ScienceWeek

CHEMISTRY: ON DENDRIMERS AS DRUG DELIVERY SYSTEMS

The following points are made by E.W. Meijer and M.H. Van Genderen (Nature 2003 426:128):

1) Dendrimers are artificial macromolecules, constructed in step-by-step fashion using repetitive chemistry. The macromolecule constituents radiate in branching form from a central core, creating a sphere of chemical groups that can be tailored according to requirements. The results of the process are not only aesthetically appealing but offer chemists wonderful opportunities for exploring new ideas(4).

2) Dendrimers are large, but can be synthesized and characterized with a precision similar to that possible with smaller organic molecules. They do not suffer from the problem of "polydispersity" that dogs linear macromolecules: that is, constituents of a given set of dendrimers have exactly the same molecular weight, rather than being a mixture of chains with a distribution of molecular weights. And the large number of identical chemical units in the branching units, as well as those at the periphery, confers great versatility. The end groups can be designed for various purposes, including sensing, catalysis or biochemical activity.

3) In this last instance, one of the potential virtues of dendrimers comes under the heading of "multivalency": the enhanced effect that stems from a great many identical molecules being present at the same time and place. The combination of multivalency with precision architectures has made dendrimers of increasing interest for biomedical applications, not least for drug delivery(5). Dendrimers can enter cells remarkably easily, a property that has produced investigations of dendrimers as potential gene-transfection agents. The chemical groups that bristle from the ends of the branches allow for tuning of biological properties, and can anchor one or more target groups onto the dendrimer. The compound that constitutes the drug itself can be physically encapsulated in the dendrimer or bound to it. There have been attempts to achieve total and simultaneous release of active agents through changing pH conditions. But generally the traditional route has been that of getting one chemical trigger to release one drug molecule.

4) Independently of one another, teams led by de Groot(1), Shabat(2) and McGrath(3) have explored a much more advanced concept -- simultaneous release of all of a dendrimer's functional groups by a single chemical trigger. All three approaches exploit the fact that the dendrimer skeleton can be constructed in such a way that it can be made to disintegrate into known molecular fragments once the disintegration process has been initiated. Variously termed "cascade-release dendrimers"(1), "dendrimer disassembly"(3) and "self-immolative dendrimers"(2), these systems in effect perform a chemical amplification reaction. Triggered by a specific chemical signal, the dendrimer scaffold falls apart in several steps in a chain reaction, releasing all of the constituent molecules.

References (abridged):

1. de Groot, F. M. H., Albrecht, C., Koekkoek, R., Beusker, P. H. & Scheeren, H. W. Angew. Chem. Int. Edn Engl. 42, 4490-4494 (2003)

2. Amir, R. J., Pessah, N., Shamis, M. & Shabat, D. Angew. Chem. Int. Edn Engl. 42, 4494-4499 (2003)

3. Li, S., Szalai, M. L., Kevwitch, R. M. & McGrath, D. V. J. Am. Chem. Soc. 125, 10516-10517 (2003)

4. Bosman, A.W., Janssen, H. M. & Meijer, E. W. Chem. Rev. 99, 1665-1688 (1999)

5. Patri, A. K., Majoros, I. J. & Baker, J. R. Jr Curr. Opin. Chem. Biol. 6, 466-471 (2002)

Nature http://www.nature.com/nature

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ON THE HISTORY OF DENDRIMER POLYMERS

The following points are made by S.M. Grayson and J.M. Frechet (Chem Revs. 2001 101:3819):

1) Dendrimers represent a key stage in the ongoing evolution of macromolecular chemistry. From the origins of polymer chemistry until 20 years ago, a major focus was the synthesis and characterization of linear polymers. Although the molecular interactions and the many conformations of linear polymers involve three dimensions, their covalent assembly is strictly a 1-dimensional process. Half a century ago, in theoretical studies, P.J. Flory (1910-1985) was among the first to examine the potential role of branched units in macromolecular architectures, but it was not until the mid-1980s that methods for the orderly preparation of these polymers became sufficiently developed to enable the practical study of these entities.

2) In 1978, Vogtle developed an iterative cascade method for the synthesis of low molecular weight branched amines. Using chemistry and conditions less prone to cyclization side-reactions and therefore more suitable for repetitive growth, Tomalia et disclosed the synthesis and characterization of the first family of dendrimers in 1984-1985. The synthesis was initiated by an addition reaction (Michael addition) of a "core" molecule of ammonia to three molecules of methyl acrylate, followed by exhaustive amidation of the triester adduct, using a large excess of ethylenediamine, a process that generates a molecule with 6 terminal amine groups. Iterative growth is then continued, using alternate Michael addition and amidation steps with appropriate excess of reagents, and optimization of this procedure enables the synthesis of globular poly(amidoamine) dendrimers on a commercial scale with molecular weights well above 25,000.

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