INTRODUCTION:

Dendrimers are hyper branched, tree-like structures and have compartmentalized chemical polymer. Dendrimer contain three different regions: core, branches and surface (Fig. 1). The macromolecule constituents radiate in branching form from the central core creating an internal cavity as well as a sphere of end groups that can be tailored according to requirements. They can be tailored or modified into biocompatible compounds with low cytotoxicity and high bio permeability. They bear promising properties for delivery of bioactive ranging from drugs, vaccines, metal, and genes to desired sites. Their hollow interior provides space to incorporate drugs and other bioactive physically or by various interactions to act as drug delivery vehicles. Most important applications of dendrimers are solubilization, gene therapy, dendrimer based drug delivery, immunoassay and MRI contrast agent. Dendrimers is ideal carrier for drug delivery due to advantages like very low size (1-5 nm), feasibility to develop with defined molecular weight, very low Polydispersity index (ratio of weight average molecular weight (Mw) to number average molecular weight (Mn) of polymer), good entrapment efficiency and offering surface for functionalization. They can be modulated for target-specific drug delivery but their toxicity profile renders them not very popular system for use as delivery means¹.Dendrimers are a new class of three- dimensional, manmade molecules produced by an unusual synthetic route.

Fig. 1: Schematic representation of a dendrimer showing core, branches, and surface

Dendrimers construction is fundamentally divided into two methods, the divergent methods, and the divergent method where one branching unit after another is successively attached to the core molecule; hence the multiplication of the number of peripheral groups is dependent on the branching multiplication of the number of peripheral group is dependent on the branching multiplicity, secondary convergent method. Basically, the divergent method as the layers built outward from the core molecule the fractal or dendritic, nature of the growing structure emerges; large regions resembles the small formed by triplets of monomers. The internal structure acquires a star like appearance and final products as appear are called “Starburst Dendrimers”.

Dendrimers were first described by Vogtleet al in 1978 as cascade molecule. They are perfect mono disperse macromolecule with a regular and highly branched 3D structure. Towards the end of the 1970s, a great deal of interest was starting to be generated in the new areas of host-guest and supramolecular chemistry. In the quest for large, substrate-selective ligands, several research groups became interested in the synthesis of 'tentacle' and 'octopus' molecular compound.

Benefits of dendrimers

They have broad applicability to interfere with protein-protein interactions. Macromolecular purity allows exploration of a whole new diversity space that could not be previously addressed with synthetics. They can be used to precisely control pharmacokinetics of drugs. They provide a scaffold for attachment of multiple functional elements in precise ratios and positions^(2,
3) Denderimers have the Capability to entrap a verity of drugs having different types of functional groups in internal hollow core or by charge interactions. These have Capability to entrap a verity of drugs having different types of functional groups in internal hollow core or by charge interactions. Better targeting efficiency due to the presence of reactive functional groups on the surface of dendrimer.

Types of Dendrimers ^{(4, 5, 6.7, 10)}

MAP-dendrimers:

Stand for “Multiple Antigen Peptide”, and is a dendron-like molecular construct based upon a two dimensions. These dendrimers are usually known under the abbreviation PAMAM (Starburst) or just Starburst.

Pamam Dendrimer:

Poly (amid amine) dendrimers (PAMAM) are synthesized by the divergent method starting from ammonia or ethylenediamine initiator core reagents. Products up to generation 10⁵(a molecular weight of over 9, 30,000 g/mol) have been obtained (by comparison, the molecular weight of human hemoglobin is approximately 65,000 g/mol). PAMAM dendrimers are commercially available, usually as methanol solutions. Starburst dendrimers is applied as a trademark name for a sub-class of PAMAM dendrimers based on a tris-aminoethylene-imine core. The name refers to the star like pattern observed when looking at the structure of the high-generation dendrimers of this type in two-dimensions.

Tecto Dendrimer:

These are composed of a core dendrimer, surrounded by dendrimers of several steps (each type design) to perform a function necessary for a smart therapeutic nanodevice. Different compounds perform varied functions ranging from diseased cell recognition, diagnosis of disease state drug delivery, reporting location to reporting outcomes of therapy

Micellar Dendrimers:

These are unimolecular micelles of water soluble hyper branched polyphenylenes.

Hybrid Dendrimers Linear Polymers:

These are hybrids (block or graft polymers) of dendritic and linear polymers.

