Elsevier

Advanced Drug Delivery Reviews

Volume 57, Issue 15, 14 December 2005, Pages 2215-2237
Advanced Drug Delivery Reviews

Dendrimer biocompatibility and toxicity

https://doi.org/10.1016/j.addr.2005.09.019Get rights and content

Abstract

The field of biomedical dendrimers is still in its infancy, but the explosion of interest in dendrimers and dendronised polymers as inherently active therapeutic agents, as vectors for targeted delivery of drugs, peptides and oligonucleotides, and as permeability enhancers able to promote oral and transdermal drug delivery makes it timely to review current knowledge regarding the toxicology of these dendrimer chemistries (currently under development for biomedical applications). Clinical experience with polymeric excipients, plasma expanders, and most recently the development of more ‘classical polymer’-derived therapeutics can be used to guide development of “safe” dendritic polymers. Moreover, in future it will only ever be possible to designate a dendrimer as “safe” when related to a specific application. The so far limited clinical experience using dendrimers make it impossible to designate any particular chemistry intrinsically “safe” or “toxic”. Although there is widespread concern as to the safety of nano-sized particles, preclinical and clinical experience gained during the development of polymeric excipients, biomedical polymers and polymer therapeutics shows that judicious development of dendrimer chemistry for each specific application will ensure development of safe and important materials for biomedical and pharmaceutical use.

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

References (146)

  • B. Devarakonda et al.

    The effect of PAMAM dendrimer generation size and surface functional group on the aqueous solubility of nifedipine

    Int. J. Pharm.

    (2004)
  • K.T. Al-Jamal et al.

    Dendrisomes: cationic lipidic dendron vesicular assemblies

    Int. J. Pharm.

    (2003)
  • A. D'Emanuele et al.

    The use of a dendrimer-propranolol prodrug to bypass efflux transporters and enhance oral bioavailability

    J. Control. Release

    (2004)
  • A.S. Chauhan et al.

    Dendrimer-mediated transdermal delivery: enhanced bioavailability of indomethacin

    J. Control. Release

    (2003)
  • Z.X. Wang et al.

    Mechanism of enhancement effect of dendrimer on transdermal drug permeation through polyhydroxyalkanoate matrix

    J. Biosci. Bioeng.

    (2003)
  • R.J. Marano et al.

    Inhibition of in vitro VEGF expression and choroidal neovascularization by synthetic dendrimer peptide mediated delivery of a sense oligonucleotide

    Exp. Eye Res.

    (2004)
  • H. Zhao et al.

    Polyamidoamine dendrimers inhibit binding of Tat peptide to TAR RNA

    FEBS Lett.

    (2004)
  • D.F. Williams

    A model of biocompatibility and its evaluation

    J. Biomed. Eng.

    (1989)
  • B. Rihova

    Biocompatibility of biomaterials: haematocompatibility, immunocompatibility, and biocompatibility of solid polymeric materials and soluble targetable polymeric carriers

    Adv. Drug Deliv. Rev.

    (1996)
  • B. Rihova et al.

    Effect of the chemical structure of N-(2-hydroxypropyl)methacrylamide copolymers on their ability to induce antibody formation in inbred strains of mice

    Biomaterials

    (1984)
  • B. Rihova et al.

    Biocompatibility of N-(2-hydroxypropyl)methacrylamide copolymers containing adriamycin. Immunogenicity, effect of haematopoietic stem cells in bone marrow in vivo and effect on mouse splenocytes and human peripheral blood lymphocytes in vitro

    Biomaterials

    (1989)
  • N. Malik et al.

    Dendrimers: relationship between structure and biocompatibility in vitro, and preliminary studies on the biodistribution of 125I-labelled polyamidoamine dendrimers in vivo

    J. Control. Release

    (2000)
  • R. Duncan, Targeting and intracellular delivery of drugs. in: R.A. Meyers (Ed). Encyclopedia of Molecular Cell Biology...
  • S. Svenson et al.

    Dendrimers in biomedical applications

    Adv. Drug Del. Rev.

