Dendrimers Project Report For Pharmacy Students - Part 2
Structure Of Dendrimer:
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 size required by the investigator. The result is a spherical macromolecular structure whose size is similar to albumin and hemoglobin, but smaller than such multimers as the gigantic IgM antibody complex.
Dendrimers possess three distinguished architectural components , namely
(i) An initiator core.
(ii) Interior layers (generations) composed of repeating units, radically attached to the interior core.
(iii) Exterior (terminal functionality) attached to the outermost interior generations.
Figure Of Deendrimer Structure
Composition Of Dendrimers:
Dendrimers consist of a core molecule and alternating layers of two monomers. Each pair of monomer layers completes a shell and a generation. The core generally consists of an amine core, although sugars and other molecules can be used. All core molecules share the characteristic of having multiple reaction sites that are identical. Even the simplest core possible, ammonia (NH3) has three amine reaction sites.
The core is mixed with an excess of the first monomer molecule which reacts with all of the core's reaction sites, giving rise to the first branches. This monomer molecule has two distinct reactive groups, one at each end. After one kind of end reacts, the other end will provide reaction sites for the next layer of the shell.
Figure of Composition of dendrimer
An excess of the second monomer, again a molecule which has two distinct reactive groups, one at each end, is reacted with this first layer to give the second layer and complete the first shell and the first generation. Each unreacted outer end of the second monomer provides a reaction site which can react with multiple molecules. This provides the branching and the reactions sites for the next shell.
Most of the dendrimersthat the Michigan Nanotechnology Institute for Medicine and Biological Sciences synthesizes are molecules. At the outer surface of every full generation, the reactive groups are all amines. At the interface of the two layers making up the one shell of a generation, there is an amide linkage.
TYPES OF DENDRIMERS:
{1} PamamDendrimer
Poly (amidoamine) dendrimers (PAMAM) are synthesized by the divergent method starting from ammonia orethylenediamineinitiator core reagents. Products up to generation 10(7)(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 dendrimersis applied as a trademark name for a sub-class of PAMAMdendrimers based on a tris-aminoethylene-imine core. The name refers to the starlike pattern observed when looking at the structure of the high-generation dendrimers of this type in two-dimensions.
{2} PamamosDendrimer
Radially layered poly(amidoamine-organosilicon) dendrimers (PAMAMOS) are inverted unimolecular micelles that consist of hydrophilic, nucleophilicpolyamidoamine (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.
{3} PPI Dendrimer
PPI-dendrimersstand for “Poly (Propylene Imine)” describing the propylamine spacer moieties in the oldest known dendrimer type developed initially by Vögtle.(8) 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. POPAM stands for Poly (Propylene Amine), which closely resembles the PPI abbreviation. In addition, these dendrimers are also sometimes denoted “DAB-dendrimers” where DAB refers to the core structure, which is usually based on Diamino butane.
{4} TectoDendrimer
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.
{5} Multilingual Dendrimers
In these dendrimers, the surface contains multiple copies of a particular functional group.
{6} Chiral Dendrimers
The chirality in these dendrimersare based upon the construction of a constitutionally different but chemically similar branches to chiral core.
{7} Hybrid Dendrimers Linear Polymers
These are hybrids (block or graft polymers) of dendritic and linear polymers.
{8}AmphiphilicDendrimers
They are built with two segregated sites of chain end, one half is electron donating and the other half is electron withdrawing.
{9}MicellarDendrimers
These are unimolecular micelles of water soluble hyper branched polyphenylenes.
{10} 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.
{11}Fréchet-Type Dendrimers
It is a more recent type of dendrimer developed by Hawker and Fréchet(6,8) based on poly-benzyl ether hyper branched skeleton. These dendrimers usually have carboxylic acid groups as surface groups, serving as a good anchoring point for further surface functionalisation, and as polar surface groups to increase the solubility of this hydrophobic dendrimer type in polar solvents or aqueous media.
SYNTHESIS OF DENDRIMERS:
There are a large number of molecules which can be used as cores, and an even larger number of possible monomers are available for building the layers. As with many plastics, particularly Nylon, this creates a great number of possibilities.
The canonical dendrimer starts with an ammonia core. This core is reacted with the double bond in acrylic acid to produce a tri-acid molecule. This tri-acid is reacted with ethylene diamineto produce a tri-amine (G0). This tri-amine is reacted with acrylic acid to produce a hexa-acid, doubling the number of acids in this half-generation (G0.5). Next, another round of ethylene diamine is reacted with the G0.5 to give a G1 molecule with six amines, twice the number at G0. This alternation of acrylic acid with ethylene diaminecontinues until the desired generation is reached.
There are two methods of dendrimer synthesis, convergent and divergent. Convergent synthesis goes from the "outside-in" and divergent goes from the "inside-out."
Evaluation Of Dendrimers:
Dendrimers, by virtue of their therapeutic value, have recently generated enormous interest among biomedical scientists. Advancement of dendrimericnano-architecture with well defined size, shape and controlled exterior functionality embraces promise in biomedical and pharmaceutical applications such as drug delivery, solubilization, DNA transfection and diagnosis.
Highly branched, monodisperse, stable molecular level and low polydispersity with micelle-like behavior possessing nano-scale container property distinguish these structures as inimitable and optimum carrier for those applications.
Dendrimers has been evaluated for delivery of different types of bioactives inside the cells. Different types of techniques are being used for exploring dendrimer safety and efficacy via cell cytotoxicity assays, cell uptake studies by fluorescent microscopy, cell line studies, flow cytometry, gamma scintigraphy and confocal microscopy; are being used over a decade. Among these, cell line studies are widely used for ex vivo characterization of dendrimers and other nanocarriers.
