventing the BBB, may be via migration along the olfactory or trigeminal nerve endings after deposition on the olfactory mucosa in the nasal region.[6]

ADVANTAGES OF USING NANOPARTICLES FOR CNS TARGETED DRUG DELIEVERY: -

The methods of preparation of particles are simple and easy to scale-up. Nanoparticles formed are stable and easily freeze-dried. Nanoparticles protect drugs against chemical and enzymatic degradation. They are also able to reduce side effects of some active drugs. Nanoparticles were able to achieve with success tissue targeting of many drugs (antibiotics, cytostatics, peptides and proteins, nucleic acids, etc.). Often, nanoparticle drugs can be delivered directly to the CNS without prior need for drug modification or functionalization (which can affect efficacy). Surface-modifications of drug-loaded nanoparticles often prevent their rapid clearances by phagocytes following IV delivery. Imaging or sensing agents might additionally be incorporated into a nanodelivery system to generate multifunctionality (e.g., drug-loaded quantum dots).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. The use of biodegradable materials for nanoparticle preparation, allows sustained drug release at the targeted site after injection over a period of days or even weeks. Controlled release and particle degradation characteristics can be readily modulated by the choice of matrix constituents. Drug loading is relatively high and drugs can be incorporated into the systems without any chemical reaction; this is an important factor for preserving the drug activity. Site-specific targeting can be achieved by attaching targeting ligands to surface of particles or use of magnetic guidance.The system can be used for various routes of administration including oral, nasal, parenteral, intraocular etc. [7-9]

LIMITATIONS OF USING NANOPARTICLES FOR CNS TARGETED DRUG DELIVERY: -

Their small size and large surface area can lead to particle-particle aggregation, making physical handling of nanoparticles difficult in liquid and dry forms. In addition, small particles size and large surface area readily result in limited drug loading and burst release. [7-9]

IDEAL PROPERTIES OF NANOPARTICLES FOR BRAIN DRUG DELIVERY:-

The nanoparticles should be nontoxic, biodegradable, and biocompatible. Particle diameter <200 nm and should have a narrow particle size distribution. It should be physically stable in blood (No aggregation). Nanoparticles should avoid opsonization, thereby prolonged blood circulation time. BBB targeted and brain delivery (receptor-mediated transcytosis across brain capillary endothelial cells). Production of nanoparticles should be scalable and also a cost-effective manufacturing process. Amenable to small molecules, peptides,proteins, or nucleic acids. Minimal nanoparticle excipient induced drug alteration (chemical degradation/alteration, protein denaturation). [9, 10, 11, 12]

DIFFERENT TYPES OF NANOPARTICLES USED FOR CNS TARGETED DRUG DELIVERY:-

a) INORGANIC NANOPARTICLES:

Ceramic nanoparticles are typically composed of inorganic compounds such as silica, alumina, metals, metal oxides, and metal sulfides can be used. Hollow silica nanoparticles have been prepared, such as calcium phosphate-based nanoshells, with surface pores leading to a central reservoir. Inorganic nanoparticles may be designed to escape the reticuloendothelial system by varying size and surface composition. Also provide a physical encasement to protect an entrapped molecular payload from degradation or denaturization. Their lack of biodegradation and slow dissolution may not be suitable for long- term administration. [13]

b) POLYMERIC NANOPARTICLES:

Most polymeric nanoparticles are biodegradable and biocompatible and have been adopted as a desired method for nanomaterial drug delivery.nanoparticle formulations include those made from gelatins, chitosan, poly(lactic-co-glycolic acid) copolymer, poly lactic acid, poly glycolic acid, poly (alkyl cyanoacrylate), poly (methyl methacrylate), and poly(butyl)cyanoacrylate.. The biologically inert polymer poly (ethylene glycol) (PEG) has been covalently linked onto the surface of nanoparticles. This polymeric coating is thought to reduce immunogenicity, and limit the phagocytosis of nanoparticles by the reticulo endothelial system, resulting in increased blood levels of drug in the brain. The US Food and Drug Administration (FDA) has approved biodegradable polymeric nanoparticles, such as PLA and PLGA, for human use. The polymer matrix prevents drug degradation and may also provide management of drug release from these nanoparticles. Changing the drug-to-polymer ratio and molecular weight and composition of the polymer can modify the extent and level of drug release can provide excellent pharmacokinetic control and are suitable for the entrapment and delivery of a wide range of therapeutic agents. Practically, large-scale production and manufacturing remains an issue with polymeric nanoparticles. [13, 14]

c) SOLID LIPID NANOPARTICLES (SLN):

