Nanoparticle- A Review
Sarika V. Khandbahale1, Prof.Dr. R. B. Saudagar2
1Department of Quality Assurance Technique, R. G. Sapkal college of Pharmacy, Anjaneri Nashik.
2Depatment of Pharmaceutical chemistry, R.G. Sapkal college of Pharmacy Anjaneri, Nashik
*Corresponding Author E-mail: sarikavkhandbahale@gmail.com
Nanotechnology refers to the creation and utilization of materials whose constituents exist at the nanoscale; and, by convention, be up to 100 nm in size. Nanotechnology explores electrical, optical, and magnetic activity as well as structural behaviour at the molecular and submolecular level. It has the potential to revolutionize a series of medical and biotechnology tools and procedures so that they are portable, cheaper, safer, and easier to administer. Nanoparticles are being used for diverse purposes, from medical treatments, using in various branches of industry production such as solar and oxide fuel batteries for energy storage, to wide incorporation into diverse materials of everyday use such as cosmetics or clothes, optical devices, catalytic, bactericidal, electronic, sensor technology, biological labelling and treatment of some cancers. Due to their exceptional properties including antibacterial activity, high resistance to oxidation and high thermal conductivity, nanoparticles have attracted considerable attention in recent years. Nanoparticles can be synthesized chemically or biologically. Metallic nanoparticles that have immense applications in industries are of different types, namely, Gold, Silver, Alloy, magnetic etc. This study aims to present an overview of nanoparticles, with special reference to their mechanism of biosynthesis and types.
KEYWORDS: Nanoparticles, silver, bactericidal, thermal conductivity, optical devices.
INTRODUCTION:
The word “Nano” is derived from Greek word Dwarf, means “a billionth ”.A Nanometer is billionth of a meter, which is 250 millionth of an inch, about 1/80,000 of the diameter of a human hair or 10 times of the diameter of hydrogen atom. The term ‘Nanotechnology’ was coined by Prof. Norio Taniguchi, Tokyo Science University in 1974 to describe the precision manufacture of materials with nanometers tolerances and was unknowingly appropriated by Drexler in his 1986 book ‘Engines of creation: The Coming Era of Nanotechnology. Nanoparticles are sub-nano sized colloidal structure of synthetic or semi synthetic polymer.
The first reported nanoparticles were based on non-biodegradable polymeric system (polyacrylamide, polymethyl-methaacrylate, polystyrene).The polymeric nanoparticles can carry drug(s) or proteineous substances, i.e. antigen(s). These bio actives are entrapped in polymer matrix as particulates or solid solution or may bound to particle surface by physical adsorption or chemically. The drug(s) may be added during preparation of nanoparticle or to the previously prepared nanoparticles. The term particulate is suggestively general and doesn’t account for morphological and structural organization of system. Nanomedicine is an emerging field of medicine with novel applications.
Nanomedicine is a subset of nanotechnology, which uses tiny particles that are more than 10 million times smaller than the human body. In nanomedicine, these particles are much smaller than the living cell. Because of this, nanomedicine presents many revolutionary opportunities in the fight against all types of cancer, neurodegenerative disorders and other diseases.(1,2)
The ADVANTAGES of using nanoparticles as a drug delivery system include the following:(3)
1. Particle size and surface characteristics of nanoparticles can be easily manipulated to achieve both passive and active drug targeting after parenteral administration.
2. They control and sustain release of the drug during the transportation and at the site of localization, altering organ distribution of the drug and subsequent clearance of the drug so as to achieve increase in drug therapeutic efficacy and reduction in side effects.
3. 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.
4. Site-specific targeting can be achieved by attaching targeting ligands to surface of particles or use of magnetic guidance.
5. The system can be used for various routes of administration including oral, nasal, parenteral, intra-ocular etc.
Other than these advantages, nanoparticles have somelimitations like their small size and large surface area can lead to particle particle aggregation, making physical handling of nanoparticles difficult in liquid and dry forms and these small particles size and large surface area readily result in limited drug loading and burst release.
Preparation of Nanoparticles(4-13):
Nanoparticles can be prepared from a variety of materials such as proteins, polysaccharides and synthetic polymers. The selection of matrix materials is dependent on many factors including:
· size of nanoparticles required
· inherent properties of the drug, e.g., aqueous solubility and stability;
· surface characteristics such as charge and permeability;
· degree of biodegradability, biocompatibility and toxicity;
· Drug release profile desired; and
· Antigenicity of the final product.
Nanoparticles have been prepared mostly by three methods:
· Dispersion of preformed polymers
· Polymerization of monomers
· Ionic gelation or coacervation of hydrophilic polymers.
Other methods such as supercritical fluid technology and particle replication in non-wetting templates have also been described in the literature for production of nanoparticles.
