Review Article

Dendrimers: a potential carrier for targeted drug delivery system

Awani Kumar Rai, Ruchi Tiwari, Priyanka Maurya*, Pooja Yadav

Pranveer Singh Institute of Technology, Kanpur, U.P., India

*For correspondence

Priyanka Maurya,

Research Scholar Pranveer Singh Institute of Technology, Kanpur, U.P., India.

Email: priyankamaurya 22061992@gmail.com

 

 

 

 

 

 

 

 

 

 

Received: 28 March 2016

Revised: 01 April 2016

Accepted: 14 April 2016

ABSTRACT

Novel drug delivery system aims to deliver the drug at a rate directed by the needs of the body during the period of treatment, and target the active entity to the site of action. A number of novel drug delivery systems have emerged encompassing various routes of administration, to achieve controlled and targeted drug delivery, dendrimer carriers being one of them. Dendrimers are highly branched, star-shaped macromolecules with nanometer-scale dimensions. It is a novel three dimensional structure and these three components are: a central core, an interior dendritic structure (the branches), and an exterior surface with functional surface groups. It is also improve the physical, chemical properties due to their structure. Its other properties like very small size, polyvalenc, monodispersit, stability make it an appropriate carrier for delivering drugs with precision and selectivity. The terminal groups are modified to attach biologically active substances for targeting purpose. Dendrimers are suitable for a wide range of targeted drug delivery, controlled drug delivery, gene delivery and industrial applications. Cationic surfaces of dendrimers show cytotoxicity, derivatization with fatty acid or PEG chains, reducing the overall charge density and minimizing contact between cell surfaces and dendrimers can reduce toxic effects. Different types of products are formulated by using dendrimers for treatment of many diseases. The present review has focused on the different strategies of their synthesis, different methods of drug entraptment, drug delivery and targeting, its applications, interactions involved in formation of drug-dendrimer complex along with characterization techniques employed for their evaluation, toxicity problems.

Keywords: Dendrimers, Targeted drug deliver, PAMAM, PPI, Synthesis, Divergen, Convergent, Application

Introduction

Polymer chemistry and technology have traditionally focused on linear polymers, which are widely in use. Linear macro-molecules only occasionally contain some smaller or longer branches. In the recent past it has been found that the properties of highly branched macromolecules can be very different from conventional polymers. The structure of these materials has also a great impact on their applications. First discovered in the early 198 by 1980's by Donald.1 These hyperbranched molecules were called dendrimers. The term originates from 'dendron' meaning a tree in Greek. At the same time, Newkome's group.2

Tomalia and co-workers, in the beginning the research on dendrimers focused on the synthesis, characterization, and properties of perfect dendrimers of higher generations. For the synthesis of dendrimers constructed by step-by-step sequences, two fundamentally different strategies, the divergent approach and convergent approach, were employed.3

Dendrimer chemistry is a rapidly expanding field for both basic and applicative reasons. From a topological viewpoint, dendrimers contain three different regions: core, branches and surface. Another important property of dendrimers is the presence of internal cavities where ions or neutral molecules can be hosted. Such a property can potentially be exploited for a variety of purposes, which include catalysis and drug delivery.4

Targeted drug delivery

Target drug delivery system may also be referred to as smart drug delivery system.8 Is the currently used form of drug delivery system where the pharmacologically active drug (or pro-drug in some cases) is targeted or is delivered specifically to the site of action. Targeted drug delivery extensively used for selective and effective localization of pharmacologically active moiety at pre-determined target in therapeutic concentration, while restricting its access to non-target normal cellular linings, thus minimizing toxic effects and maximizing therapeutic index. Targeting of drugs also help us to bypass first pass metabolism so a drug can be administered in a form such that it reaches the receptor sites in sufficient concentration without disturbing in extraneous tissue cells. Products based on such a delivery system are being prepared by considering the Specific properties of target cells, Nature of markers or transport carriers or vehicles, which convey drug to specific receptors and Ligands and physically modulated components.5

Ideally targeted drug delivery system should have following characteristics:

  • Should be biochemically inert (non-toxic)
  • Should be non-immunogenic.
  • Should be physically and chemically stable in vivo and in vitro conditions.
  • Should have restricted drug distribution to target cells or tissues or organs and should have uniform capillary distribution.
  • Should have Controllable and predictable rate of drug release and also Drug release should not affect the drug action.
  • Should have therapeutic amount of drug release.
  • Should have minimal drug leakage during transit.
  • Carriers used should be bio-degradable or readily eliminated from the body without any problem.
  • The preparation of the delivery system should be easy or reasonably simple, reproductive and cost effective.5