Fréchet-Type Dendrimers:

It is a more recent type of dendrimer developed by Hawker and Fréchet^{(8, 9)} based on poly-benzyl ether hyper branched skeleton. This is more recent type of dendrimers based on a poly-benzyl ether hyper branched skeleton. This type of dendrimers can be symmetric or built up asymmetrically consisting of 2 or 3 parts of segmental elements (dendrons) with, e.g. different generation or surface motif. These dendrimers usually have carboxylic acid groups as surface groups, serving as a good anchoring point for further surface functionalization, and as polar surface groups to increase the solubility of this hydrophobic dendrimer type in polar solvent.

Pamamos Dendrimer:

Radially layered poly (amidoamine-organosilicon) dendrimers (PAMAMOS) are inverted unimolecular micelles that consist of hydrophilic, nucleophilic polyamidoamine (PAMAM) interiors and hydrophobic organosilicon (OS) exteriors. These dendrimers are exceptionally useful precursors for the preparation of honeycomb-like networks with nanoscopic PAMAM and OS domains.

Multiple Antigen Peptide Dendrimers:

It is a dendron-like molecular construct based upon a polylysine skeleton. Lysine with its alkyl amino side-chain serves as a good monomer for the introduction of numerous of branching points. This type of dendrimer was introduced by J. P. Tam in 1988, has predominantly found its use in biological applications, e.g. vaccine and diagnostic research

Chiral Dendrimers:

The chirality in these dendrimers are based upon the construction of a constitutionally different but chemically similar branches to chiral core

Multilingual Dendrimers

In these Dendrimers, the surface contains multiple copies of a particular functional group.

PPI Dendrimers

PPI-dendrimers stand for “Poly (Propylene Imine)” describing the propylamine spacer moieties in the oldest known dendrimer type developed initially by Vögtle.These dendrimers are generally poly-alkyl amines having primary amines as end groups, the dendrimer interior consists of numerous of tertiary tris-propylene amines. PPI dendrimers are commercially available up to G5, and has found widespread applications in material science as well as in biology. As an alternative name to PPI, POPAM is sometimes used to describe this class of dendrimers.

SYNTHESIS ⁽¹¹⁾

Dendrimers can be synthesized using one or more of the available approaches, namely divergent, convergent, hyper cores and branched monomers, double exponent and mixed growth and other accelerated growth techniques.

Divergent Dendrimers growth

This name is derived from the manner in which the dendrimers grows outward from the core, diverging into space starting from a reactive core, or generation is grown and then new periphery of the molecule is activated for reaction with more monomers. The divergent approach is successful for the production of large quantities of dendrimers. Problems occur from side reactions and incomplete reactions of the end groups that lead to structure defects (fig.-2).

Fig. 2 Divergent growth methods

Convergent Dendrimers growth:

The convert approach was developed as a response to the pitalls of divergent synthesis viz. non –conduciveness to control growth and selective functionalization. Convergent growth begins at what will end up being the surface of the dendrimers, and works inwards by gradually linking surface units together with more monomer. In contrast of divergence growth, only two simultaneous reactions are required for any generating adding step (fig.-3).

Figure 3: Convergent growth method

The convergent growth method has several advantages. It is relatively easy to the desired product and the occurrence of defects in the final structure is minimized. It becomes possible to introduce subtle engineering into the dendritic structure by precise placement of functional groups at the periphery of the macromolecule.

Hyper core and Branched monomers:

These methods involve the pre-assembly at oligomeric species, which can then be linked together to give higher yield of dendrimers in fewer steps (fig.-4).

Figure 4: Hyper core and Branched monomers

In this method exponential growth similar to a rapid growth technique for linear polymers involves an ab2 monomer with orthogonal protecting groups for the functionalities. This approach allows the preparation of monomers for both convergent and divergent growth from a single starting material

Double exponential and mixed growth:

The most recent fundamental breakthrough in the practice of dendrimers synthesis has come with the concept and implication of double exponential growth. Double exponential growth similar to a rapid growth technique for linear polymers involves an ab2 monomer with orthogonal protecting groups for the a and b functionalities. This approach allows the preparation of monomers for both convergent and divergent growth from a single starting material. These two products reach together to give an orthogonally protected trimmer, which may be used to repeat the growth process again (fig.-5).

Figure 5: Double exponential and mixed growth

APPLICATIONS:

Dendrimers have to exhibit low toxicity and non-immunogenic in order to be widely used in biomedical applications ⁽¹²⁾Many potential applications of dendrimers are based on their unparalleled molecular uniformity, multifunctional surface and presence of internal cavities. These specific properties make dendrimers suitable for a variety of high technology uses including biomedical and industrial applications.