    (2005)
  • R. Duncan et al.

    The role of polymer conjugates in the diagnosis and treatment of cancer

    S.T.P. Pharma. Sci.

    (1996)
  • R. Duncan

    The dawning era of polymer therapeutics

    Nat. Rev. Drug Discov.

    (2003)
  • J.M. Harris et al.

    Effect of pegylation on pharmaceuticals

    Nat. Rev. Drug Discov.

    (2003)
  • R. Duncan

    Polymer-drug conjugates

  • E. Wagner, J. Kloeckner, Gene delivery using polymer therapeutics, Adv. Polym. Sci. (in...
  • U.C. Herborn et al.

    Coronary arteries: contrast-enhanced MR Imaging with SH L 643A- experience in 12 volunteers

    Radiology

    (2003)
  • D.I. Bernstein et al.

    Evaluation of formulated dendrimer SPL7013 as a microbicide

    Antivir. Res.

    (2003)
  • R. Duncan

    N-(2-hydroxypropyl) methacrylamide copolymer conjugates

  • P. Ohana et al.

    Regulatory sequences of the H19 gene in DNA based therapy of bladder

    Gene Ther. Mol. Biol.

    (2004)
  • E. Buhleier et al.

    “Cascade” and “nonskid-chain-like” synthesis of molecular cavity topologies

    Synthesis

    (1978)
  • D.A. Tomalia et al.

    A new class of polymers: starburst-dendritic macromolecules

    Polym. J.

    (1985)
  • C.J. Hawker et al.

    Preparation of polymers with controlled molecular architecture — a new approach to dendritic macromolecules

    J. Am. Chem. Soc.

    (1990)
  • G.R. Newkome et al.

    Dendritic Molecules

  • A.-M. Caminade et al.

    Characterisation of dendrimers

    Adv. Drug Del. Rev.

    (2005)
  • S.-E. Stiriba et al.

    Dendritic polymers in biomedical applications: from potential to clinical use in diagnostics and therapy

    Angew. Chem., Int. Ed.

    (2002)
  • U. Boas et al.

    Dendrimers in drug research

    Chem. Soc. Rev.

    (2004)
  • J.F.G.A. Jansen et al.

    Encapsulation of guest molecules into a dendritic box

    Science

    (1994)
  • D.A. Tomalia et al.

    Starburst dendrimers: molecular level control of size, shapes, surface chemistry, topology and flexibility from atoms to macroscopic matter

    Angew. Chem., Int. Ed.

    (1990)
  • J.M.J. Frechet

    Dendrimers and hyperbranched polymers: two families of three-dimensional macromolecules with similar but clearly distinct properties

    J. Mater. Sci. Pure Appl. Chem.

    (1996)
  • J. Roovers et al.

    Dendrimers and dendrimer-polymer hybrids

    Adv. Polym. Sci.

    (1999)
  • D.A. Tomalia et al.

    Comb-burst dendrimer topology. New macromolecular architecture derived from dendritic grafting

    Macromolecules

    (1991)
  • D.A. Tomalia et al.

    Dendrimeric supramolecular and supromacromolecular assemblies

  • S.M. Grayson et al.

    Convergent dendrons and dendrimers: from synthesis to applications

    Chem. Rev.

    (2001)
  • A.D. Schlueter et al.

    Dendronized polymers: synthesis, characterization, assembly at interfaces, and manipulation

    Angew. Chem., Int. Ed.

    (2000)
  • I. Gitsov et al.

    Synthesis and properties of novel linear-dendritic block copolymers. Reactivity of dendritic macromolecules toward linear polymers

    Macromolecules

    (1993)
  • H. Ihre et al.

    Polyester dendritic systems for drug delivery applications: design, synthesis, and characterization

    Bioconjug. Chem.

    (2002)
  • Cited by (0)

    This review is part of the Advanced Drug Delivery Reviews theme issue on “Dendrimers: a Versatile Targeting Platform”, Vol. 57/15, 2005.

    View full text