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 Table of Contents  
REVIEW ARTICLE
Year : 2012  |  Volume : 1  |  Issue : 4  |  Page : 217-223

Polymeric nanoparticles for drug delivery and targeting: A comprehensive review


1 Department of Pharmaceutics, JSS College of Pharmacy, Ootacamund, Tamil Nadu, India
2 Department of Pharmaceutical Analysis, JSS College of Pharmacy, Ootacamund, Tamil Nadu, India

Date of Web Publication27-Feb-2013

Correspondence Address:
Natarajan Jawahar
Department of Pharmaceutics, JSS College of Pharmacy, Ootacamund - 643 001, Tamil Nadu
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/2278-344X.107832

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  Abstract 

In the recent years, many modern technologies have been established in the pharmaceutical research and development area. The field of nanotechnology has been revolutionary as substantial and technical, and scientific growth, in basic sciences plus manipulation by physical or chemical process of individual atoms and molecules have widened its horizon. Polymeric nanoparticles with a size in the nanometer range protect drugs against in vitro and in vivo degradation; it releases the drug in a controlled manner and also offers the possibility of drug targeting. The use of polymeric drug nanoparticles is a universal approach to increase the therapeutic performance of poorly soluble drugs in any route of administration. The present review discusses the physico-chemical properties of polymeric nanoparticles, production methods, routes of administration and potential therapeutic applications.

Keywords: Drug delivery, drug release kinetics, nanoparticles, physico-chemical characteristics, targeting


How to cite this article:
Jawahar N, Meyyanathan S N. Polymeric nanoparticles for drug delivery and targeting: A comprehensive review. Int J Health Allied Sci 2012;1:217-23

How to cite this URL:
Jawahar N, Meyyanathan S N. Polymeric nanoparticles for drug delivery and targeting: A comprehensive review. Int J Health Allied Sci [serial online] 2012 [cited 2019 Sep 20];1:217-23. Available from: http://www.ijhas.in/text.asp?2012/1/4/217/107832


  Introduction Top


Technological advancements have brought about many new innovative drug delivery systems. Polymeric nanoparticulate systems from biodegradable and biocompatible polymers are interesting options for controlled drug delivery and drug targeting. [1],[2],[3] Polymeric nanoparticles are solid colloidal particles with diameter ranging from 1 to 1000 nm. [1] They have been investigated especially in drug delivery and drug targeting owing to their particle size and long circulation in the blood. [4],[5] They consist of macromolecular materials and can be used therapeutically as adjuvant in vaccines or drug carriers in which the active ingredient is dissolved, entrapped, encapsulated, adsorbed or chemically attached. [6]


  Advantages Top


The advantages of using nanoparticles as a drug delivery system include the following:

  • Controlled and sustained release of the drug during transportation and at the site of localisation, altering the 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.
  • Decreased toxicity and occurrence of adverse drug reactions.
  • Better drug utilisation.
  • Site-specific targeting can be achieved by attaching targeting ligands to the surface of the particles or through use of magnetic guidance.
  • The system can be used for various routes of administration, including oral, nasal, parenteral, intra-ocular, etc.

  Limitations Top


In spite of these advantages, nanoparticles have some limitations. Due to their smaller size and large surface area:

  • Particle-particle aggregation makes physical handling of nanoparticles difficult in liquid and dry form.

  Types of Nanoparticles Top


There are two types of nanoparticles depending on the preparation processes:

  • Nanospheres
  • Nanocapsules
The term nanoparticles are a collective name for both nanospheres and nanocapsules.

Nanospheres have a monolithic-type structure (matrix) in which drugs are dispersed or adsorbed onto their surfaces or encapsulated within the particles.

