Dendrimers popularly known as tree like macromolecules has been subject of countless discussion among scientists, researchers, polymer technologists, nanotechnology experts and academics since the late 1970s, when scientists Fritz Vögtle and Donald Tomalia first synthesized the branching polymer molecules. The word, dendrimer is derived from the Greek word, dendron, meaning a tree. The graphical representation of the structure of a typical dendrimer resembles a tree with branches. The unique molecular architecture (Fig 1) of dendrimers has caused an explosion of scientific interest in many fields. There are more than 6000 dendrimers related scientific papers published by the end of 2006.
Importance of dendrimers
Dendrimers have many potential applications, including diagnostic and therapeutic applications. Nanotechnologists are using the hollow cavities deep within the dendrimer molecules to hold nanoparticles, genetic materials, drugs, and imaging agents. By controlling dendrimer architecture scientists have been developing dendrimers for drug delivery, diagnostic imaging and carriers of genetic materials. Aside from these, dendrimers can also be used in coatings, electronics and photonics, among others.
Synthesis of dendrimers
Dendrimers are mono disperse polymers that have a precise molecular weight and size with a regular highly branched three-dimensional architecture. They consist of major three architectural components: core, branches and end groups (Fig 1). They can be synthesized either assembling the molecules from the central core to the periphery (divergent synthesis) or starting from the outermost residues to termination at the central core (convergent synthesis). Dendrimers are produced by stepwise synthesis around a simple small core molecule and the branches constructed by successive reactions that introduces series of chemical shells (repeat units) on the core molecule. The core of the dendrimers is known as "generation 0". Each successive repeat unit along all branches forms the next generation. Each new generation creates double the number of active sites (called end groups) and approximately the double the molecular weight of previous generation. The polyamidoamine (PAMAM) dendrimer is a seventh generation dendrimers, which has 256 terminal functional groups. The sizes of the dendrimers are very small in the nanometer range, having diameters in the range of 3 to 10 nm.
However, there are serious obstacles to the synthesis of large quantities of dendrimers because of difficulty in protecting active core site during long stepwise reactions. That means the cost of dendrimers is too high. One hundred milligrams PAMAM dendrimers costs about USD 200. Diagnostic grade, tenth generation dendrimers go for USD 1,650/ 100 mg. Therefore, commercial development of dendrimers has been very slow because of their relatively high costs. The first exhaustively investigated dendritic systems were PANAM (described by Tomalia) and arborol (described by Newkome in 1985) dendrimers that received widespread attention. Today, PPI (polypropyleneimine) dendrimers, based on original work of Fritz Vögtle, and PAMAM dendrimers are already being manufactured by companies such as DSM and Dendritech and available commercially for research purposes.
Dendrimers can act as molecular rigidified micelles in which they become containers for small molecules, providing the potential of dendrimers as drug and gene delivery. The physical characteristics of size, geometry combined with their low specific viscosities, make them especially suitable for use as carrier for drug delivery. In addition, small drug molecules including DNA can be trapped in the core of the dendrimers and many ionic polymeric molecules can be attached to the surface (having opposite charge). Drugs, solubilizing agents and ligands can be covalently attached to the surface of the dendrimers. Hence dendrimers are promising to be solubilizers for poorly soluble drugs, and one can foresee their applications as film-formers and as lubricants. Many drugs and anti-cancer agents are being investigated using dendrimers as carriers and also as covalently attached to the surface. Examples of some of the drugs/agents carried by dendrimers are anthracene, DNA, 5-fluorouracil, heparin, ibuprofen, indomethacin and methotrexate. And drugs/agents covalently attached to dendrimers are antibodies, 5-fluorouracil, folic acid and polyoxyethylene glycol etc.
Dendrimer based products-myth or reality
According to some scientists, there are two myths about dendrimers. The first myth is that dendrimers, as mentioned earlier, are too costly for commercial applications, and the second one is that the polymer has been synthesized way back in 1980s with no commercial uses. Nevertheless, the reality lies in the fact that the world's first dendrimer-based pharmaceutical, developed by Australian-based Starpharma, has got the consent for clinical trials by the US FDA. The product, a topical vaginal microbicide gel called VivaGel for use as liquid condom to reduce the risk of HIV and STD infections in women. It has completed a phase I clinical trials, and plans to bring the product to market by 2008 after completion of requisite clinical trials. The most interesting fact about VivaGel is that the dendrimer (a fourth generation polylysine) itself acts as active ingredient, wherein the microbicide effect results from the polyanionic functional groups attached to dendrimer's surface. Another dendrimer-based tool for cardiac analysis is being developed by Dade Bering, one of the world's largest medical diagnostic companies.
Are interesting dendrimers systems in the offing?
Some of the most interesting applications for dendrimers are in the pharmaceutical and biomedical area. Although these applications are in their infancy, dendrimers offer several attractive features, including creation of biologically active or inert dendrimers. Recent report mentions mutli-purpose dendrimers that can deliver a drug, document that the drug is there and report back cell's response. The flexibility of engineering all sorts of behaviour in dendrimers holds promise for a number of interesting systems for delivery of pharmaceuticals in the coming years.
(The author is Reader in Pharmacy, Annamalai University, Annamalai Nagar 608 002, Tamil Nadu)