Dispersion of preformed polymers:
Dispersion of preformed polymers is a common technique used to prepare biodegradable nanoparticles from poly (lactic acid) (PLA); poly (D,L-glycolide), PLG; poly (D, L-lactideco- glycolide) (PLGA) and poly (cyanoacrylate) (PCA).
This technique can be used in various ways as described below.
1. Solvent evaporation method:
In this method, the polymer is dissolved in an organic solvent such as dichloromethane, chloroform or ethyl acetate which is also used as the solvent for dissolving the hydrophobic drug. The mixture of polymer and drug solution is then emulsified in an aqueous solution containing a surfactant or emulsifying agent to form an oil in water (o/w) emulsion. After the formation of stable emulsion, the organic solvent is evaporated either by reducing the pressure or by continuous stirring. Particle size was found to be influenced by the type and concentrations of stabilizer, homogenizer speed and polymer concentration. In order to produce small particle size, often a high-speed homogenization or ultra-sonication may be employed.
Figure 1:Schematic representation of the solvent-evaporation technique
2. Polymerization method:
In this method, monomers are polymerized to form nanoparticles in an aqueous solution. Drug is incorporated either by being dissolved in the polymerization medium or by adsorption onto the nanoparticles after polymerization completed. The nanoparticle suspension is then purified to remove various stabilizers and surfactants employed for polymerization by ultracentrifugation and re-suspending the particles in an isotonic surfactant-free medium. This technique has been reported for making polybutylcyanoacrylate or poly (alkylcyanoacrylate) nanoparticles. Nano capsule formation and their particle size depends on the concentration of the surfactants and stabilizers used.
3. Coacervation or ionic gelation method:
Much research has been focused on the preparation of nanoparticles using biodegradable hydrophilic polymers such as chitosan, gelatin and sodium alginate. Calvo and co-workers developed a method for preparing hydrophilic chitosan nanoparticles by ionic gelation 19, 20.The method involves a mixture of two aqueous phases, of which one is the polymer chitosan, adi-block co-polymer ethylene oxide or propyleneoxide (PEO-PPO) and the other is a polyanion sodium tripolyphosphate. In this method, positively charged amino group of chitosan interacts with negative charged tripolyphosphate to form coacervates with a size in the range of nanometer. Coacervates are formed as a result of electrostatic interaction between two aqueous phases, whereas, ionic gelation involves the material undergoing transition from liquid to gel due to ionic interaction conditions at room temperature.
Figure 2:Schematic representation of ionic gelation method
4. Production of nanoparticles usingsupercritical fluid technology:
Conventional methods such as solventextraction-evaporation, solvent diffusion and organic phase separation methods require the use of organic solvents which are hazardous to the environment as well as to physiological systems. Therefore, the supercritical fluid technology has been investigated as an alternative to prepare biodegradable micro- and nanoparticles because supercritical fluids are environmentally safe. A supercritical fluid can be generally defined asa solvent at a temperature above its critical temperature, at which the fluid remains a single phase regardless of pressure. SupercriticalCO2 (SC CO2) is the most widely used supercritical fluid because of its mild critical conditions (Tc = 31.1 °C, Pc = 73.8 bars), nontoxicity, non-flammability, and low price. The most common processing techniques involving supercritical fluids are supercritical anti-solvent(SAS) and rapid expansion of critical solution(RESS). The process of SAS employs a liquid solvent, e.g. methanol, which is completely miscible with the supercritical fluid (SC CO2), to dissolve the solute to be micronized; at the process conditions, because the solute is insoluble in the supercritical fluid, the extract of the liquid solvent by supercritical fluid leads to the instantaneous precipitation of the solute, resulting the formation of nanoparticles. Thoteand Gupta (2005) reported the use of a modified SAS method for formation of hydrophilic drug dexamethasone phosphate drug nanoparticles for microencapsulation purpose.
RESS differs from the SAS process in that its solute is dissolved in a supercritical fluid (such as supercritical methanol) and then the solution is rapidly expanded through a small nozzle into a region lower pressure, Thus the solvent power of supercritical fluids dramatically decreases and the solute eventually precipitates.
Figure 3: Experimental set-up for preparation of polymer nanoparticles by rapid expansion of supercritical fluid solution
This technique is clean because the precipitate is basically solvent free. RESS and its modified process have been used for the product of polymeric nanoparticles. Supercritical fluid technology technique, although environmentally friendly and suitable for mass production, requires specially designed equipment and is more expensive.
