Cisplatin-incorporating polymeric micelles (NC-6004) can reduce nephrotoxicity and neurotoxicity of cisplatin in rats

Abstract

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 (Po0.001 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 (Po0.05) 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 (Po0.05). 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.

Formation and Characterization of Polyglutamate Core−Shell Microspheres

“…7 This polymer has been conjugated to hydrophobic drugs such as Taxol to enhance uptake and retention; some of these conjugates are now in clinical trials. 8 Recently, large poly(R,L-glutamic acid) microspheres (∼5 µm) were reported in passing using ultrasound under strongly acidic conditions. 9 From this prior report, it is probable that their microspheres are not core-shell (n.b., at low pH, PG is insoluble at MW > 6000).…”

NK105, a paclitaxel-incorporating micellar nanoparticle, is a more potent radiosensitising agent compared to free paclitaxel

“…New micellar drugs are designed based on the idea that DDS can accumulate in the tumour selectively, while showing reduced distribution in normal tissues. We demonstrated that the incorporation of cisplatin into micelles significantly reduced the nephrotoxicity and neurotoxicity of cisplatin (Uchino et al, 2005). However, it was also shown that micelle-incorporated cisplatin caused transient liver dysfunction because it was trapped more avidly by the RES as compared to free cisplatin, even though the PEG of the outer shell of the micelle confers the so-called stealth effect.…”

Análise do potencial citotóxico agudo da bupivacaína e bupivacaína em excesso enantiomerico de 50% (S75-R25) incorporadas a microesferas sobre o nervo ciático de ratos

“…The choice of study through analysis of semi-fine and ultrafine sections can be considered the most appropriate because often the clinical and histological changes do not correspond to or are very subtle; thus only ultrastructural study allows the observation of discrete lesions [9][10] . Given the need for a careful analysis in the search for axonal and demyelination damage, this study presents an evaluation of the ultrastructure of sciatic nerves.…”