1. Dendrimers as vaccines, artificial proteins and enzymes:

The antibodies induced by peptide dendrimers in rabbits and mice were not only reactive but were specific to the corresponding peptide dendrimers, monovalent peptide and cognate native proteins. This approach to the preparation of peptide dendrimers with multiple epitopes. These diepitope peptide dendrimers induced strong immunological response to both cognate native proteins. They have also designed an amphiphilic peptide dendrimer as a synthetic AIDS vaccine capable of forming liposomes or micelles by attaching tripalmitoyl-s-glyceryl cysteine group to a tetravalent peptide antigen containing glycoprotein gp 120 of HIV-1 Virus.^{(14,15, 16)}

2. Starburst Dendrimers for enhanced performance and flexibility for immunoassays :

Dendrimers composed of polyamidoamine groups to which were coupled several specific antibodies, to investigate the potential formats based on radial partition immunoassay. The coupled antibodies retained their stability and immunological bonding after coupling, both in solution and when immobilized on to a solid support. On the basis of feasibility studies with model systems they concluded that immunoassay on to a solid support. On the basis of feasibility studies with model systems they concluded that immunoassays can be developed with performance equivalent to or better than that in many established systems and demonstrated enhanced sensitivity for creatinine kinase MB isoenzyme thyrotropin and myoglobin assay and reduced instrumental analysis time for the CKMB assay. ⁽¹⁷⁾

3. Drug conjugation:

Various strategies have been devised to modify dendrimers with drug molecules, genetic materials, targeting agents, dyes and imaging agents, either by encapsulation or conjugation By conjugating appropriate targeting moieties, drugs, and imaging agents to dendritic polymers, ‘smart’ drug-delivery nano devices can be developed that can target, deliver, and monitor the progression of therapy. Drugs can be conjugated to dendritic nano devices through either ester or amide linkage, which can be hydrolyzed inside the cell by endosomal or lysosomal enzymes. Encapsulation of drugs in PEGylated dendrimers can lead to enhanced permeation and retention (EPR) of the drug. The nanoscale branching architecture of the dendrimers provides them with several advantages over linear polymers, nanoparticles and liposomes such as rapid cellular entry, reduced macrophage uptake and targetability. PAMAM–NH2 dendrimer–ibuprofen complexes involving ionic interaction between amine groups of dendrimer and carboxyl groups on ibuprofen have been investigated.^{(18, 19).}

4. Gene therapy:

Several types of PAMAM Dendrimers have been investigated as gene vectors for the purpose. Experiments show that PAMAM are effective transferring agents proving high successful rate of transferring genetic material into the cell. G5 PAMAM Dendrimers (dia =5m, MW= 21, 563) fictionalized through disulphide linkage with cysteine containing amphipathic peptide and carrying luciferase and b- galactosidase plasmids have been used as expression vectors.⁽²⁰⁾ They are synthetic hyper branched polymers which are highly soluble in aqueous solutions, with positively charged terminal groups that can bind DNA forming complexes termed as dendriplexes, analogy with similar complexes formed by liposomes and DNA called lipoplexes. The DNA within dendriplexes is protected from cellular and restriction nucleases. Currently liposomes and genetically engineered viruses have been mainly used for this. PAMAM dendrimers have also been tested as genetic material carriers; they are terminated in amino groups which interact with phosphate groups of nucleic acids^{(21, 22, 23)}

5. Dendrimers as drug carriers:

One of the stellar characteristics of Dendrimers is that they can carry the pharmaceutical material in their interior. They carried drug material is conjugated with the Dendrimers, as in starburst PAMAMS. The conjugated material include, any antigen, hapten, organic moiety or organic or inorganic compound that will raise an immune response associated with starburst Dendrimers without appreciably disturbing the physical integrity of the latter. These systems have been intensively investigated in the recent past and even several patents have been field. These encompass, the patent used in the treatment of malaria, cholera and urinary tract infection using a synthetic peptide, bacterial polysaccharides, viral protein for the production of vaccines^{. (24)}