5. Emulsification solvent evaporation Technique (14):
One of the methods used for the preparation of nanoparticles is emulsification solvent evaporation technique. It is basically used for encapsulating hydrophobic drugs, but shows the poor results for incorporation of bioactive agents of a hydrophilic nature. The solvent evaporation is carried out the polymer and the compound are dissolved in an organic solvent such as chloroform, ethylacetate, or methylene chloride and then it is emulsified in an aqueous phase containing a stabilizer (e.g., PVA). Just after formation of the nanoemulsion the solvent diffuses to the external phase until saturation. The solvent molecules that reach the water-air interphase evaporate, which leads to continuous diffusion of the solvent molecules from the inner droplets of the emulsion to the external phase; simultaneously, the precipitation of the polymer leads to the formation of Nano spheres. In many cases, the induction of Nanosized polymer droplets can be done by sonication or homogenization. The organic solvent is then evaporated and the nanoparticles are usually collected by centrifugation and lyophilisation. The small changes in this method are used for encapsulating hydrophilic compounds and proteins, which can be done by, the double, or multiple emulsion technique. As the name signifies firstly, a hydrophilic drug and a stabilizer dissolve in water. The primary emulsion is prepared by dispersing the aqueous phase into an organic solvent containing a dissolved polymer. This is then emulsified in an outer aqueous phase also containing stabilizer. The nanoparticles can be achieved by the solvent evaporation method. One of the main problems associated for the encapsulation of a hydrophilic molecule like a protein or peptide-drug is the rapid diffusion of the molecule into the outer aqueous phase during the emulsification. This can result in poor encapsulation efficiency, i.e. drug loading.
6. Emulsification Diffusion method (15):
Another method which can be used for preparation of nanoparticles is the emulsification diffusion method. The method utilizes a partially water-soluble solvent like acetone or propylene carbonate. The polymer and the drug are dissolved in the solvent and it is emulsified in the aqueous phase containing the stabilizer. The role of stabilizer prevents the aggregation of emulsion droplets by adsorbing of the surface of the droplets. Addition of water to the emulsion, allow the diffusion of the solvent into the water. The solution is stirred leading to the Nanoprecipitation of the particles. Further, it can be collected by centrifugation, or the solvent can be removed effectively by dialysis. The main problem with this method is that the water soluble drugs tend to leak out from the polymer phase during diffusion steps. So, in order to avoid this problem the dispersing medium changed from aqueous medium to medium chain triglycerides and a small amount of surfactant is added into it. The nanoparticles are collected from the oily suspension by centrifugation.
7. Nanoprecipitation method (16,17):
Nanoparticles can be synthesized by the nanoprecipitation method. In this method, polymer and drug are dissolved in acetone, ethanol, or methanol and incorporated undermagnetic stirring into an aqueous solution of the surfactant. The organic solvent diffuses instantaneously to the external aqueous phase, followed by precipitation of the polymer and drug. After formation of the nanoparticles, the solvent is eliminated and the suspension concentrated under reduced pressure. The advantage of this method is that no surfactant is employed; however, the method is limited to drugs that are highly soluble in a polar solvent. \
8. Salting-out method (18):
The salting-out process is another method for the preparation of nanoparticles. This technique is based on the precipitation of a hydrophobic polymer, is useful for the encapsulation of either hydrophilic or hydrophobic drugs because a variety of solvents, including polar (e.g., acetone or methanol) and non-polar (methylene chlorideor chloroform) solvents can be chosen for dissolving the drug.
Synthesis of Nanoparticles (19-22):
Nanoparticles can be synthesized chemically or biologically. Many adverse effects have been associated with chemical synthesis methods due to the presence of some toxic chemical absorbed on the surface.
Figure 4: Schematic representation of the emulsification/solvent diffusion technique
Figure 5:Schematic representation of the nanoprecipitation technique. Surfactant is optional.
Figure 6:Schematic representation of the salting out technique
Eco friendly alternatives to Chemical and physical methods are Biological ways of nanoparticles synthesis using microorganisms, enzymes4, fungus, and plants or plant extracts. The development of these eco-friendly methods for the synthesis of nanoparticles is evolving into an important branch of nanotechnology especially silver nanoparticles, which have many applications.
Biosynthesis: Mechanism:
Biosynthesis of nanoparticles by microorganisms is a green and eco-friendly technology. Diverse microorganisms, both prokaryotes and eukaryotes are used for synthesis of metallic nanoparticles viz. silver, gold, platinum, zirconium, palladium, iron, cadmium and metal oxides such as titanium oxide, zinc oxide, etc. These microorganisms include bacteria, actinomycetes, fungi and algae. The synthesis of nanoparticles may be intracellular or extracellular according to the location of nanoparticles.
Intracellular synthesis of nanoparticles by fungi:
This method involves transport of ions into microbial cells to form nanoparticles in the presence of enzymes. As compared to the size of extracellularly reduced nanoparticles, the nanoparticles formed inside the organism are smaller. The size limit is probably related to the particles nucleating inside the organisms.
