Coordination Chemistry Reviews 249 (2005) 2845–2853 Review Targeting platinum anti-tumour drugs: Overview of strategies employed to reduce systemic toxicity Steven van Zutphen, Jan Reedijk ∗ Leiden Institute of Chemistry, Gorlaeus Laboratories, Leiden University, P.O. Box 9502, 2300 RA Leiden, The Netherlands Received 3 November 2004; accepted 4 March 2005 Available online 30 March 2005 Contents 1. Introduction ........................................................................................................ 2845 2. Passive tumour targeting based on the EPR effect ....................................................................... 2846 3. Receptor mediated targeting .......................................................................................... 2849 4. Enzymatically activated prodrugs ..................................................................................... 2849 5. Compounds targeted towards cellular DNA ............................................................................ 2850 6. Concluding remarks and outlook ...................................................................................... 2851 Acknowledgements ................................................................................................. 2852 References ......................................................................................................... 2852 Abstract Selective drug delivery is an important approach with great potential for overcoming problems associated with the systemic toxicity of chemotherapy, in particular, platinum-based chemotherapy. Finding successful strategies for the targeting of platinum anticancer drugs has therefore been a subject of extensive research. This review paper gives an overview of some of the different approaches that have recently been used in the development of targeted platinum anticancer drugs. © 2005 Elsevier B.V. All rights reserved. Keywords: Cancer; Chemotherapy; Cisplatin; Platinum; Toxicity; Targeting 1. Introduction Cisplatin is one of the leading drugs currently used in the treatment of a number of solid malignancies (1; Fig. 1) [1]. For reasons of toxicity and drug resistance, however, there has been a widespread search for related complexes with similar or improved activity. Although cisplatin can in- duce apoptosis selectively in cancer cells through binding to DNA, the drug undergoes many non-selective reactions with a variety of biomolecules, such as proteins and phos- pholipids [2]. Furthermore, the drug is rapidly distributed throughout the whole body upon administration, interacting ∗ Corresponding author. Tel.: +31 71 527 4459; fax: +31 71 527 4671. E-mail address: reedijk@chem.leidenuniv.nl (J. Reedijk). with both healthy and cancerous tissue [3]. This interaction gives rise to the dose-limiting nephro- and hepatoxicities, as well as to drug resistance [4]. Targeting of the drug to the DNA of tumour cells is therefore highly desirable. This tar- geting can be achieved via different strategies, e.g. improving plasma stability, regulating tumour-selective uptake and in- creasing the affinity of the drug for its ultimate target, nuclear DNA. Most targeted platinum compounds consist of a vector ligand tethered to a platinum drug moiety. Cisplatin and the other platinum drugs that have entered the clinic, all have two leaving groups in cis-position facing two amine groups [5]. The cisplatin pharmacophore can be conjugated to the vec- tor either via the leaving groups, or via the amine groups. In the first case, the drug can dissociate from the carrier ligand, 0010-8545/$ – see front matter © 2005 Elsevier B.V. All rights reserved. doi:10.1016/j.ccr.2005.03.005