Targeted Analogues

( 1,2-diaminoethane)dichloro- c/i-[PtCl(NH3)2(JV7-ACV)]+ platinum(II) linked to acridine orange by hexamethylene chain

Figure 25.6 Targeted and anti-viral analogues of cisplatin intercalator. An example is (1,2-diaminoethane)dichloroplatinum(II) linked to acridine orange by trimethylene or hexamethylene chains (Figure 25.6).55

In the reaction with DNA, the platinum residues cross-link two base residues, while acridine orange is intercalated between the base pairs at a distance of one to two base pairs from the platinum-binding site. Other DNA-targeted platinum compounds that show anti-tumor activity include analogues of cisplatin containing as a carrier DNA minor groove non-intercalative binders netropsin and distamycin.56 58 Polymer-based delivery of platinum to tumors has also been proposed to minimize the toxicity of the cytotoxic agent.59 61 However, to date, there have been no clinically significant advances that have developed from this design approach.

Tumor targeting has also been the focus of much work in liposomal delivery of platinum drugs.62,63 Other mechanisms of action, such as release from drug depot formulations, heat-triggered local drug release and transfection of genetic materials, may prove to be useful in human patients. Liposomal formulations of cisplatin and its analogues have shown promise in vitro and in animal models.64,65 A novel method has been described66 allowing the efficient encapsulation of cisplatin in a lipid formulation. The method is unique in that it generates nanocapsules which have an unprecedented drug-to-lipid ratio and an in vitro cytotoxicity up to 1000-fold higher than the free drug. Analysis of the mechanism of nanocapsule formation suggests that the method may be generalized to other drugs showing low water solubility and lipophilicity.

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