Extracellular synthesis of nanoparticles by fungi:
Extracellular synthesis of nanoparticles has more applications as compared to intracellular synthesis since it is void of unnecessary adjoining cellular components from the cell. Mostly, fungi are known to produce nanoparticles extracellularly because of their enormous secretory components, which are involved in the reduction and capping of nanoparticles.
Microbes for production of nanoparticles:
Both unicellular and multicellular organisms produce inorganic materials either intra- or extracellularly. The ability of microorganisms like bacteria and fungi to control the synthesis of metallic nanoparticles is employed in the search for new materials. Because of their tolerance and metal bioaccumulation ability, fungi have occupied the centre stage of studies on biological generation of metallic nanoparticles.
Types of nanoparticles applied in drug delivery (23-25):
The types of nanoparticles applied in the drug delivery system include:
1. Nano suspension:
A suspension of drug nanoparticles in a liquid is called as Nano suspension. A size of nanoparticle lies in between 200 to 500 nm and outstanding feature of nanosuspension is the increased saturation, solubility, increased dissolution rate of compound. The saturation and solubility increases below a particle size of 1 mcm. An additional feature of nanosuspension is that they may induce changes in the crystalline structure increase the amorphous fraction in particle or even creating completely amorphous particles. Nanoparticles and Nanosuspensions show an increased adhesiveness to tissue. The oral administration of drug in the form of nanosuspension has been reported to enhance absorption rate and bioavailability.
2. Solid lipid Nanoparticles (SLN):
The solid lipid nanoparticles are sub-micron colloidal carriers (50-1,000nm) which are composed of physiological lipid, dispersed in water or in aqueous surfactant solution. In order to overcome the disadvantages associated with liquid state of oil droplets, liquid lipid replaced by a solid lipid, which eventually transformed into solid lipid nanoparticles.
3. Polymeric nanoparticles:
The drug is dissolved, entrapped, absorbed, attached or encapsulated into nanoparticle matrix. Depending on the method of preparation, nanoparticles, nanospheres or nanocapsules can be obtained with different properties and release characteristics for encapsulated therapeutic agent. Nanoparticles are vesicular systems in which the drug is confined to a cavity surrounded by unique polymer membranes, where as nanospheres are matrix systems in which the drug is physically and uniformly dispersed. The advantages of using nanoparticles for drug delivery result from their two main basic properties. First nanoparticles, because of their small size, can penetrate through smaller capillaries and are taken up by cells, which allow efficient drug accumulation at the target sites. Second, the use of biodegradable materials for nanoparticle preparation allows sustained drug release within the target site over a period of days or even weeks.
4. Polymeric micelles:
Polymeric micelles have been extensively studied as drug carrier. Polymeric micelles have better thermodynamic stability in physiological solution, as indicated by their low critical micellar concentration, which makes polymeric micelles stable and prevent their rapid dissociation in vivo.
Micelles have a fairly narrow size distribution in the nanometer range and are characterized by their unique core-shell architecture, in which hydrophobic segments are segregated from the aqueous exterior.
Micellar systems are useful for the systemic delivery of water-insoluble drugs. Drugs can be partitioned in the hydrophobic cores of micelles and the outer hydrophilic layer from stable dispersion in aqueous media which can then be administered intravenously. The distribution of drug-loaded polymeric micelles (less than 100 nm in diameter), following intravenous administration, polymeric micelles have been shown to have prolonged systemic circulation time because of their smaller size and hydrophilic shell, which minimizes their uptakes by the reticuloendothelial system. Polymeric micelle-incorporated drugs may accumulate to a greater extent than free drugs into tumours and demonstrate reduced distribution in non-targeted areas.
5. Magnetic Nanoparticles:
Magnetic nanoparticles are powerful and versatile diagnostic tool in field of medicine. Magnetic immunoassay techniques have been developed in which the main field generated by the magnetically labelled target detected directly with sensitive magnetometer. Superparamagnetic nanoparticles are used as contrast agents in magnetic resonance imaging. The magnetic nanoparticle are coated with inorganic core of iron oxide with polymer such as dextran. Magnetic nanoparticles of indomethacin demonstrated selective targeting under magnetic field of 8000 Oe-strength, following normal administration, the drug concentration was higher in the liver and spleen where endocytosis and phagocytosis could occur.
6. Carbon Nanotubes:
Carbon nanotubes are a new form of carbon molecule around in a hexagonal network of carbon atoms, these hollow cylinders can have diameter as a small as 0.7nm and reach several millimetres in length. Each end can be opened or closed by a fullerene half molecule. The small dimensions of nanotubes, combined with their remarkable physical, mechanical and electrical properties, make them unique materials. The mechanical strength of carbon nanotubes is more than sixty times greater than that of the best steels, even though they weigh six times less. They also represent a very large specific surface area, are excellent heat conductors and display unique electronic properties, offering three dimensional configurations. They have higher capacity for molecular absorption.
