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British Journal of Cancer*.
In spite of the clinical usefulness of cisplatin ( CDDP), there are many occasions in which it is difficult to
continue the administration of CDDP due to its nephrotoxicity and neurotoxicity. We examined the
incorporation of CDDP into polymeric micelles to see if this allowed the resolution of these disadvantages.
Cisplatin was incorporated into polymeric micelles through the polymer - metal complex formation
between polyethylene glycol poly( glutamic acid) block copolymers and CDDP (NC-6004). The
pharmacokinetics, pharmacodynamics, and toxicity studies of CDDP and NC-6004 were conducted in
rats or mice. The particle size of NC-6004 was approximately 30 nm, with a narrow size distribution.
In rats, the area under the curve and total body clearance values for NC-6004 were 65-fold and
one-nineteenth the values for CDDP ( P<0.001 and 0.01, respectively). In MKN-45-implanted mice,
NC-6004 tended to show antitumour activity, which was comparable to or greater than that of CDDP.
Histopathological and biochemical studies revealed that NC-6004 significantly inhibited the nephrotoxicity
of CDDP. On the other hand, blood biochemistry revealed transient hepatotoxicity on day 7 after the
administration of NC-6004.
Furthermore, rats given CDDP showed a significant delay (P<0.05) in sensory nerve conduction velocity
in their hind paws as compared with rats given NC-6004. Electron microscopy in rats given CDDP
indicated the degeneration of the sciatic nerve, but these findings were not seen in rats given NC-6004.
These results were presumably attributable to the significantly reduced accumulation of platinum in nerve
tissue when NC-6004 was administered (P<0.05).
NC-6004 preserved the antitumour activity of CDDP and reduced its nephrotoxicity and neurotoxicity,
which would therefore seem to suggest that NC-6004 could allow the long-term administration of CDDP
where caution against hepatic dysfunction must be exercised.
NanoCarrier is an R&D-driven venture company established to commercialize polymeric micellar
nanoparticles drugs incorporating a wide variety of pharmaceuticals, genes, and diagnostic products.
Drug-incorporating polymeric micellar nanoparticles show long and stable drug retention in the blood
stream and concentration in target sites for longer periods, which is aimed to show improved
pharmacological performance and diminished adverse effects. A paclitaxel formulation has achieved
good efficacy/safety results in pre-clinical and Phase-I clinical studies. A new platinum entity has also
shown good efficacy/safety results in pre-clinical studies and has recently entered Phase-I clinical
study.
About Polymeric Micelle
- They are nano-sized, ultrafine particles.
- They can stably retain a drug in the inner core.
- They are highly stable in the blood (they can avoid the foreign matter-recognizing response
because the outer shell is made of a hydrophilic radical). - They allow the selection of the class and molecular weight of block copolymers to apply,
depending on the property of a drug to be incorporated. - They can control the release of a drug from micelles.
- They can control the size of optimal micellar particles, depending on the target disorder.
BRITISH JOURNAL OF CANCER 93 (6): 678-687 SEP 19 2005
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