Nanocapsules are the vesicular system in which the drug is confined to a cavity consisting of an inner liquid core surrounded by a polymeric membrane. In this case the active substance is usually dissolved in the inner core, but may also be adsorbed to the capsule surface [Figure 1]. [7]
Figure 1: Types of nanoparticles

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  Criteria for Ideal Polymeric Carrier for Nanoparticles Top


The criteria for the ideal polymeric carrier for nanoparticles are [7] as follows:

  • Easy to synthesise and characterise
  • Inexpensive
  • Biocompatible
  • Biodegradable
  • Non-immunogenic
  • Non-toxic
  • Water-soluble
Carriers Used in the Preparation of Nanopaticles

The polymers used for preparation of nanoparticles are as follows:

  • Natural hydrophilic polymer
  • Synthetic hydrophobic polymer
Natural hydrophilic polymer

Natural hydrophilic polymers such as proteins (gelatine, albumin, lecithin, legumin and vicillin) and polysaccharides (alginate, dextran, chitosan, agarose and pullulan) are widely used. But these polymers have certain disadvantages such as poor batch-to-batch reproductivity, the specific conditions for their degradation and potential antigenicity.

Synthetic hydrophobic polymer

These polymers are divided into two groups: The first group includes polyesters (poly ( -caprolactone), poly (lactic acid), poly (lactide-co-glycolide), polystyrene) and the second group includes poly (alkyl cyanoacrylates) (poly (isobutyl cyanoacrylates), poly (butylcyanoacrylates), poly methyl (methcyanoacrylates)).


  Preparation of Nanoparticles Top


Ionic gelation

In this method, chitosan is dissolved in an aqueous acidic solution to obtain the cation of chitosan. This solution is then added dropwise under constant stirring to a poly anionic tripolyphosphate (TPP) solution. Due to complexation between oppositely charged species, chitosan undergoes ionic gelation and precipitates to form spherical particles. Three kinds of phenomena were observed: Solution, aggregation and opalescent suspension. The resulting chitosan particle suspension was subsequently centrifuged and dried. [8]

Nanoprecipitation

Nanoparticle formation is instantaneous and the entire procedure is carried out in only one step. Briefly, it requires two solvents that are miscible. Ideally, both the polymer and the drug must dissolve in the first one (the solvent) but not in the second system (the non-solvent). Nanoprecipitation occurs by rapid desolvation of the polymer when the polymer solution is added to the non-solvent. [9],[10],[11]

Emulsion cross-linking method

In this method, a water-in-oil (w/o) emulsion is prepared by emulsifying the chitosan solution in the oil phase. Aqueous droplets are stabilised using a suitable surfactant; the stable emulsion is cross-linked by an appropriate cross-linking agent such as glutaraldehyde to harden the droplets, and the particles are filtered and washed repeatedly. By this method particle size can be controlled by controlling the size of the aqueous droplets. However, the particle size of the final product depends upon the extent of the cross-linking agent used while hardening in addition to the speed of stirring during the formation of emulsion. The drawback of this method involves tedious procedure as well as use of harsh cross-linking agents, which might possibly induce chemical reactions with the agents; however, complete removal of un-reacted cross-linking agent may be difficult in this process. [12]

Spray-drying

In this method chitosan is first dissolved in acetic acid; the drug is dissolved or dispersed in the solution and then a suitable cross-linking agent is added; this solution or dispersion is then atomised in a stream of hot air. Atomisation leads to the formation of small droplets, from which the solvent evaporates, leading to the formation of free-flowing powders. Particle size depends upon size of the nozzle, spray flow rate, atomisation pressure and inlet air temperature, and extent of cross-linking. [13]

Salting-out method

In this method acetone is chosen as the water-miscible organic solvent because of its pharmaceutical acceptance with regard to toxicity. The method consists of addition of water-soluble polyvinyl alcohol (PVA) in a highly concentrated salt solution in water (aqueous phase) to a polymer solution in acetone (organic phase). Although acetone is miscible with pure water in all ratios, the high salt concentration of the aqueous phase prevents mixing of the phase. After emulsification, addition of pure water in a sufficient quantity causes acetone to diffuse into the aqueous phase, resulting in the formation of nanoparticles. [14]


