The Use of a Vesicular Delivery System in the Enhancement of Cisplatin Bioavailability

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 (n6)
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 (n5)
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 (n5)
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 (n3)
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).