Cell lines are homogeneous population of cells, stable after mitosis, and have an unlimited capacity for division. This review focuses on the use of different cell line studies including anticancer drugs, anti-HIV drugs, anti-inflammatory drugs, anti-tubercular-drugs, photodynamic therapy, hormonal therapy employing dendritic nanocarrier.
APPLICATIONS OF DENDRIMERS:
DENDRIMERS IN DRUG DELIVERY
The development of an efficient drug delivery system is very important to improve the pharmacological activity of drug molecules. Dendrimers have emerged as new
alternatives and efficient tools for delivery of drug molecules. As compare to linear polymeric carriers, the multivalent functionalities of dendrimers can be linked to drug molecules or ligands in a well-defined manner and can be used to increase the binding efficiency and affinity of therapeutic molecules to receptors via synergistic interaction.
1) Oral drug delivery
Oral drug delivery systems are very important to the field of medicine, since most of the common illnesses are treated via oral rout of medication. Dendrimers those are able to hold medication with good durability but also biodegradable within a biological system. By combining the ideas of drug carriers and degradability, research has recently focused on controlled degradation ofdendrimersand release of compounds via oral route4. Encapsulation and conjugation of drug with dendrimers have shown immense employment for delivery of hydrophobic and labile drugs5. Transport of dendrimers throughout epithelial part of gastrointestinal tract depends upon its characteristics6. Packaging a drug in a dendrimer host not only makes it soluble but also allows it to bypass the transporter protein that would normally stop it from being absorbed in the intestines after it has been taken orally. Anticancer and antihypertensive drugs are most promising candidate for oral rout using dendrimer as carrier.
Dendrimers with diameters in the range of 2.5 to 6 nm seemed to offer the ideal progression to smaller and smaller systems. Problem of flocculation and aggregation of the system in vivo, oral uptakes of dendrimers are not better as accepted. Using polyoxyethylene glycol chains or ionic groups can reduce this problem, but oral uptake is then hindered by the hydrophilic nature of the surface dendrimers4-7.Dendrimer-drug size, molecular weight, surface charge, incubation time and concentration of active molecule impart different characteristics for oral delivery of dendrimers.
2) Ocular drug delivery
The topical application of active drugs to the eye is the most prescribed route of administration for the treatment of various ocular disorders. It is generally agreed that the intraocular bioavailability of topically applied drugs is extremely poor. These results mainly due to drainage of the excess fluid via nasolacrimal duct and elimination of the solution by tear turnover.
Several research advances have been made in ocular drug delivery systems by using specialized delivery systems such as polymers, liposomes, or dendrimers to overcome some of these disadvantages. Ideal ocular drug-delivery systems should be nonirritating, sterile, isotonic, biocompatible, does not run out from the eye and biodegradable. Dendrimers provide unique solutions to complex delivery problems for ocular drug delivery. Recent research efforts for improving residence time of pilocarpine in the eye was increased by using PAMAM dendrimers with carboxylic or hydroxyl surface groups. These surface-modified dendrimers were predicted to enhance pilocarpine bioavailability.
3) Transdermal drug delivery
In recent era, dendrimers have found applications in transdermal drug delivery systems. Generally, bioactive drugs have hydrophobic moieties in their structure, resulting in low water-solubility that inhibits efficient delivery into cells.
Dendrimers designed to be highly water-soluble and biocompatible have been shown to be able to improve drug properties such as solubility and plasma circulation time via transdermal formulations and to deliver drugs efficiently. The viscosity imparting property of a dendrimers solution allows for ease of handling of highly concentrated dendrimer formulations for these applications.
Dendrimers have been shown to be useful as transdermal drug delivery systems for nonsteroidal anti-inflammatory drugs (NSAIDs), antiviral, antimicrobial, anticancer, or antihypertensive drugs. PAMAM dendrimers have been studied as carrier transdermal systems for the model NSAIDs: ketoprofen and diflunisa. It is well known that the molecular transport through intact skin is related to the molecular weight of the drug-carrier molecule.
4) Targeted gene delivery
Ongoing product development using dendrimer as carrier Although the application of dendrimers in the field of drug and gene delivery is in its infancy compared to liposomes and other nanomaterialsDendrimers can act as carriers, called vectors, in gene therapy.
Vectors transfer genes through the cell membrane into the nucleus. Currently liposomes and genetically engineered viruses have been mainly used for this. PAMAM dendrimers have also been tested as genetic material carriers. Cationic dendrimers (Polypropylenimine (PPI) dendrimer) deliver genetic materials into cells by forming complexes with negatively charged genetic materials through electrostatic interaction.
Cationic dendrimers lend themselves as non-viral vectors for gene delivery because of their ability to form compact complexes with DNA. Another potential application could be the use of dendrimers coated withsialic acid for the influenza virus to attach to the cell surface. In addition, dendrimers are non-immunogenic and are thus uniquely suited as carrier structures for drugs or bioactive molecules without degradation in immune system .
. Dendrimers are already making an impact with the first therapeutic product based on dendrimer technology, VivagelTM topical micobicide, currentely undergoing phase-II trial. Another two products based on dendrimer technology are an anti-herpes and anti-mycotic for nail fungus, in clinical phase III trials.
5) Future prospect
Dendrimer drug delivery systems are increasingly viewed as an advantageous solution for bioactive like drugs and gene. They provide a platform for the attachment of drugs or genes and their release through several mechanisms. Scientists have explored the use of dendrimers for various applications in oral, transdermal, ophthalmic, and gene delivery.
Although dendrimer drug delivery requires attention to certain manufacturing and biological considerations to be successful. Boosting of commercial applications of dendrimer technology will provide strength for its usefulness in coming years.