7. Liposomes:
Liposomes have been used as a versatile tool in biology, biochemistry and medicine. Liposomes are small artificial vesicles of spherical shape that can be produced from natural non-toxic phospholipids and cholesterol. Because of their size, hydrophilic and hydrophobic character, as well as biocompatibility, liposomes are promising system for drug delivery. Properties of Liposomes vary substantially with lipid composition, size, surface charge and the method of preparation. They are therefore classified into three classes based on their size and number of bilayers. Small unilamellar vesicles (SUV) are surrounded by a single lipid layer and are 25-50nm in diameter. Large unilamellar vesicles (LUV) are heterogeneous group of vesicles similar to SUVs and are surrounded by a single lipid layer. Multilamellar vesicles (MLV) consist of several lipids separated from one another by a layer of aqueous solution. Drugs associated with liposomes have markedly altered pharmacokinetic properties compared to drugs in solution. They are also effective in reducing systemic toxicity and preventing early degradation of the encapsulated drug after introduction to the target organism.
8. Nanoshells coated with gold:
Gold nanoshells are new composite nanoparticles that combine infrared optical activity with the uniquely biocompatible properties of gold colloid. Metal nanoshells are concentric sphere nanoparticles consisting of a dielectric (typically gold sulphide or silica) core and a metal (gold) shell. By varying the relative thickness of core and shell layers, the Plasmon-derived optical resonance of gold can be dramatically shifted in wavelength from visible region of highest physiological transmissivity. By varying absolute size of the gold nanoshell, it can be made to either selectively absorb(for particle diameter < 75nm) or scatter incident light. Because the gold shell layer is deposited using the same chemical method used to grow gold colloid, the surface properties of gold nanoshells are virtually identical to those of gold colloid. Gold nanoshells can be used to ablate breast cancer cells.
9. Ceramic nanoparticles:
The newly emerging area of using inorganic (ceramic) particles with entrapped biomolecule has potential applications in many frontiers of modern materials science including drug delivery system. The advantages of ceramic nanoparticles include easy preparation with desired size, shape and porosity, and no effect on swelling or porosity with no change in pH.
10. Nano pores:
Materials with defined pore-sizes in the nanometer range are of special interest for a broad range of industrial application because of their outstanding properties with regard to thermal insulation, controllable material separation and release and their applicability as templates or fillers for chemistry and catalysis. One example of nanoporous material is aerogel, which is produced by sol-gel chemistry.
11. Nanowires:
Nanowires are conductive or semi conductive particles with a crystalline structure of a few dozen nm and a high length /diameter ratio. Silicon, Cobalt, Gold or Copper-based nanowires have already been produced. They are used to transport electrons in nanoelectronics they could be composed of different metals, Oxides, sulphides and nitrites.
Advantages of Nanoparticles:
1. Fairly easy preparation.
2. Targeted and drug delivery.
3. Due to their small size Nanoparticles penetrate small capillary and are taken up by the cell which allows for efficient drug accumulation at the target sites in the body.
4. Good control over size and size distribution.
5. Good protection of the encapsulated drug.
6. Retention of drug at the active site.
7. Longer clearance time.
8. Increased therapeutic efficacy.
9. Increased bioavailability.
10. Dose proportionality.
11. Stable dosage forms of drug which are either unstable or have unacceptably low bioavailability in non-Nano particulate dosages forms.
12. Increased surface area results in a faster dissolution of active agents in an aqueous environment.
13. Faster dissolution generally equates with greater bioavailability.
14. Smaller drug doses.
15. Reduction in fed/fasted variability.
16. Less toxicity.
Disadvantages of Nanoparticles:
