Dendrimer biocompatibility and toxicity☆
Section snippets
Background
There is a recognised need to identify novel therapeutic strategies able to bring improved treatments for life threatening and debilitating diseases [1]. The search for better diagnostics, more selective medicines, and approaches designed to either engineer new tissues or promote in situ tissue repair is ongoing. The technologies proposed are becoming ever more sophisticated. In this context, the current status of biomedical applications of dendrimers is reviewed elsewhere in this volume [2].
Dendrimer biocompatibility or toxicology: some general reflections on terminology
Should we refer to dendrimer “biocompatibility” or “toxicity”? The pharmaceutical industry refers to a drug in terms of its “toxicity”. This is a measure of non-specific, unwanted harm it may elicit towards cells, organs, or indeed the patient as a multi-organ system (Fig. 2). The field of biomedical materials has over recent decades seen the development of sophisticated, novel polymeric biomaterials, for example, hydrogels used as soft contact lenses, protheses (including stents) and devices.
Cytotoxicity
Many studies have examined dendrimer cytotoxicity in vitro. They use different cell lines, a variety of incubation times (hours to days), and various assay methods (for examples see Refs. [98], [99], [100], [101], [102], [103], [104], [105], [106], [107]). The maximum concentration of dendrimer used is frequently relatively low, and time of cell exposure short — the duration of exposure chosen to match the contact time during a transfection or pharmacological assay. Variability in cell culture
Biodistribution of dendrimers and dendronised polymers
Biodistribution of parenterally administered dendrimers has been widely studied, particularly in relation to their development of dendrimer-based imaging agents designed to monitor the cardiovascular system, liver or kidney function and for imaging tumour vasculature, their use for tumour targeted boron neutron capture therapy (BNCT) and as parenterally administered drug delivery systems. It is worthwhile to consider their biodistribution in the context of toxicokinetics. A number of analytical
Effect of dendrimers on cytokine and chemokine release
Dendrimers can modulate cytokine and chemokine release. This may prove a useful therapeutic tool, but, as has been shown before for linear polymers, it can produce catastrophic clinical toxicity. The synthetic polyanion divinylether maleic anhydride (DIVEMA or pyran copolymer) was known to induce interferon release, activate macrophages and to promote tumour cell killing, but it failed dramatically in early clinical trials as an anticancer agent due to its severe toxicity [131]. For many years
Conclusions
Interest in novel synthetic dendrimers and dendritic polymers proposed for biomedical use continues to grow exponentially (see reviews [19], [37], [136]). The architectures are ever more complex [72], [137], [138], [139], [140]. It is not unusual to see sweeping statements in respect of toxicological properties, e.g. “these dendrimers are not toxic nor immunogenic”. This creates unhelpful dogma and frequently the experimentation is not available to back up claims in respect of the specific
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This review is part of the Advanced Drug Delivery Reviews theme issue on “Dendrimers: a Versatile Targeting Platform”, Vol. 57/15, 2005.