They consist of a relatively rigid core consisting of hydrophobic lipids that are solid at room and body temperatures, surrounded by a monolayer of phospholipids. These aggregates are further stabilized by the inclusion of high levels of surfactants. Because of their ease of bio- degradation, they are less toxic than polymer or ceramic nanoparticles. They have controllable pharmacokinetic parameters and can be engineered with three types of hydrophobic core designs: a homogenous matrix, a drug-enriched shell, or a drug-enriched core. SLNs can easily gain access to the blood compartment, through their small size and lipophilic nature. SLN formulations stable for even three years have been developed. The detection of these particles by the reticulo-endothelial system is a major disadvantage. [13,15]

d) 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. The hydrophilic layer aids in the biological distribution and bioavailability and prevents aggregation of the crystalline drug material. These factorscombine to increase the efficiency of overalldrug delivery. High dosages can be achievedwith this formulation. Poorly soluble drugs canbe formulated to increase bioavailability viatreatment with an appropriate coating layer.Both oral and parenteral deliveries arepossible. The limited carrier consisting of primarily the thin coating of surfactant may reduce potential toxicity. A drawback however, is that the stability of nanocrystals is limited. Moreover, this technique requires crystallization; some therapeutic compounds may not be easily crystallized. [13]

e) CARBON NANOTUBES:

Carbon nanotubes are used as carriers for drug or oligonucleotide delivery and represent the most investigated therapeutic strategies for intra-tumoral drug and 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. [13]

f) DENDRIMERS:

Dendrimers are polymer-based macromolecules formed from monomeric or oligomeric units, such that each layer of branching units doubles or triples the number of peripheral groups. Dendrimers require further improvements in cytotoxicity profiles and biocompatibility. [13, 16]

g) QUANTUM DOTS (QD):

QDs are luminescent nanocrystals made of semiconductors used for imaging in biological systems. This interaction allows 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. [13]

h) GOLD NANOPARTICLES:

Gold nanoparticles (NPs) are made of a silica core coated with a thin gold shell. Gold NPs can be prepared with different geometries, such as nanospheres, nanoshells, nanorods, and nanocages. [13, 17]

i) MAGNETIC NANOPARTICLES:

Magnetic NPs are iron oxide particles with a diameter of 10 nm. Many groups have tested these molecules as contrasting agents for MRI, through conjugation of iron oxide NPs with hydrophilic polymer coatings of dextran or polyethylene glycol. [13]

PREPARATION OF NANOPARTICLES:

There are different methods to manufacture nanoparticles: (1) emulsion polymerization, (2) interfacial polymerization, (3)solvent evaporation, (4) solvent deposition, and (5) denaturation. The properties of nanoparticles vary with different polymers, stabilizers, and surfactants used during the manufacturing process. Each excipient added may have an influence on the bioavailability of the drug carried, the brain drug uptake, and the stability of the drug in the plasma.

1. EMULSION POLYMERIZATION:

Emulsion polymerization is one of the most rapid and most frequently used methods for nanoparticle preparation. Here, the monomer is added to a continuous phase, usually an aqueous phase at room temperature under constant stirring conditions. It is also possible to use an organic phase as the continuous phase. The polymerization can be initiated either by free radicals or by ion formation. The polymerization is initiated by the reaction of a monomer molecule with an initiator molecule. Triggers for the initiation of the reaction can be ultraviolet (UV) light, hydroxyl ions, or high-energy radiation. The polymer chain starts to grow when these initiated monomer ions or monomer radicals react with other monomer molecules. Additional monomer is solubilized in surfactant micelles or emulsified in larger droplets. After completion of polymerization, the reaction mixture is filtered, neutralized, and purified by centrifugation to remove any residual monomer. An example for an anionic process is the preparation of "poly (alkyl cyanoacrylate) nanoparticles" and an example for a free radical-initiated emulsion polymerization is the manufacturing of poly methyl methacrylate nanoparticles [18]. The process of emulsion polymerization has numerous advantages. Compared with other methods, it is rapid and in general there is no need to use stabilizers and surfactants. In addition, for industrial requirements it is easily scaled up [19]. In contrast, with the requirement of UV light, radiation, or free radicals to initiate the polymerization process, the incorporation of proteins and peptides during the polymerization is not possible. Furthermore, if one wishes to scale up this procedure, the need for purification of the nanoparticles via dialysis and centrifugation represents a problem [20].