Types of drug targeting

These two approaches are used for drug targeting. An ideal targeted drug delivery approach would not only increase therapeutic efficacy of drug but also decrease the toxicity associated with drug to allow lower doses of the drug to be used in therapy.6

Active targeting

Active targeting means a specific ligand–receptor type interaction for intracellular localization which occurs only after bloodcirculation and extravasations. This active targeting approach can be further classified into three different levels of targeting which are,

  • First order targeting refers to restricted distribution of the drug carrier systems to the capillary bed of a predetermined target site, organ or tissue e.g. compartmental targeting in lymphatics, peritoneal cavity, plural cavity, cerebral ventricles and eyes, joints.
  • Second order targeting refers to selective delivery of drugs to specific cell types such as tumour cells and not to the normal cells e.g. selective drug delivery to kupffer cells in the liver.
  • Third order targeting refers to drug delivery specifically to the intracellular site of targeted cells e.g. receptor based ligand mediated entry of a drug complex into a cell by endocytosis. 6

Passive targeting

It refers to the accumulation of drug or drug-carrier system at a particular (like in case of anti-cancerous drug) site whose explanation may be attributed to physicochemical or pharma-cological factors of the disease. Hence in case of cancer treatment the size and surface properties of drug delivery nanoparticles must be controlled specifically to avoid uptake by the reticulo-endothelial system (RES), to maximize circulation times and targeting ability. For attaining such conditions the optimal size should be less than 100 nm in diameter and the surface should be hydrophilic to circumvent clearance by macrophages (large phagocytic cells of the RES)2 Other examples include targeting of anti- malarial drugs for treatment of leishmiansis, brucellosis, candiadsis.7

Structure of dendrimers

Dendrimers are built from a starting atom, such as nitrogen, to which carbon and other elements are added by a repeating series of chemical reactions that produce a spherical branching structure. As the process repeats, successive layers are added and the sphere can be expanded to the desired size by the investigator. The final entity is spherical macromolecular structure whose size is similar to blood albumin and haemoglobin.Dendrimers possess three separate architectural Components.9

  • An initiator core
  • Interior layers (generations) composed of repeating units, radically attached to the interior core.
  • Exterior (terminal functionality) attached to the outermost interior generations.The structure of dendrimers are shown in Figure 1.10

Dendrimers consist of three basic components: the shell, pincer and end group (Figure 1).

Figure 1: Structure of dendrimers.9,10

Three dimensional projection of dendrimer of core shell architecture for G=4.5 PAMAM dendrimer with principle architecture component(I)core,(II)interior and (III) surface

The dendrimer shell is the homo-structural spatial segment between the focal points, the "generation space". The "outer shell" is the space between the last outer branching point and the surface. The "inner shells" are generally referred to as the dendrimer interior.10

In dendrimers, the outer shell consists of a varying number of pincers created by the last focal point before reaching the dendrimer surface. In PPI and PAMAM dendrimers the number of pincers is half the number of surface groups (because in these dendrimers the chain divides into two chains in each focal point ).10

End group is also generally referred to as the "terminal group" or the "surface group" of the dendrimer. Dendrimers having amine end-groups are termed "amino-terminated dendrimers".10

Ideal properties of dendrimers

  • Dendrimers are monodisperse macro-molecules, unlike linear polymers.
  • Dendrimers have some unique properties because of their globular shape and the presence of internal cavities. The most important one is the possibility to encapsulate guest molecules in the macromolecule interior.
  • Dendrimers have been applied in in vitro diag- nostics. Dade Internati-onal Inc. (U.S.A.) has in- troduced a new method in cardiac testing. Proteins present in a blood sample bind to immunoglobulins which are fixed by dendrimers to a sheet of glass. The result shows if there is any heart (2.5 and 3.5) are weaker.
  • Anionic dendrimers, bearing a carboxylate surface, are not cytotoxic over a broad concentration range.11
  • Dendrimers are Inert and non-toxic.
  • It is Biodegradable.
  • Non-immunogenic.
  • Able to cross barriers such as intestine, blood-tissue barriers, cell membranes etc.
  • Able to stay in circulation for the time needed to have a clinical effect.
  • Able to target to specific structures.
  • Compatible with guest molecules.
  • Must protect the drug until it reaches to the desired site of action and release the drug.12

