Transcript Manal Alsaadi Research Day Poster

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
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,
thereby delivering more drug to the target tissue and
increasing its therapeutic index and overcoming resistance.
Lung
Cancer
Mean % inhibition of cell
growth ± SEM
50
40
30
20
10
0
0
0.2
0.4
0.6
0.8
1
-10
-20
-30
Cisplatin concentration (mM)
Cisplatin NIVs
Cisplatin solution
Empty NIVs
Figure 1: Effect
of different
cisplatin
formulations
on the
proliferation
of B16-F0
cell line
using
Alamar
Blue assay
(n=6)
Mean cisplatin conc.
(μg/gm tissue) ± SEM
Drug
Delivery
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
6
5
4
3
2
1
0
lung
spleen
Cisplatin solution
liver
kidney
Figure 2: Tissue
levels of
different
cisplatin
formulations
given by
intravenous
administration
(n=5)
Cisplatin NIVs
Methods:
Results:
Mean
parameter
measured ± SD
Time
(days post
production)
Table 1:
Characterization
of cisplatin
NIVs (n=3)
%
Entrapment
Size (nm)
Zeta
potential
(mV)
0
20.95 ± 3
650.6 ± 30
-96.9 ± 1
1
20.33 ± 3
676.3 ± 27
-87.1 ± 2
3
15.21 ± 3
623.9 ± 34
-84.5 ± 1
7
24.15 ± 4
826.0 ± 82
-88.0 ± 1
Figure 3: Tissue
levels of
different
cisplatin
formulations
given by
inhalation
(n=5)
0.4
Mean cisplatin conc.
(μg/gm tissue) ± SEM
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.
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.
0.35
0.3
0.25
0.2
0.15
0.1
0.05
0
lung
spleen
Cisplatin solution
liver
kidney
Cisplatin NIVs
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.
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).