2. INTERFACIAL POLYMERIZATION:

To achieve interfacial polymerization, monomers are polymerized at the interface between two immiscible phases. Interfacial polymerization takes place in a medium consisting of an aqueous and an organic phase, which are homogenized, emulsified, or micro-fluidized by vigorously mechanical stirring. Al KouhriFallouh et al. [21] introduced the formation of poly alkyl cyanoacrylate nanocapsules. In this process the monomer and the drug are dissolved in a mixture of oil and ethanol (oil/ethanol) and then slowly added through a small tube or needle to an aqueous phase containing surfactants (poloxamer 188 or 407 or phospholipids). The oil used can be Miglyol or benzylic acid. The primary disadvantage of this method is the occurrence of strong shear forces. This excludes the possibility of adding proteins and peptides during the polymerization process for incorporation purposes. The monomer spontaneously polymerizes and forms nanocapsules that consist of an oil droplet and a polymeric shell [21]. An advantage of this process is that the drug is encapsulated into the nanocapsule and not just adsorbed onto the surface. This would protect it from enzymes, thus preventing premature biodegradation before it reaches the blood brain barrier.

3. SOLVENT EVAPORATION:

The solvent evaporation method is a well-established and frequently used method for the manufacturing of particles with sizes above 1 pm and also sizes of less than 1000 nm. In this process the preformed polymer and the drug are dissolved in a volatile, water-immiscible organic solvent. This organic phase is then added to the aqueous phase under stirring, and the organic solvent is removed by heating and/or under reduced pressure. The polymer precipitates and forms micro or nanospheres instantaneously containing the drug dispersed in the polymer matrix network. The particles are then purified by filtration and centrifugation [22]. Examples of this process are the manufacturing of poly (lactic acid) nanoparticles and poly (lactic-coglycolic acid) nanoparticles. [23, 24]

4. SOLVENT DEPOSITION:

In this process the polymer, e.g., poly (DL--lactide), and phospholipids are dissolved in a volatile organic solvent such as acetone. Then a solution of the drug in benzyl benzoate is added to the organic phase and the reaction mixture is poured into the water phase, which contains poloxamer 188 under moderate stirring conditions. Nanocapsules consisting of an oily core and a poly (lactic acid) shell are formed instantaneously. The organic solvent is then removed under reduced pressure. Partial removal of water also occurs [25, 26].

5. DENATURATION:

Nanoparticles can also be produced by denaturation of natural macro-molecules such as albumin and gelatin in an oil emulsion. Then both phases are emulsified using a homogenizer. The size of the forming particles depends on the stirring velocity, slit width, and power of the homogenizer. Then the particles are hardened by crosslinking with an aldehyde, by heat denaturation, or by cooling below the gelation point [27, 28, 29].

CONCLUSION:

It emerges from this review that colloidal systems can easily enter brain capillaries before reaching the surface of the brain micro-vascular endothelial cells, under the condition that the surface of these colloids is modified in a proper way. The prolonged blood circulation of these surface modified colloidal particles enhances exposure of the BBB, which favors interaction and penetration into brain endothelial cells. Colloidal systems may further be modified with specific targeting molecules aiming to enhance their binding with surface receptors of the bone marrow micro-vascular endothelial cells (BMEC), thus promoting their transport across the BBB. Therefore, when drug is loaded, colloidal carriers may be helpful for the treatment of brain diseases (with or without disruption of BBB), because they offer clinical advantages such as decreased drug dose, reduced drug side effects, increased drug viability, non-invasive routes of administration and improved patient quality of life. However, there is an urgent need to clarify the mechanisms which manage the carrier-mediated transport of the drugs to the brain.

REFERENCES:

1) P.M. Bummer, Physical Chemical Considerations of lipid based oral drug delivery-solid lipid nanoparticles, Crit. Rev. Therapeutics Drug carrier system. 21 (2004): 1-20.

2) R.H. Muller, C.M. Keck, Challenges and solutions for the delivery of biotech drugs- a review of drug nanocrystal technology and lipid nanoparticles. J. Biotechnology 113 (1-3) (2004): 151-170.

3) D.J. Begley, Delivery of therapeutic agents to the central nervous system: the problems and possibilities. Pharm. Therapeutics 104 (1) (2004): 29-45.

4) J.X. Wang, X. Sun, Z.R. Zhang, Enhanced brain targeting by synthesis of 3’,5’-dioctanoyl-5-fluoro-2’-deoxyuridine and incorporation into solid lipid nanoparticles. Eur. J. pharm. Biopharm. 54 (3) (2002): 285-290.

