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Ligand Modifications
Ligand Modifications
Figure 23. Structures of both cisplatin and transplatin. Comparison of the trans or cis orientation of the chloride ligands is shown.39
Although it was initially thought that the efficacy of cisplatin was entirely dependent on the cis conformation of the chloride ligands in the structure, a study found that trans conformations exhibited similar cytotoxicity toward cancer cells.23 Transplatin was originally disregarded due to its greater reactivity and its tendency to deactivate in circulation in comparison to cisplatin.
Without modifications, transplatin ((trans-[Pt(NH3)2Cl2]) (Figure 23) showed limited anti-tumor activity due to quick deactivation by sulfur proteins at the DNA binding site.4 Further modifications involved oxidation by H2O2, the introduction of two hydrophobic aliphatic chains, and encapsulation by a biodegradable polymer. This properly protected transplatin and made it as effective as cisplatin or carboplatin in vitro.26
Figure 24. Sterically hindered picoplatin by addition of the 2-methylpyridine group.
Figure 25. Structure of VP-128 employs an estrogen ligand.
One of these modifications was an increase in the size of the ligands. The bulkiness of the ligand (2-methylpyridine) made the complex more sterically hindered. In turn, the toxicity factor of the drug was reduced. While this new drug, picoplatin (cis-[PtCl2(NH3)(2-methylpyridine)]), (Figure 24) exhibited anti-tumor activity, it was not significantly beneficial over current methods.4
Biologically active carriers in conjunction with platinum ligands have also been theorized to be more effective in vivo. KR Barnes et al. synthesized estrogen carriers and successfully bound them to platinum complexes.4 This new complex showed promising anti-tumor activity as well as increased cytotoxicity with no apparent increase in toxicity to the host. Moreover, this specific compound, VP-128 (Figure 25), which featured an estradiol-tethered platinum complex, showed activity in ovarian cancers that were highly resistant to standard cisplatin.
Drug Delivery and Specificity
Drug Delivery and Specificity
Figure 26. Schematic representation of carboplatin-based lipolatin. Liposomes are denoted by the mPEG-DSPE and the cisplatin complexes are shown as the CHEMS-cisplatin structure.27
Platinum based drugs often face obstacles of low bioavailability and low water solubility. Moreover, selectivity for malignant tissue over healthy tissue is a primary concern to decrease toxicity to the host. Therefore, researchers are focusing on synthesizing delivery systems on the nanoscale so that these drugs can easily pass through membranes of cancerous tissue.
Liposomal varieties of delivery systems have been studied recently. Lipoplatin is a modified version of cisplatin that is protected by a phospholipid bilayer with an aqueous interior so that it can be used for both hydrophilic and hydrophobic drugs. Lipoplatin comprises 9% cisplatin and 91% lipids. This study showed an increase in bioavailability in relevant tissues as well as lower toxic complications normally associated with cisplatin. Moreover, Lipoplatin showed clinical benefit in patients that had inconclusive results with previous chemotherapies.2,4
Figure 27. Three-dimensional animation of lipolatin and its liposome shell.28
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