RESEARCH FRONT CSIRO PUBLISHING Current Chemistry www.publish.csiro.au/journals/ajc Aust. J. Chem. 2008, 61, 675–681 Drug Delivery Devices andTargeting Agents for Platinum(II) Anticancer Complexes Anwen M. Krause-Heuer, A Maxine P. Grant, A Nikita Orkey, A and Janice R. Aldrich-Wright A,B A School of Biomedical and Health Sciences, University of Western Sydney, Locked Bag 1797, Penrith South DC, NSW 1797, Australia. B Corresponding author. Email: j.aldrich-wright@uws.edu.au An ideal platinum-based delivery device would be one that selectively targets cancerous cells, can be systemically delivered, and is non-toxic to normal cells. It would be beneficial to provide drug delivery devices for platinum-based anticancer agents that exhibit high drug transport capacity, good water solubility, stability during storage, reduced toxicity, and enhanced anticancer activity in vivo. However, the challenges for developing drug delivery devices include carrier stability in vivo, the method by which extracellular or intracellular drug release is achieved, overcoming the various mechanisms of cell resistance to drugs, controlled drug release to cancer cells, and platinum drug bioavailability. There are many potential candidates under investigation including cucurbit[n]urils, cyclodextrins, calix[n]arenes, and dendrimers, with the most promising being those that are synthetically adaptable enough to attach to targeting agents. Manuscript received: 16 April 2008. Final version: 12 June 2008. Introduction Cancer accounts for three of the top 10 leading causes of death for people over the age of 60, and is the primary cause of ∼13% of all deaths worldwide per year. [1] With the ageing baby-boomer population in the Western World, cancer and its associated costs are becoming significant health issues. Cisplatin and carboplatin have been used in the treatment of ovarian, lung, testicular, breast, and stomach cancer but their clinical use is limited by toxicity [2] and drug resistance (intrinsic or acquired). [3,4] Fur- thermore, these platinum anticancer drugs bind indiscriminately to proteins and peptides that contain methionine or cysteine residues such as glutathione, [5–7] and are known to be read- ily degraded into non-active complexes by these biomolecules. For these reasons there has been a search for new and related platinum anticancer drugs with greater activity and biological properties that eliminate drug resistance. [8,9] While the design of effective anticancer agents has been an important focus of our work [10,11] and that of many others, [12–19] more clinically efficacious platinum drugs are unlikely to be found by following existing paradigms alone. [20–22] We believe that the ability to specifically target cancerous cells and deliver an effective dose is crucial for improved cancer therapy. It is rare that anticancer drugs fail to reach clinical use because of insuf- ficient in-vitro potency – rather they fail because of undesirable in-vivo properties. This can be due to what the body does to the drug (pharmacokinetics) or what the drug does to the body (pharmacodynamics). This paper presents some approaches that have been used for the delivery and targeting of drugs. Delivery devices that target cancerous cells preferentially could be used to enhance the sta- bility and effectiveness of drugs without affecting normal cells. As such we have been examining possible methods of protecting our platinum-based DNA intercalators to prevent degradation and enhance the specificity of the drug–host complex. Molecu- lar hosts including cucurbit[n]urils (CB[n]), [23–28] cyclodextrins (n-CDs), [29–40] calix[n]arenes (CX[n]), [41] and dendrimers [42–47] have been reported to improve the potency of many drugs where bioavailability is restricted. [48–50] These classes of molecular hosts can provide association sites for both hydrophobic and hydrophilic molecules and as such are potential drug delivery devices. More importantly, they can be functionalized so that tar- geting molecules, such as folic acid or aptamers, can be appended to deliver platinum anticancer agents intact and specifically to cancer cells. Cucurbit[n]urils Cucurbit[n]urils consist of several repeating glycoluril subunits (CB[n], where n = 5, 6, 7, 8, or 10), connected by two methylene bridges (Fig. 1). They are small barrel-shaped molecules that have two symmetrical, hydrophilic portals lined with carbonyl groups and an internal hydrophobic cavity [51–54] that has the abil- ity to encapsulate a wide variety of molecules. There are two pos- sible modes of binding between CB[n] and the guest molecule: (1) hydrophobic interactions between the guest and the CB[n] [51] and/or (2) cavity interactions between the positively charged guest and the polar carbonyl groups that line the portals. The size of the cavity (Table 1) influences the inclusion complexes formed. [51,52,54] CB[n] has been previously shown to encapsulate anticancer drugs such as cisplatin, [55] oxaliplatin, [55] and multi- nuclear platinum complexes [56] and reduce the rate of reaction with biological nucleophiles (e.g., l-glutathione, l-cysteine, and guanosine). [57,58] Partial CB[n] encapsulation of the metallo- intercalators, such as [(5,6-dimethyl-1,10-phenanthroline) © CSIRO 2008 10.1071/CH08157 0004-9425/08/090675