6. Dendrimers in solubility enhancement:

Dendrimers seem to have immense potential as the solubility enhancers for poorly soluble lipophilic drugs. They have been known to improve the aqueous solubility of the oil soluble Bengal rose dye through the formation of unimolecular micelles or encapsulation in dendritic box. Very recently, one report employed for successful improvement in water solubility of ibuprofen is through electrostatic interaction of carboxyl group of drug with amino group Dendrimer. There are many substances which have a strong therapeutic activity but due to their lack of solubility in pharmaceutically acceptable solvents have not been used for therapeutic purposes. Water soluble dendrimers are capable of binding and solubilising small acidic hydrophobic molecules with antifungal or antibacterial properties^{(25, 26)}

7. Dendrimers as bio mimetic artificial proteins:

Dendrimers provide a multiple bonding sites on the periphery, allowing many magnetic resonance imaging (MRI) contrasting agent complexes to attach to Dendrimers. One Dendrimer molecule can host up 24 contrasting agent complexes and hence attain higher signal to noise ratio. The Dendrimer prevent any complex from diffusing into untargeted area. The star bust conjugates can be used for variety of in vitro and in vivo diagnostic application such as RIA, electron microscopy, ELISA, NMR, contrast imaging and immuno scintography, in analytical application, radionuclide drug or other agent suitable for use in the treatment of disease such as cancer, autoimmune disease, genetic defects, CNS disorders, infections disease and cardiac disorders. Dendrimers can be used for serodiagnosis (system with surface legands), biosensor system (system containing dyes, reactive molecules). Dendritic deliveries of PDT agents are used in order to improve upon tumor selectivity, retention, and pharmacokinetics.^{(27, 28,
29).} Dendrimers are nanosized, non-immunogenic, and hyper branched vehicles that can be efficiently tailored for spatial distribution of bioactives, thereby reducing untoward cytotoxicity on normal cells. These nanoparticulate drug delivery vehicles provide a unique platform that has precisely placed functional groups so that multiple copies of ligands can be attached to it and facilitate targeting to the tumor surface or neo-vascularising vessels proliferating around these cells. Dendrimers have been explored as transport vehicles for the delivery of bioactive at these necrotic sites. Dendrimers as nanoconstructs have a highly controlled architectural design, along with unique and myriad interfacial properties⁽³⁰⁾

8. In vitro diagnosis:

Dendrimers are also used for invitro diagnostics e.g. in cardiac testing. Dendrimers due to their properties are highly suited for use as image contrast media. Several groups have prepared dendrimers containing gadoliniumions chelated on the surface^{(31, 32).} Preliminary tests show that such dendrimers are stronger contrast agents than conventional ones. They also improve visualisation of vascular structures in magnetic resonance angiography (MRA) of the body^(33).

9. Dendrimer as magnetic resonance imaging contrast agents:

Dendrimer based metal chelates act as a magnetic resonance imaging contrast agent. In this large proton relaxation enhancements and high molecular relaxivities by using polyamidoamine form of dendrimers in which free amines have been conjugated to chelator 2-(4-isothiocyanatobenzyl)-6-methyl-diethylene tri-amine pent acetic acid and suggested that new and powerful class of contrast agents have the potentials for diverse and extensive application in MR imaging. These novel classes have more proton relaxation times indicating their superiority for MRI application. they have more half life period. Dendrimers are currently under investigation as potential polymeric carriers of contrast agents for magnetic resonance imaging (MRI) is a diagnostic method producing anatomical images of organs and blood vessels. Placing a patient in a generated, defined, inhomogeneous magnetic field results in the nuclear resonance signal of water, this is assigned to its place of origin and converted into pictures^{(34, 35).}

10. Biochemical analysis:

The design of sugar binding receptor for detection of suger levels in dibetic patients by introducing boronic acid base fluorescence sensor. The anthracene units (chromophore) and boronic acid (sugar binding moiety) were attached to second generation PAMAM Dendrimer through a tertiary amine. The enhanced binding was observed which was attributed to the high local concentration effect.

11. Isolation of biological:

Dendrimers are isotropic ally soluble functional polymers with a great potential for precise arrangement or isolation of functional groups ⁽³⁶⁾

12. To improve many industrial processes:

Dendrimers can be used to improve many industrial processes. The combination of high surface area and high solubility makes dendrimers useful as nanoscale catalysts ⁽³⁷⁾They combine the advantages of homogenous and heterogeneous catalysts. Homogenous catalysts are effective due to a good accessibility of active sites but they are often difficult to separate from the reaction stream. Heterogeneous catalysts are easy to separate from the reaction mixture but the kinetics of the reaction is limited by mass transport. Dendrimers have a multifunctional surface and all catalytic sites are always exposed towards the reaction mixture⁽³⁸⁾ An alternative application of dendrimers that has gained some attention is based on nanostructures which can find use in environment friendly industrial processes. Dendrimers can encapsulate insoluble materials, such as metals, and transport them into a solvent within their interior. Synthesized fluorinated dendrimers which are soluble in supercritical CO2 and can be used to extract strongly hydrophilic compounds from water into liquid CO2. This may help develop technologies in which hazardous organic solvents are replaced by liquid CO2.It has been a progressing field of research and at present all these industrial applications are under study^(39).

