Platinum-based chemotherapeutics

Fig. 10.18 The platinum based chemotherapeutic agents are stable and small enough to fit within the interior of an SWNT or MWNT...

Cisplatin was the first example of a platinum-based chemotherapeutic but it has been followed by others carboplatin, oxoplatin, and cycloplatam. All are variations on the original theme and all find use in the chemotherapy of cancer. 

Platinum-based chemotherapeutics induced hair cell death in rodents, albeit in variable patterns. In guinea pig, mice, and rat, cisplatin caused hearing loss that correlated to the loss of hair cells [36]. In the chinchilla, cisplatin predominantly affected outer hair cells and neurons [57], In contrast, carboplatin damaged IHCs, vestibular hair cells and auditory nerves only in chinchillas, and showed little ototoxic potency in other rodents and humans [41, 57, 58]. 

Fig. 13.2 Two- and three-dimensional structures of platinum-based chemotherapeutic drugs. Cisplatin, the first of the so-caUed organoplatinum drugs, contains no organic component. It is a metal coordination compound with a square-planar platinum (II) center coordinated to two ammonia and two chlorine ligands in a cw-ligand conformation. Carboplatin contains the CM-Pt(NH )2 active group...

Platinum-based chemotherapeutics are used clinically to treat soft tissue tumors. These types of platinum-based compounds bind to the nucleotide bases of DNA forming a bond which terminates ceU division and triggers ceU death (Kelland and Ferrell 2000). Although these compounds are highly effective anticancer therapies, their use commonly results to hearing loss. Common platinum-based chemotherapeutics are cisplatin, carboplatin, and oxaliplatin. 

The CuAAC has also been used to identify the cellular target of platinum-based chemotherapeutics [85]. DeRose et al. have used Picazoplatin 90, an azide-modified version of the anticancer drug of picoplatin 89, which readily binds to DNA and RNA oligonucleotides, offering a site for selective click-mediated labeling with fluorophores such as the dansyl alkyne 87 (Figure 10.26) [86]. 

Chemotherapeutic agents that have significant cancer response when combined with hyperthermia (up to 43°C) include doxorubicin, melphalan, mitomycin C (MMC), mitoxantrone, gemcitabine, etoposide, and especially the platinum-based agents carboplatin and oxaliplatin (Mohamed et al., 2003 Sugarbaker et al., 2005). Agents that do not work well with hyperthermia include irinotecan, paclitaxel, docetaxel, 5-fluorouracil, and floxuridine (Mohamed et al., 2003 Sugarbaker et al., 2005). 

There are three major approaches to assessing the potential activity of a chemotherapeutic compound prior to human clinical trials. In vitro assays, either solution- or solid-phase, are often used early in the screening process, especially when a biologically relevant molecular interaction has been identified. Studies in cultured mammalian cells are employed to predict the activity of a compound. If a compound shows promise in such in vitro and cell-based assays, then it is tested extensively in animals before proceeding to humans. The remainder of this chapter discusses these three methods as potential routes to identifying active platinum compounds from combinatorial libraries. 

An ELISA, which measures dsplatin-DNA intrastrand adducts, and atomic absorbance spectrometry, which measures total platinum bound to DNA, have been used to quantify DNA modification in samples from patients receiving platinum drug-based therapy and rats in which the treatment of human cancer patients has been modeled. Adducts measured in blood cell DNA samples from cancer patients have correlated with dose and chemotherapeutic efficacy. Human tissue DNA adducts have a widespread distribution, and long-term adduct persistence (> 1 year) has been observed in many organs including tumor and target sites for drug toxicity. 

Many metal complexes have been shown to possess bioactivity and several drugs based on metal complexes have been developed. These include platinum, gold, and bismuth compounds used in the treatment of certain kinds of cancer, arthritis, and stomach ailments, respectively [82]. The development of analogous polymeric chemotherapeutic materials, that would less easily diffuse through membranes, is also an important objective. 

Duncan and co-workers also created one of the first covalently linked DDS based on a dendrimer scaffold [52]. Carboxylated (COOH) PAMAM dendrimers were used to attach cisplatin, a common chemotherapeutic in clinical use. The covalent attachment of the drug increases the specific solubility of cisplatin ten-fold, and enables a loading of approximately 25% to be achieved for the PAMAM dendrimer. However, dendrimer clusters form as a consequence of the multiple COOH groups on the dendrimer scaffold and intermolecular reactions involving cisplatin. In vitro evaluation has shown that the covalent conjugation to the dendrimer results in a lower toxicity, and in vivo experiments have shown that the blood clearance rate is lower, with higher intra-tumoral concentrations of platinum than those achieved with the free drug. 

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