Types of dendrimers

Dendrimer can be differentiated on the basis of their shape, end functional groups and internal cavities which can be classified in Table 1.13-20

Technology of dendrimers production

Divergent method

As mentioned earlier, the first applied method of dendrimer synthesis was the divergent method proposed by the Tomalia group21. In this method growth of dendrimers originates from a core site. The core is reacted with two or more moles of reagent containing at least two protecting branching sites, followed by removal of the protecting groups, lead to the first generation dendrimers. This process is repeated until the dendrimer of the described size is obtained. By this approach the first synthesized dendrimers were polyamidoamines (PAMAM), also known as starbust dendrimers.22

The major disadvantage of this approach is that the incomplete growth and the side reactions lead to imperfect dendrimers. To minimize these side reactions and imperfections, it's recommended to use a large excess of reagents. The divergent growth reaction of dendrimer can be shown in Figure 2.23

Figure 2: Divergent method.23

Convergent method

Convergent dendrimer growth begins at what will end up being the surface of the dendrimer, and works inwards by graduall- y linking surface units together with more. When the growing wedges are large enough, several are attached to a suitable core to give a complete dendrimer. convergent growth method has several advantages like relatively easy to purify the desired product, occurrence of defects in the final structure is minimised, does not allow the formation of high generation dendrimer because stearic problems occur in the reactions of the dendrons and the core molecule.21

The convergent growth reaction of dendrimer can show in Figure 3.23

Figure 3: Convergent method.23

Double exponential and mixed growth

In this approach two products (monomers for both convergent and divergent growth) are reacted together to give an orthogonal- ly protected trimer, which may be used to repeat the growth process again. Strength of double exponential growth is more subtle than the ability to build large dendrimers in relatively few steps.24

Table 1: Type of dendrimers.

S.NO.

Type of dendrimer

Synthesis

Example

Identification

1.

PAMAM (Poly Amido Amine) Dendrimer

Divergent

Dendritech TM

(USA)

These are spheroidal or ellipsoidal in shape.13 It has high solubility and reactivity due to incidence of a number of functional end groups and empty internal cavities.14,15

2.

PPI (Poly Propylene Imine ) Dendrimer

Divergent

Asramol by DSM

(Netherlands)

Its core structure is based on Di amino butane with primary amines as end groups and tertiary propylene amines as center. These are commercially available up to G-5 and are extensively used in material science and biology.16

3.

Chiral Dendrimer

Convergent

chiral dendrimers derived from pentaerythritol

The chirality of the dendrimers was based upon the building of constitutionally different but chemically alike branches to chiral core.17

4.

Multilingual

Dendrimers

Convergent

VivaGel

These are the dendrimers which hold multiple copies of a particular functional group on their surface.18

5.

Tecto Dendrimers

Divergent

Mercapto

These were made up of core dendrimers, which can be surrounded by other dendrim-ers, which execute a specific function leading to a smart therapeutic system used for diagnose the diseased state and deliver API to the accepted diseased cell.18

6.

Hybrid

Dendrimers

Divergent

 

Hybrid dendritic linear polymer, Polysilsesquioxanes

These dendrimers have characteristic of both dendritic and linear polymer.18

7.

Peptide Dendrimers

Convergent

Beta Casomorphin

(human)

Peptide dendrimers are those which hold amino acid as branching or interior unit.

These are used for the diagnostic purpose and vaccine delivery.19

8.

Frechet-Type Dendrimers

Convergent

Frechet type dendron azides,

TM Priostar

 

These were based on polybenzyl ether hyper branched skeleton. Carboxylic acid group attached on the surface of dendrimers that provides site for further functionalization and also improve the solubility of dendrimers.19

9.

PAMAMOS (Poly Amidoamine Organosilicon) Dendrimers

Convergent and Divergen

SARSOX

These are silicon containing commercial dendrimers which are inverted unimolecular micelles and contains exterior hydrophobic organosilicon (OS) and interiorly hydrophilic, nucleophilic polyamidoam-ine.19

10.