1. Extensive use of polyvinyl alcohol as a detergent –issues with toxicity.
2. Limited targeting abilities.
3. Discontinuation of therapy is not possible.
4. Cytotoxicity.
5. Pulmonary inflammation and pulmonary carcinogenicity.
6. Alveolar inflammation.
7. The disturbance of autonomic imbalance by nanoparticles having direct effect on heart and vascular function.
Effect of Characteristics of Nanoparticles on Drug Delivery (23-25):
Particle size:
Particle size and size distribution are the most important characteristics of nanoparticle systems. They determine the in vivo distribution, biological fate, toxicity and the targeting ability of nanoparticle systems. In addition, they can also influence the drug loading, drug release and stability of nanoparticles. Many studies have demonstrated that nanoparticles of sub-micron size have a number of advantages over microparticles as a drug delivery system. Generally nanoparticles have relatively higher intracellular uptake compared to microparticles and available to a wider range of biological targets due to their small size and relative mobility. Desai et al found that 100 nm nanoparticles had a 2.5 fold greater uptake than 1 μmmicroparticles, and 6 fold greater uptakethan 10 μmmicroparticles in a Caco-2 cell line. In a subsequent study, the nanoparticles penetrated throughout the submucosal layers in a rat in situ intestinal loop model, while microparticles were predominantly localized in the epithelial lining. It was also reported that nanoparticles can across the blood-brain barrier following the opening of tight junctions by hyper osmotic mannitol, which may provide sustained delivery of therapeutic agents for difficult-to-treat diseases like brain tumours. Tween 80 coated nanoparticles have been shown to cross the blood-brain barrier. In some cell lines, only submicron nanoparticles can be taken up efficiently but not the larger size microparticles. Drug release is affected by particle size. Smaller particles have larger surface area, therefore, most of the drug associated would be at or near the particle surface, leading to fast drug release. Whereas, larger particles have large cores which allow more drug to be encapsulated and slowly diffuse out. Smaller particles also have greater risk of aggregation of particles during storage and transportation of nanoparticle dispersion. It is always a challenge to formulate nanoparticles with the smallest size possible but maximum stability.
Surface properties of nanoparticles:
When nanoparticles are administered intravenously, they are easily recognized by the body immune systems, and are then cleared by phagocytes from the circulation. Apart from the size of nanoparticles, their surface hydrophobicity determines the amount of adsorbed blood components, mainly proteins (opsonins). This in turn influences the in vivo fate of nanoparticles. Binding of these opsonins onto the surface of nanoparticles called opsonisation acts as a bridge between nanoparticles and phagocytes. The association of a drug to conventional carriers leads to modification of the drug bio distribution profile, as it is mainly delivered to the mononuclear phagocytes system (MPS) such as liver, spleen, lungs and bone marrow. Indeed, once in the blood stream, surface non-modified nanoparticles (conventional nanoparticles) are rapidly opsonized and massively cleared by the macrophages of MPS rich organs. Generally, it is IgG, compliment C3 components that are used for recognition of foreign substances, especially foreign macromolecules.
The zeta potential of a nanoparticle is commonly used to characterise the surface charge property of nanoparticles. It reflects the electrical potential of particles and is influenced by the composition of the particle and the medium in which it is dispersed. Nanoparticles with a zeta potential above (+/-) 30 mV have been shown to be stable in suspension, as the surface charge prevents aggregation of the particles. The zeta potential can also be used to determine whether a charged active material is encapsulated within the centre of the nanocapsule or adsorbed onto the surface.
Drug release (26,27):
To develop a successful nanoparticulate system, both drugrelease and polymer biodegradation are important
consideration factors.
In general, drug release rate depends on:
(1) Solubility of drug
(2) Desorption of the surface bound/ adsorbed drug
(3) Drug diffusion through the nanoparticle matrix
(4) Nanoparticle matrix erosion/degradation
(5) Combination of erosion/diffusion process.
Thus solubility, diffusion and biodegradation of the matrix materials govern the release process. In the case of nanospheres, where the drug is uniformly distributed, the release occurs by diffusion or erosion of the matrix under sink conditions. If the diffusion of the drug is faster than matrix erosion, the mechanism of release is largely controlled by a diffusion process. The rapid initial release or ‘burst’ is mainly attributed to weakly bound or adsorbed drug to the large surface of nanoparticles. It is evident that the method of incorporation has an effect on release profile. If the drug is loaded by incorporation method, the system has a relatively small burst effect and better sustained release characteristics. If the nanoparticle is coated by polymer, the release is then controlled by diffusion of the drug from the core across the polymeric membrane. The membrane coating acts as a barrier to release, therefore, the solubility and diffusivity of drug in polymer membrane becomes determining factor in drug release. The release rate can also be affected by ionic interaction between the drug and addition of auxiliary ingredients. When the drug is involved in interaction with auxillary ingredients to form a less water soluble complex, then the drug release can be very slow with almost no burst release effect[39], whereas if the addition of auxillary ingredients e.g., addition of ethylene oxide-propylene oxide block copolymer (PEO-PPO) to chitosan, reduces the interaction of the model drug bovine serum albumin (BSA)with the matrix material (chitosan) due to competitive electrostatic interaction of PEO-PPO with chitosan, then an increase in drug release could be observed.
Various methods which can be used to study the in vitro release of the drug are:
(1) Side-by-side diffusion cells with artificial or biological Membranes
(2) Dialysis bag diffusion technique
(3) Reverse dialysis bag technique
(4) Agitation followed by ultracentrifugation/centrifugation
(5) Ultra-filtration or centrifugal ultra-filtration techniques.