5) WHD Jong, PJA Borm. Drug delivery and nanoparticles: Applications and hazards. International Journal Nanomedicine. 3; (2008): 133–149.

6) DF Emerich, CG Thanos. Targeted Nanoparticle Based Drug Delivery and Diagnosis. Journal of Drug Targeting. 15;(2007): 163-183.

7) A Misra, S Ganesh, AShahiwala, SP Shah. Drug Delivery To The Central Nervous System: A Review. Journal Pharmacy Pharmaceutical Science. 6; (2003): 252- 273.

8) C Roney, P Kulkarni, V Arora, P Antich, F Bonte, A Wu, NN Mallikarjuana, S Manohar, H Liang, AR Kulkarni, H Sung, M Sairam, TM Aminabhavi. Targeted Nanoparticles for Drug DeliveryThrough the Blood–Brain Barrier for Alzheimer’s disease. Journal of Controlled Release. 108: (2005):193–214.

9) IP Kaur, R Bhandari, S Bhandari, V Kakkar. Potential of Solid Lipid Nanoparticles In Brain Targeting. Journal of Controlled Release, 127; (2008): 97-109.

10) HL Wong, N Chattopadhyay, XY Wu, R Bendayan. Nanotechnology Applications For Improved Delivery Of Antiretroviral Drugs To The Brain. Advanced Drug Delivery Reviews, 62; (2010): 503–517.

11) A Rasheed, I Theja, G Silparani, Y Lavanya, CKA Kumar. CNS Targeted Drug Delivery: Current Perspectives. JITPS. 1; (2010): 9- 18.

12) A Kroll, R DVM, N Edward. Outwitting the Blood-Brain Barrier for Therapeutic Purposes: Osmotic Opening and Other Means. Neurosurger. 42; (1998): 1083- 1099.

13) AH Faraji, P Wipf. Nanoparticles In Cellular Drug Delivery. Bioorganic AndMedicinal Chemistry, 17; (2009): 2950-2962.

14) JC Olivier.Drug Transport to Brain with Targeted Nanoparticles. Neuro RX. 2 ;(2005): 108-119.

15) N K Jain, Advances in Controlled and Novel Drug Delivery, CBS Publishers and Distributors Pvt. Ltd., New Delhi, India.408-422.

16) OM Koo, I Rubinstein, H Onyuksel. Role of nanotechnology in targeted drug delivery and imaging: a concise review. Nanomedicine: Nanotechnology, Biology and Medicine. 1; (2005): 193-212.

17) PR Lockman, RJ Mumper, MA Khan, DD Allen. Nanoparticle Technology for Drug Delivery across the Blood-Brain Barrier, 28; (2002): 1-13.

18) J. Kreuter, "Encyclopedia of Pharmacy Technology," 165 (1994).

19) J. Kreuter, in "Specialized Drug Delivery Systems (P Tyle, E d.), p. 257. Marcel Dekker, New York, 1990.

20) G. Birrenbach and P P Speiser J, Pharm. Sci. 65,1763 (1976).

21) N. Al Khouri Fallouh, L. Roblot: Treubel, H. Fessi, J. P. Devissaguet, and E Puisieux, Int. I. Pharm. 28, 125 (1986).

22) T. R. Tice and R. M. Gilley, J. Controlled Release2 ,343 (1985).

23) H.-J. Krause, A. Schwartz, and P Rohdewald, Int. J. Pharm. 27, 145 (1985).

24) W.P. Yu, J. P Wong, and T M. S. Chang, L Microencaps1. 5,515 (1998)

25) H. Fessi F . Puisieux J . Devissaguet N, Ammoury and S. Benita, Int. J. Pharm.55,R l (1989).

26) N. Ammoury, H. Fessi, J . P.D Evissaguet F, ,Puisieux, and S. Benita, l. Pharm. Sci 79,763 (1990).

27) L. Zolle, F, Hosain, B. A. Rhodes, and H. N. Wagner, Jr., J. Nucl. Med. 11,379 (1970).

28) U. Scheffel, B. A. Rhodes, T K. Natarajan, and H. N. Wagner, Jr., I. Nucl. Med. 13,498 (1972).

29) J. J. Burger, E. Tomlinson, and J. W Mulder, Int. J. Pharm.23, 333 (1985).

Received on 07.02.2013 Modified on 01.03.2013

Research J. Pharm. and Tech. 6(5): May 2013; Page 454-458