Chemistry

Dendrimers set to self-destruct

The versatility of the branched macromolecules known as dendrimers is being exploited in various ways — explosively so, in the context of their application as potential drug-delivery systems.

If a good idea for scientific innovation emerges, you can be sure that several teams of researchers will be quickly on the case. An example comes in the form of three reports1,2,3 that explore the prospects of using dendrimers for drug release inside diseased cells.

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 ideas4. 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.

In this last instance, one of the potential virtues of dendrimers comes under the heading of 'multivalency': the enhanced effect that stems from lots of 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 delivery5. Dendrimers can enter cells remarkably easily, a property that means they have been investigated 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.

Independently of one another, teams led by de Groot1, Shabat2 and McGrath3 have explored a much more advanced concept — simultaneous release of all of a dendrimer's functional groups by a single chemical trigger. All three 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 — colourfully — “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.

Two of the teams2,3 demonstrate the process in systems in which relatively simple molecular fragments are released. De Groot and colleagues1, however, have applied the principle in an especially elegant and appropriate way. They have not only devised methods for releasing the anticancer drug paclitaxel (Taxol), but also show that the dendrimer degradation products are not cytotoxic — except for paclitaxel itself, of course, which has the job of killing cancerous cells.

The first reaction activates the dendrimer core, initiating a cascade of 'elimination' reactions that lead to drug release (Fig. 1). Biodegradable polymers have been used before as drug carriers. But because dendrimers are so well defined, they allow fine control of the size, shape and composition of the release system. Their dendritic form, with many identical units, means that amplification can be achieved as a kind of explosion. A possible drawback, however, is the same that applies to every bomb — if the trigger is activated at the wrong time or place, the result will be devastating.

Figure 1: Bang on — a simplified depiction of the simultaneous release of biologically active end groups from a dendrimer1,2,3.
figure1

a, The basic dendrimer, shown here as a two-dimensional part of a sphere. b, Triggered by a specific signal, the dendrimer scaffold falls apart in a chain reaction. c, The result is release of all the constituent molecules, including the end groups. In the experiments of de Groot et al.1, these end groups consisted of molecules of the anticancer drug paclitaxel (Taxol).

The concept described in the three papers1,2,3 is intriguing, but will obviously need much more development before it can be put into practice in living cells. The next hurdle to overcome will be identifying a fuse that can be ignited to act as the trigger in biologically relevant conditions. Enzymatic reactions seem a promising avenue to explore. The pay-off of this approach, if it proves feasible, would be dendrimers that are specific for the enzymes present only in the cells to be targeted by a particular drug.

References

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Correspondence to E. W. Meijer.

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Meijer, E., van Genderen, M. Dendrimers set to self-destruct. Nature 426, 128–129 (2003). https://doi.org/10.1038/426128a

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