Usually the release study is carried out by controlled agitation followed by centrifugation. Due to the time-consuming nature and technical difficulties encountered in the separation of nanoparticles from release media, the dialysis technique is generally preferred.
Polymeric Nanoparticles- (28,29):
The polymeric nanoparticles (PNPs) are prepared from biocompatible and biodegradable polymers in size between 10-1000 nm where the drug is dissolved, entrapped, encapsulated or attached to a nanoparticle matrix. Depending upon the method of preparation nanoparticles, nanospheres or nanocapsules can be obtained. Nanocapsules are systems in which the drug is confined to a cavity surrounded by a unique polymer membrane, while nanospheres are matrix systems in which the drug is physically and uniformly dispersed. The field of polymer nanoparticles (PNPs) is quickly expanding and playing an important role in a wide spectrum of areas ranging from electronics, photonics, conducting materials, sensors, medicine, biotechnology, pollution control and environmental technology. PNPs are promising vehicles for drug delivery by easy manipulation to prepare carriers with the objective of delivering the drugs to specific target, such an advantage improves the drug safety. Polymer-based nanoparticles effectively carry drugs, proteins, and DNA to target cells and organs. Their nanometer-size promotes effective permeation through cell membranes and stability in the blood stream. Polymers are very convenient materials for the manufacture of countless and varied molecular designs that can be integrated into unique nanoparticle constructs with many potential medical applications. Several methods have been developed during the last two decades for preparation of PNPs, these techniques are classified according to whether the particle formation involves a polymerization reaction or nanoparticles form directly from a macromolecule or preformed polymer or ionic gelation method.
Figure 7:Difference between the nanosphere and nanocapsule
Advantages of polymeric nanoparticles (28,29):
· Increases the stability of any volatile pharmaceutical agents, easily and cheaply fabricated in large quantities by a multitude of methods.
· They offer a significant improvement over traditional oral and intravenous methods of administration in terms of efficiency and effectiveness.
· Delivers a higher concentration of pharmaceutical agent to a desired location.
· The choice of polymer and the ability to modify drug release from polymeric nanoparticles have made them ideal candidates for cancer therapy, delivery of vaccines, contraceptives and delivery of targeted antibiotics.
· Polymeric nanoparticles can be easily incorporated into other activities related to drug delivery, such as tissue engineering.
Polymers used in preparation of nanoparticles:
The polymers should be compatible with the body in the terms of adaptability (non-toxicity) and (non-antigenicity) and should be biodegradable and biocompatible.
Natural polymers: The most commonly used natural polymers in preparation of polymeric nanoparticles are
· Chitosan
· Gelatine
· Sodium alginate
· Albumin
· There are many synthetic polymers like
· Polylactides(PLA)
· Polyglycolides(PGA)
· Poly(lactide co-glycolides) (PLGA)
· Polyanhydrides
· Polyorthoesters
· Polycyanoacrylates
· Polycaprolactone
· Poly glutamic acid
· Poly malic acid
· Poly(N-vinyl pyrrolidone)
· Poly(methyl methacrylate)
· Poly(vinyl alcohol)
· Poly(acrylic acid)
· Poly acrylamide
· Poly(ethylene glycol)
· Poly(methacrylic acid)
Mechanisms of drug release (30):
The polymeric drug carriers deliver the drug at the tissue site by any one of the three general physico-chemical mechanisms.
By the swelling of the polymer nanoparticles by hydration followed by release through diffusion.
By an enzymatic reaction resulting in rupture or cleavage or degradation of the polymer at site of delivery, there by releasing the drug from the entrapped inner core.
Dissociation of the drug from the polymer and its de-adsorption/release from the swelled nanoparticles.
Application of nanoparticulate delivery systems (31,32):
Tumour targeting using nanoparticulate delivery systems:
The rationale of using nanoparticles for tumour targeting is based on
1. Nanoparticles will be able to deliver a concentrate dose of drug in the vicinity of the tumour targets via the enhanced permeability and retention effect or active targeting by ligands on the surface of nanoparticles
2. Nanoparticles will reduce the drug exposure of health tissues by limiting drug distribution to target organ.
3. The polymeric composition of nanoparticles such as type, hydrophobicity and biodegradation profile of the polymer along with the associated drug’s molecular weight, its localization in the nanospheres and mode of incorporation technique, adsorption or incorporation, have a great influence on the drug distribution pattern in vivo.
