The Use of a Vesicular Delivery System in the Enhancement of Cisplatin Bioavailability Manal M. Alsaadi, Katharine C. C

1. The Use of a Vesicular Delivery System in the Enhancement of Cisplatin Bioavailability Manal M. Alsaadi, Katharine C. Carter and Alexander B. Mullen Strathclyde Institute of Pharmaceutical and Biomedical Sciences, University of Strathclyde, Glasgow, G4 0NR, UK is the leading cause of cancer death claiming the lives of 1.3 million patients a year worldwide [1]. Lung cancer is mainly treated by cisplatin, where it is presently administered as an intravenous infusion over Lung Cancer Figure 1:Effect of different cisplatin formulations on the proliferation of B16-F0 cell line using Alamar Blue assay (n=6) 6-8 hours. This results in entire body exposure leading to undesirable and chronic side effects mainly renal failure and hearing loss, as well as the distress and inconveniency the patient suffers from prolonged treatment. using lipid bilayer vesicles have been proven to enhance the bioavailability of the drugs doxorubicin, daunorubicin and amphotericin B. It is hypothesised that vesicular delivery systems can also enhance the bioavailability of cisplatin by protecting it from being excreted rapidly, Drug Delivery thereby delivering more drug to the target tissue and increasing its therapeutic index and overcoming resistance. Figure 2:Tissue levels of different cisplatin formulations given by intravenous administration (n=5) in non-ionic surfactant vesicles (NIVs) were used in this study aiming to assess their ability in enhancing the in vivo pharmacokinetics and activity of cisplatin against cancer cells. Cisplatin Methods: Cisplatin NIVs were prepared and characterised by measuring their size, zeta potential and drug loading over time as an indication of their stability. Drug loading was evaluated using an HPLC method modified from Lopez-Flores et al [2]. In vitro studies comparing the cytotoxic effect of cisplatin solution and cisplatin NIVs on the proliferation of B16-F0 melanoma murine cell line was conducted using Alamar Blue assay. Figure 3:Tissue levels of different cisplatin formulations given by inhalation (n=5) In vivo pharmacokinetic profile of cisplatin was assessed by administering single dose of cisplatin to BALB/c mice, inoculated with B16-F0, by inhalation or intravenous route and detecting tissue levels. Discussion: The results demonstrated that high cisplatin loading in NIVs was achievable and that the vesicles were stable (Table 1). Cisplatin NIVs had significantly greater cytotoxicity on the in vitro proliferation of B16-F0 over free cisplatin and the lipid ingredients themselves were safe and non-toxic (Fig.1). In vivo results showed failure of free cisplatin to reach target tissues after a single dose. In contrast significant tissue uptake was observed from a single dose of cisplatin NIVs, particularly following intravenous administration, exploiting their uptake by the mononuclear phagocytic system (Figs.2 and 3). Conclusion: NIVs can offer a suitable way of targeting cisplatin delivery, which could play a role in reducing exposure of other tissues to free cisplatin which is currently a major drawback. Further studies will facilitate the development of a safe and effective dose. Results: Table 1: Characterization of cisplatin NIVs (n=3) References: [1] Accessed from the World Health Organization fact sheet no. 297 of February 2009 at http://www.who.int/mediacentre/factsheets/fs297/en/print.html on 19/05/2009. [2] Lopez-Flores et al., Journal of Pharmaceutical and Toxicological Methods, 52, 366-372 (2005).