Multiple Antigen Peptide Dendrimers

Convergent and Divergent

vaccine and diagnostic research

These are dendron-like molecular assembly based upon a polylysine frame. Lysine with its alkyl amino side-chain performed as a excellent monomer for the overture of frequent branching points.20

 

Hypercores and branched monomer growth

This method involved the pre-assembly of oligomeric species which can be linked organic methodologies.25 In this approach two products (monomers for both convergent and divergent growth) are reacted together to give an orthogonally protected trimer, which may be used to repeat the growth process again. Strength of double exponential growth is more subtle than the ability to build large dendrimers in relatively few steps.22,11

Click chemistry

Dendrimers have been prepared via click chemistry,employing Diels-Alder reactions.26 Click chemistry was first introduced by K. Barry Sharoless of the Scripps Research Institute in 2001 and describe chemistry modified to engender substances rapidly and consistent by combination of small units collectively. It is not a solitary reaction, but was intended to imitate nature, that can also generate molecules by joining small modular units.27

Drug entrapment with dendrimers

Simple encapsulation

The ellipsoidal or spheroidal shape, empty internal cavities, and open nature of the architecture of dendrimers make it possible to directly encapsulate guest molecules into the macromolecule interior (Fig. 4). These empty internal cavities usually have hydrophobic properties, which make it suitable to interact with poorly-soluble drugs through hydrophobic interactions. In addition, there are nitrogen or oxygen atoms in these internal cavities, which can interact with the drug molecules by hydrogen bond formation. In view of these specific properties, the relationship between the internal cavities of dendrimers and drug molecules may involve physical encapsulation, hydrophobic interaction, or hydrogen bonding.28

Covalently conjugation

In this case, the drug is covalently bound to dendrimers, and its release occurs via chemical or enzymatic cleavage of hydrolytically labile bonds. covalent attachment of drugs to the surface groups of dendrimers through chemical bonds offers the opportunity for a better control over drug release than that can be achieved by simple encapsulation/electrostatic complexation of drugs into/with the dendrimers. Naturally, a problem may arise as a consequence of coupling large numbers of drugs to the dendrimer surface by covalent conjugation,that is, the insolubility of the resultant product.This problem often can be resolved through the concomitant attachment of short PEG chains.28

Figure 4: Drug entrapment with dendrimers.28

Potential strategies for interactions between dendrimers and drug molecules (A) electrostatic interactions or covalent conjugate, and (B) simple encapsulation.

Electrostatic intraction

The high density of functional groups (such as amine groups and carboxyl groups) on the surface of dendrimers may be expected to have potential applications in enhancing the solubility of hydrophobic drugs by electrostatic interaction. In recent years, nonsteroidal antiinflammatory drugs with carboxyl groups, including ibuprofen, ketoprofen, diflunisal, naproxen,and indomethacin, have been widely been complexed with dendrimers by electrostat- ic interactions. Studies on other drugs, such as some anti-cancer drugs and anti-bacterial drugs, have also been reported.28

Characterization of dendrimers

The dendrimers are characterize by different methods and that characterization is given in Table 2.29-51

Table 2: Characterization of dendrimers.

A
 

Spectroscopy and spectrometry methods

Spectroscopy and spectrometry methods of characterization of dendritic polymer are as follows29-34

 

Ultra-violet-visible spectroscopy

(UV-VIS)

Provides information for monitoring the synthesis of dendrimers. The intensity of the absorption band is basically proportional to the number of chromophoric units.

 

Infra red spectroscopy (IR)

Provides information for routine analysis of the chemical transformations going at the surface of dendrimers.

 

Near infra red spectroscopy

Provides information for the characterization of delocalize π-π stacking interaction between end groups of modified PAMAM.

 

Fluorescence

Provides information for increasingly high Sensitivity of fluorescence used to quantify defects during the synthesis of dendrimers.

 

Mass spectroscopy

Chemical ionization or fast atom bombardment used for the characterization of small dendrimers whose mass is below 3000Da. Electrospray ionization used for dendrimers which are able to form stable multicharged species.

 

X-ray diffraction (XRD)

Provides information to allow precise determination of the chemical composition, structure, size and shape of Dendrimer.

B

Scattering techniques

Scattering techniques for characterization of dendritic polymer are as Follows 35-38

 

Small angle X-ray scattering (SAXS)

Provides information about their average radius of gyration (Rg) in solution. The intensity of the scattering also provides information on the arrangement of polymer segments.