Long circulating nanoparticles:
To be successful as a drug delivery system, nanoparticles must be able to target tumours which are localized outside mononuclear phagocytic system –rich organs. In the past decade, a great deal of work has been devoted to developing so called “stealth particles or PEGylated nanoparticles, which are invisible to macrophages or phagocytes. A major breakthrough in the field came when the use of hydrophilic polymers (such as polyethylene glycol, poloxamines, poloxamers, and polysaccharides) to efficiently coat conventional nanoparticle surface produced an opposing effect to the uptake by the MPS. These coatings provide a dynamic “cloud” of hydrophilic and neutral chains at the particle surface which repel plasma proteins. As a result, those coated nanoparticles become invisible to MPS, therefore, remained in the circulation for a longer period of time. Extensive efforts have been devoted to achieving “active targeting” of nanoparticles in order to deliver drugs to the right targets, based on molecular recognition processes such as ligand-receptor or antigen-antibody interaction. Considering that fact that folate receptors are over expressed on the surface of some human malignant cells and the cell adhesion molecules such as selectins and integrins are involved in metastatic events, nanoparticles bearing specific ligands such as folate may be used to target ovarian carcinoma while specific peptides or carbohydrates may be used to target integrins and selectins.
Nanoparticles for oral delivery of peptides and proteins:
Significant advances in biotechnology and biochemistry have led to the discovery of a large number of bioactive molecules and vaccines based on peptides and proteins. Development of suitable carriers remains a challenge due to the fact that bioavailability of these molecules is limited by the epithelial barriers of the gastrointestinal tract and their susceptibility to gastrointestinal degradation by digestive enzymes. Polymeric nanoparticles allow encapsulation of bioactive molecules and protect them against enzymatic and hydrolytic degradation. For instance, it has been found that insulin-loaded nanoparticles have preserved insulin activity and produced blood glucose reduction in diabetic rats for up to 14 days following the oral administration.
Targeting of nanoparticles to epithelial cells in the GI tract using ligands:
Targeting strategies to improve the interaction of nanoparticles with adsorptive enterocytes and M-cells of Peyer’s patches in the GI tract can be classified into those utilizing specific binding to ligands or receptors and those based on nonspecific adsorptive mechanism. The surface of enterocytes and M cells display cell-specific carbohydrates, which may serve as binding sites to colloidal drug carriers containing appropriate ligands. Certain glycoproteins and lectins bind selectively to this type of surface structure by specific receptor mediated mechanism. Different lectins, such as bean lectin and tomato lectin, have been studied to enhance oral peptide adsorption. Vitamin B12 absorption from the gut under physiological conditions occurs via receptor-mediated endocytosis. The ability to increase oral bioavailability of various peptides (e.g., granulocyte colony stimulating factor, erythropoietin) and particles by covalent coupling to vitamin B- 12 has been studied.
Nanoparticles for gene delivery:
Nanoparticles loaded with plasmid DNA could also serve as an efficient sustained release gene delivery system due to their rapid escape from the degradative endo-lysosomal compartment to the cytoplasmic compartment. Hedley et al. reported that following their intracellular uptake and endolysosomal escape, nanoparticles could release DNA at a sustained rate resulting in sustained gene expression. This gene delivery strategy could be applied to facilitate bone healing by using PLGA nanoparticles containing therapeutic genes such as bone morphogenic protein.
Nanoparticles for drug delivery into the brain:
Strategies for nanoparticle targeting to the brain rely on the presence of nanoparticle interaction with specific receptor-mediated transport systems in the BBB (blood brain barrier). For example polysorbate 80/LDL, transferrin receptor binding antibody (such as OX26), lactoferrin, cell penetrating peptides and melanotransferrin have been shown capable of delivery of a self non transportable drug into the brain via the chimeric construct that can undergo receptor-mediated transcytosis.
Therapeutic Applications of Nanoparticles:
Nanoparticles with different compositions and characteristics and investigated for various therapeutic applications as follows:-
· Carriers of drugs and biological agents
· Carriers of gene and DNA s
· Carriers of antigens & vaccines
· Controlled & targeted drug delivery
· Carriers of diagnostic agent
· Carriers of MRI contrast
CONCLUSION:
Nanoparticles represents promising drug carrier for various drug delivery systems Nanotechnology is breakthrough technology pervading all fields newer applications of this field are being explored worldwide. Nanoparticles represent a technology to overcome solubilities and bioavailability problems of drugs which can be generally applied to all poorly soluble drugs. Any drug can be transformed to drug nanoparticles leading to increasing saturation solubility, dissolution rate and providing in general feature of an increased adhesiveness to surfaces. Nanoparticulate drug delivery system is increasingly viewed as an advantageous solution for biological drugs. In addition, nanoparticles provide efficient treatment by enabling targeted and controlled release thus in feature nanoparticulate drug-delivery system seem to be a viable and promising strategy for the biopharmaceutical industry.
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Received on 29.05.2017 Accepted on 29.07.2017
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Asian J. Res. Pharm. Sci. 2017; 7(3):162-172.
DOI: 10.5958/2231-5659.2017.00026.1