  Pharmaceutical Consideration Top


Isolation

Nanoparticles are normally isolated by freeze-drying using cryoprotective agents (sugars such as glucose and trehalose) to assess the re-dispersibility of the colloidal system and to prevent the aggregation of nanoparticles during the freeze-drying process. [7]

Purification

Nanoparticles should be free from impurities and the degree of purification depends upon the final purpose of the formulation developed. The most commonly used procedures are gel filtration, ultracentrifugation, centrifugal filtration, dialysis and cross-flow filtration.

Stability

Generally a colloidal suspension is stable and does not tend to separate as a result of slow deposition of particles or due to the mixing tendencies of diffusion and convection. However, some agglomeration can occur. To prevent complete precipitation, it is necessary to incorporate some additives. Chemical integrity of the drug is also a fundamental aspect of the overall stability of nanoparticles. Some other parameters are also crucial for stability, such as the duration of contact with the aqueous environment when the drug is water-soluble; the surrounding pH when the drug degradation is pH-dependent; and light exposure when the drug is light-sensitive. It is observed that the presence of anionic surfactants in the dispersion causes rapid degradation of nanoparticles as they are made up of hydrolytic degradable polymers. The degradation pathway varies from polymer to polymer. However, the common pathways are by erosion of the polymer backbone and cleavage of ester. Hence stability studies are important and can be performed according to the drug and polymer properties. [7]


  Physicochemical Characteristics Top


The physicochemical methods for characterisation of nanoparticles are tabulated [Table 1]. [5],[7]
Table 1: Physicochemical methods for characterisation of nanoparticles

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  Drug Loading Top


Drug loading in the nanoparticulate system can be done by two methods: [5]

  • Incorporation method
  • Incubation method
Incorporation method: Incorporating at the time of nanoparticle production.

Incubation method: Adsorbing the drug after the formation of nanoparticles by incubating the carrier with the concentrated drug solution.

Both methods result in:

  • A solid solution of the drug in the polymers.
  • Solid dispersion of the drug in the polymer.
  • Surface adsorption of the drug.
  • Chemical bonding of the drug in the polymer.
In these systems the drug is physically embedded into the matrix or adsorbed onto the surface. Various methods of loading have been developed to improve the efficiency of loading, which largely depend upon the method of preparation as well as the physiochemical properties of the drug and the polymer. Maximum loading can be achieved by incorporating the drug during the time of formation of particles, but it may get affected by process parameters such as method of preparation, presence of additives, etc.


  Drug Release and Release Kinetics Top


Drug release from the carrier-based particulate system depends upon the cross-linking, morphology, size, density of the particulate system and the physiochemical properties of the drug, as well as presence of adjuvant. [15] In vitro drug release also depends upon pH, polarity and presence of enzymes in the dissolution medium.

The release of drug from the particulate system depends upon three different mechanisms:

  • Release from the surface of particles.
  • Diffusion through the swollen rubbery matrix.
  • Release due to erosion.
In the majority of cases, drug release follows more than one type of mechanism [Figure 2].
Figure 2: Drug release mechanisms in nanoparticles

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Mechanism of drug release from particle system

When it comes in contact with the release medium, the drug instantaneously dissolves, thus affecting its release from the surface. Drug entrapped in the surface layers of the particles also follows this mechanism. This type of drug release leads to a burst effect.

Drug release through diffusion involves three steps:

  • Penetration into the particulate system, which causes swelling of the matrix.
  • Conversion of the glassy polymer into a rubbery matrix.
  • Diffusion of the drug from the rubbery matrix.
Various methods, which can be used to study the in vitro release of drug, are as follows:

  • Side-by-side diffusion cells with an artificial or biological membrane.
  • Dialysis bag method.
  • Ultracentrifugation.
  • Centrifugal ultrafiltration.