 

Small angle neutron scattering (SANS

Provides access to the radius of gyration, but may also disclose more accurate information than SAXS. The location of the ending groups has also been determined by SANS experiments conducted with PAMAM dendrimers and PPI dendrimers

 

Laser light scattering (LLS)

It determines the hydrodynamic radius of dendrimers. Dynamic LLS is mostly used for the detection of aggregates.

C

Microscopy methods

Microscopy methods for characterization of dendritic polymer are39-40

 

Transmission microscopy

Electron or light produce images that intensify the original, with a resolution eventually limited by the wavelength of the source.

 

Scanning microscopy

It produces an image by touch contact Q at a few angstroms of a sensitive canilever arm with sample. Ex. Atomic force microscopy.

D

Size exclusive chromatography

It allows the partition of molecules according to size.41

E

Electrical techniques

Electrical techniques for characterization of dendritic polymer are as Follows 42-44

 

Electron paramagnetic resonance (EPR)

Quantitative determination of the substitution effectiveness on the surface of PANAM dendrimers

 

Electrochemistry

It provides information about the possibility of interaction of electroactive end groups.

 

Electrophoresis

It provides the information about the assessment of purity and homogeneity of several types of water soluble dendrimers.

F

Rheology and Physical properties

Rheology and physical properties used for characterization of dendritic polymer are as follows45-48

 

Intrinsic viscosity

It is as analytical probe of the morphological structure of dendrimers.

 

Differential scanning calorimetry (DSC)

It used to detect the glass transition temperature depends on the moleculer weight, entangment and chain composition of polymers.

 

Dielectric spectroscopy (DS)

Gives complete information about molecular dynamic processes (α-, β).

G

Miscellaneous

Other methods used of characterization of dendritic polymer are as Follows49-51

 

X-ray Photoelectron Spectroscopy (XPS)

It provides detailed information about chemical composition of dendrimers such as poly (aryl ether) dendrons or PAMAM dendrimers which was obtained using XPS. This technique is most generally used for the characterization of layers.

 

Sedimentation

Technique used for lactosylated PAMAM dendrimers, measurements of dipole moments for PMMH dendrimer.

 

Titrimetry

It is used for determining number of NH2 end groups of PAMAM Dendrimers.

Table 3: Factors affecting dendrimers properties.52-54

S.NO. Factor Level Effect

1.

Effect of pH

Low

Structural behaviour of PAMAM dendrimers is depended upon pH. At low pH (< 4) the interior is getting increasingly hollow. Repulsion between the positively charged amines both at the dendrimer surface and the tertiary amines in the interior increases at high generation.

   

Neutral

At neutral pH, back-folding occurs which may be a consequence of hydrogen bonding between the uncharged tertiary amines in the interior and the positively charged surface amines.

   

High

At higher pH (pH>10) the dendrimer contract as the charge of the molecule becomes neutral, acquiring a more spherical (globular) structure, where the repulsive forces between the dendrimer arms and between the surface groups reaches minimum

2.

Effect of Salt

High

High concentration of salt have a strong effect on charged PPI dendrimers. Favours a contracted conformation of dendrimers, with a high degree of back-folding somewhat similar to what is observed upon increasing pH or poor solvation.

   

Low

The repulsive forces between the charged dendrimer segments results in an extended conformation in order to minimize charge repulsion in the structure.

3.

Effect of Solvent

 

The solvation power of any solvent to solvate the dendrimer is a very important parameter. Dendrimers of all generations generally exhibit a larger extent of back-folding with decreasing solvent quality. The dendrimer arms induce a higher molecular density on the dendrimer surface. NMR studies performed on PPI dendrimers concluded that a nonpolar Solvent like benzene, poorly solvates the dendrimers favouring intramolecular interactions between the dendrimer segments and back-folding.

4.

Effect of Concentration of Dendrimer

 

1.Small angle X-ray scattering (SAXS) experiments performed on PPI dendrimers (G4, G5) in a polar solvent like methanol show that the molecular conformation of dendrimers upon increasing concentration becomes increasingly contracted. 2.This molecular contraction may minimize the repulsive forces between the dendrimer molec-ules and increase the ability of the dendrimers to exhibit a more tight intermolecular packing.