13. Dendrimers Continues to Advance Anticancer Gene Therapy :

Cancer is a disease in which genetic errors play a major role; it should come as no surprise that many experts envision a time when gene therapy will play an equally important role in the treatment of cancer. But before that day can come, researchers much overcome a major hurdle: safely delivering therapeutic genes and other nucleic acid-based regulatory agents into malignant cells. Enter nanotechnology. With the ability to sequester a wide variety of molecules and deliver them in a targeted manner to tumors, nanoparticles could prove to be the ideal delivery vehicle for oligonucleotide-based drugs such as anticancer genes, antisense oligodeoxynucleotides, and small interfering RNAs. ZMedical School, demonstrated that dendrimer-based nanoparticles can deliver antisense oligodeoxynucleotides into breast cancer cells. The researchers, who reported their work in the journal Nanotechnology, formed the nanoparticles using a biocompatible dendrimer made of poly (propyleneimine) (PPI). This particular type of dendrimer belongs to a family of what are known as amine-terminated polymers, a class of compounds that other investigators have found promote gene uptake by cells. These dendrimers are also relatively easy to modify chemically, affording the option of adding tumor-targeting agents or additional anticancer drugs to the nanoparticles. In this study, the investigators showed that simply mixing the dendrimer with antisense oligodeoxynucleotides triggered a self-assembly process that generated stable nanoparticles. Electron microscopy revealed that these nanoparticles were toroidal in shape, a finding that implies that the dendrimer and oligodeoxynucleotide first zip together to form a single structure that then wrap around them to create the final nanoparticle. Using an antisense oligodeoxynucleotide that they labeled with a fluorescent dye, the investigators were then able to track uptake of this agent by breast cancer cells. Little, if any, native oligodeoxynucleotide entered breast cancer cells, but oligodeoxynucleotide trapped within the dendrimer nanoparticle accumulated rapidly in the cells. Confocal microscopy revealed that the oligodeoxynucleotide not only entered the cells but built up in the cells’ nuclei. Austria used the naturally occurring polymer chitosan as the starting material for gene delivery nanoparticles. The researchers first modified chitosan, a polymer obtained from shrimp and crab shells, with a chemical that added multiple free sulfur-containing thiol groups to each molecule of chitosan. Thiol groups play an important role in stabilizing some proteins by linking to one another – under certain cellular conditions, two thiol groups that come close to each other will react to form a sulfur-sulfur bond. These so-called disulfide bonds can stabilize a protein’s three-dimensional structure. The investigators in this study took advantage of this process to form chitosan-DNAnanoparticles that are stable in blood. Mixing thiol-modified chitosan with DNAtriggers a self-assembly process that creates nanoparticles. As the chitosan chains fold up upon one another, some of the thiol groups come close to other thiol groups. Disulfide bonds form as a result, stabilizing the nanoparticle. Experiment, the researchers showed that the thiol-modified chitosan-DNA was more effective at getting DNA into cells than unmodified chitosan nanoparticles⁽⁴⁰⁾

CONCLUSION:

Dendrimers are highly branched three dimensional macromolecules with highly controlled structure, a single molecular weight, a large number of controllable peripheral functionalities and a tendency to adopt a globular shape once a certain size is reached. The beauty of dendrimers is that they can be designed and synthesized for specific application, as truly functional excipients. Until now, the most commonly studied system has been the family of PAMAM dendrimers, but the variety of constructs of dendrimers and their building blocks of partial dendrimers grows rapidly. The interest in these dendrimers have grown mainly due the fact that these mono-disperse polymers offer the control that modern drug delivery and targeting demands This novel class have more proton relaxation times indicating their superiority for MRI application. They have more half life period.

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Received on 08.01.2011 Modified on 25.01.2011

Research J. Pharm. and Tech. 4(6): June 2011; Page 835-841