  Administraion of Nanoparticles Top


The main administration routes for nanoparticles are intravenous injection, subcutaneous or intramuscular injection; peroral administration; and ophthalmic application.

Intravenous administration

Nanoparticles, like other colloidal carriers such as liposome, micro-emulsions and erythrocyte ghosts, are taken up by the reticuloendothelial systems (RES) after intravenous injection and distributed mainly to the liver, spleen and to a lesser degree, the bone marrow; varying amounts can be found in the lungs. All these organs contain sessile, actively phagocytosing cells. Other phagocytosing cells are found in the blood and lymphatic system, and in the endothelial lining of the blood vessels. These cells can take up nanoparticles by varying degrees. The sequence of events during distribution of nanoparticles and their phagocytosis is not currently known. It is believed that immediately after injection, the particles are coated by the serum components, the opsonins, which act as labels to passively target the nanoparticles to certain phagocytic cells.

Passive targeting

Passive targeting refers to the natural distribution pattern of the drug carrier in vivo. Nanoparticle distribution by the above method is called passive targeting. The mechanical entrapment of large microspheres and large nanoparticles agglomerates (>4 μm) by capillary blockage also is referred to as passive targeting. This process can be exploited to target passively to the lungs via the venous supply or to other organs via the appropriate arterial supply. [14]

Active targeting

Active targeting refers to a change in the natural distribution pattern of a carrier particle by deliberate modification of its properties, thereby directing it to specific cells, tissues or organs.

The following methods are mainly used:

  • Alteration of the surface properties by coating the nanoparticles with surfactants or macromolecules;
  • Incorporation of magnetite particles into the particles and application of magnetic field;
  • Alteration of surface charge; and
  • Attachment of specific antibiotics to the nanoparticle surface.
The first two methods seem to be promising. Coating of nanoparticles with surfactants for instance can drastically reduce liver uptake from 80% to 30%, and increase in blood concentration can be from 0.14 up to about 40%. Poloxamine 1508 is the principal agent for reducing liver uptake and increasing blood concentration, whereas polysorbate 80 increases the concentration in non-RES organs. Other surfactants such as poloxamer 184 and 407 have a high targeting capacity to the bone marrow. The possibility of bone marrow targeting is size-dependent. [15]

Subcutaneous and intramuscular injection

After subcutaneous and intramuscular injection of 14 C-labelled polymethacrylate nanoparticles in rat, over 99% of the injected radioactivity remains at the injection site. The elimination rate of the administered dose per day in the form of oligomeric components of the nanoparticulate polymer is found to be lesser in the urine and faeces initially and later elimination is found to be more in faeces.

Oral administration

Nanoparticles are retained in the gut of rats and mice up to 6 days. In addition, they are taken up in the intestine and appear in lymph nodes, blood, liver, spleen and at the site of inflammation in the body. Three different mechanisms are possible:

  • Intracellular uptake.
  • Intracellular-paracellular uptake.
  • Uptake via M-cells and Peyer's patches in the gut.
Ophthalmic application

After ophthalmic application to rabbits, polyhexyl cyanoacrylate nanoparticles are eliminated from tears with a half-life of about 15-20 min. Aqueous eye drops, on the other hand, have a half-life of 1-3 min. A small amount of polycyanoacrylate nanoparticles adhere mainly to the conjunctiva, but also to the cornea and to the nictitating membrane of rabbits, and penetrate into the first two layers of the cell layers. [5]

Nanoparticles and targeted drug delivery

The greatest immediate impact of nanotechnologies in cancer therapy is in drug targeting. The therapeutic index of nearly all drugs currently being used can be improved if they are more efficiently delivered to their biological targets through appropriate application of nanotechnologies. In the case of central nervous system cancers (brain tumour), many drugs have difficulty in crossing the blood-brain barrier to attack the tumour. Drug-loaded nanoparticles are able to penetrate this barrier, and have been shown to greatly increase therapeutic concentration of anticancer drugs in brain tumours. [16]