Factors affecting dendrimers properties

Different types of factors which are affect dendrimers properties. Those factors are given in Table 3.52-54

Mechanism of drug delivery through dendrimers

The well-defined 3D structure and many functional surface groups, drug molecules can be loaded both in the interior of the Dendrimers as well as attached to the surface groups ( as shown in the figure). Dendrimers can function as drug carriers either by encapsulating drugs within the dendritic structure, or by inter-acting with drugs at their terminal functional groups via electrostatic or covalent bonds (prodrug). There are broadly two mechanisms for drug delivery. 55

A] Drug molecules can be physically entrapped within the dendritic structure, which are given in Figure 5.1.55

B] Drug molecules can be covalently linked onto the dendrimer surface (or) other functionalities to produce dendrimer-drug conjugate,which are given in Figure 5.2.55

Figure 5.1: A Dendrimer molecule with drug molecules loaded at terminal surface of branches.

Figure 5.2: Dendrimer molecules with drug molecules Encapsulated within branches.

Functional component

A dendrimer of higher generations consists of shell. A shell consists of a central core and alternating two layers of monomers around it. Amines constitute the central core which may sometimes be replaced by sugar. All core molecules have multiple and identical reaction site. Amine is the simplest core molecule present with three functional sites. The surface of all full generations consists of multiple amines, while the surface of the half generations consists of multiple acids.These two kinds of surfaces provide the means of attachme-nt of multiple different functional components.55

Application

  • There are now more than fifty families of dendrimers, each with unique properties, since muscle damage. This method significantly reduces the waiting time for the blood test results (to about 8 min).
  • Dendrimers can act as carriers, called vectors, in gene therapy. Vectors transfer genes through the cell membrane into the nucleus.
  • Besides biomedical applications dendrimers can be used to improve many industrial processes. The combination of high surface area and high solubility makes dendrimers useful as nanoscale catalysts.11

Therapeutic application

  • Dendrimer in photodynamic therapy.
  • Dendrimers for Boron Neutron capture therapy.22

Diagnostic application

  • Dendrimers as MRI contrast agent.
  • Dendrimers as X-Ray contrast agent.
  • Dendrimer as molecular probe.22

Pharmaceutical application

  • Dendrimer in pulmonary drug delivery.
  • Dendrimer in ocular drug delivery.
  • Dendrimers in oral drug delivery.
  • Dendrimers in colon drug delivery.
  • Dendrimers in intranasal drug delivery.
  • Dendrimers in pulmonary drug delivery.
  • Dendrimers in transdermal drug delivery.
  • Dendrimers for controlled release drug delivery.
  • Dendrimers in targeted drug delivery.
  • Dendrimers in gene delivery.
  • Dendrimers as solubility enhancer.
  • Cellular delivery using dendrimers carrier.
  • Dendritic polymers are used in the purification of water.
  • Dendrimers based product in cosmetics.
  • Dendrimers based commercial products.
  • Applications of Dendrimers in Waste Water Treatment.22

Cytotoxic issues of dendrimers in vivo

  • Dendrimers with positively charged surface groups- prone to destabilize cell membranes and cause cell lysis.
  • Generation dependent toxicity-higher generation dendrimers being the most toxic.
  • Degree of substitution, type of amine functionality is important- primary amines being more toxic than secondary or tertiary amines.12

Dendrimers based products

Different types of products are formulate by using Dendrimers and some dendrimer based products are given in Table 4.56

Table 4: Dendrimers based products.56

S.NO.

Brand name

Type of dendrimer

Companey

Application

1.

Vivagel

Multiple Antigen

Star Pharma

HIV Prevention

2.

Alert ticket

PAMAM

US army research laboratory

Anthrax Detection

3.

Superfect

Ampiphilic

Qiagen

Gene Transfection

4.

Startus CS

Tecto

Dade Behring

Cardiac Marker

5.

Priofect™, Priostar™

Tecto

Starpharma

Targeted diagnostic, therapeutic delivery for cancer cells

Conclusion

Due to their unique architecture dendrimers have improve physical and chemical properties and its characterstics is also improve the drug bioavailability. Dendrimers size, shape, density and their surface functionality makes dendrimers ideal carrier for various applications of drug delivery like therapeutic, diagnostic and many other fields of pharmaceutical applications. Few drawbacks like toxicity, localization, biodistribution and costly synthesis step. This review is based on several research reports and their outcomes have been cited here in a concise manner.

Funding: No funding sources

Conflict of interest: None declared

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