The best way to increase the efficacy and reduce the toxicity of a cancer drug is to direct the drug to its target and maintain its concentration at the site for a sufficient time for therapeutic action to take effect. The efficiency of drug delivery to various parts of the body is directly affected by particle size. Nanostructure-mediated drug delivery, a key technology for realisation of nanomedicine, has the potential to enhance drug bioavailability, improve timed release of drug molecules and enable precision drug targeting. Additional benefits of using targeted nanoscale drug carriers are reduced drug toxicity and more efficient drug distribution. Anatomic features such as the blood-brain barrier, the branching pathways of the pulmonary system and the tight epithelial junctions of the skin make it difficult for drugs to reach many desired physiologic targets. Nanostructured drug carriers help to penetrate or overcome these barriers to drug delivery, and it has been shown that the greatest efficiency for delivery into the pulmonary system is achieved for particle diameter < 100 nm. Greater uptake efficiency has also been shown for gastrointestinal absorption and transcutaneous permeation, with particles about 100 nm and 50 nm in size, respectively. However, such small particles travelling in the pulmonary tract may also have a greater chance of being exhaled. Larger, compartmental or multilayered drug carrier architectures may help with delivery to the pulmonary extremities. For instance, the outer layers of the carrier architecture may be formulated to biodegrade as the carrier travels through the pulmonary tract. As the drug carrier penetrates further into the lung, additional shedding will allow the encapsulated drug to be released. Biodegradable nanoparticles of gelatin and human serum albumin show promise as pulmonary drug carriers.

Advantages of nanostructure-mediated drug delivery include the ability to deliver drug molecules directly into cells and the capacity to target tumours within healthy tissue. Nanoscale drug delivery architectures are able to penetrate tumours due to the discontinuous, or "leaky," nature of the tumour microvasculature, which typically contains pores ranging from 100 to 1000 nm in diameter. The microvasculature of healthy tissue varies by tissue type, but in most tissues, including the heart, brain and lung, there are tight intercellular junctions less than 10 nm. Therefore, tumours within these tissue types can be selectively targeted by creating drug delivery nanostructures greater than the intercellular gap of the healthy tissue but smaller than the pores found within the tumour vasculature. Nanoparticles have already been used for targeted drug delivery, which enables much earlier detection and immediate treatment of cancer. Nanoparticles attached to chemotherapeutic drugs allow them to traverse the blood-brain barrier for brain tumour treatment. In January 2005, a nanoparticle-based drug called Abraxane (paclitaxel protein-bound particles, Abraxis Oncology) was approved by the Food and Drug Administration for breast cancer treatment. Abraxane uses nanoscale particles of the natural protein albumin that can be delivered in the body without the use of solvents.


  Therapeutic Applications Top


The various therapeutic applications of nanoparticles have been shown in [Table 2].
Table 2: Therapeutic applications of nanoparticles

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  Conclusion Top


In the past few decades, researchers have studied alternative delivery systems to improve the efficacy of different medicines. Nanotechnology is an exciting novel field with hopes for improvements in wide variety of uses in drug delivery in pharmaceutical research. Polymeric nanoparticles offer a new avenue to achieve drug delivery and drug targeting with newly discovered disease site-specific drugs and existing poorly soluble drugs. Overcoming the obstacles in conventional drug delivery systems, polymeric nanoparticles are anticipated for better application and effective drug delivery, and would ultimately enhance treatment and patient compliance.

 
  References Top

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    Figures

  [Figure 1], [Figure 2]
 
 
    Tables

  [Table 1], [Table 2]


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Abstract
Introduction
Advantages
Limitations
Types of Nanopar...
Preparation of N...
Pharmaceutical C...
Physicochemical ...
Drug Loading
Drug Release and...
Administraion of...
Therapeutic Appl...
Conclusion
Criteria for Ide...
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