NK105, a paclitaxel-incorporating micellar nanoparticle formulation, can extend in vivo antitumour activity and reduce the neurotoxicity of paclitaxel

Abstract

Paclitaxel (PTX) is one of the most effective anticancer agents. In clinical practice, however, high incidences of adverse reactions of the drug, for example, neurotoxicity, myelosuppression, and allergic reactions, have been reported. NK105, a micellar nanoparticle formulation, was developed to overcome these problems and to enhance the antitumour activity of PTX. Via the self-association process, PTX was incorporated into the inner core of the micelle system by physical entrapment through hydrophobic interactions between the drug and the well-designed block copolymers for PTX. NK105 was compared with free PTX with respect to their in vitro cytotoxicity, in vivo antitumour activity, pharmacokinetics, pharmacodynamics, and neurotoxicity. Consequently, the plasma area under the curve (AUC) values were approximately 90-fold higher for NK105 than for free PTX because the leakage of PTX from normal blood vessels was minimal and its capture by the reticuloendothelial system minimised. Thus, the tumour AUC value was 25-fold higher for NK105 than for free PTX. NK105 showed significantly potent antitumour activity on a human colorectal cancer cell line HT-29 xenograft as compared with PTX (Po0.001) because the enhanced accumulation of the drug in the tumour has occurred, probably followed by its effective and sustained release from micellar nanoparticles. Neurotoxicity was significantly weaker with NK105 than with free PTX. The neurotoxicity of PTX was attenuated by NK105, which was demonstrated by both histopathological (Po0.001) and physiological (Po0.05) methods for the first time. The present study suggests that NK105 warrants a clinical trial for patients with metastatic solid tumours.

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

“…Furthermore, in an animal model, the plasma and tumour area under the curve (AUC) values for taxol-incorporating polymeric micelle (NK105) showed 85-and 25-fold increases, respectively, as compared with those for taxol. Therefore, NK105 showed significant enhancement (Po0.001) of the antitumour activity of free taxol and a significant reduction (Po0.05) in its neurotoxicity (Hamaguchi et al, 2005). Based on these results, the Phase I clinical trial of NK105 is currently being conducted at the National Cancer Center Hospital, Tokyo.…”

A phase I and pharmacokinetic study of NK105, a paclitaxel-incorporating micellar nanoparticle formulation

“…This recommended dose of NK105 is less than that of conventional PTX (210 mg m À2 ). Since the plasma AUC of the recommended dose of NK105 was 15-to 20-fold higher than that of the recommended dose of conventional PTX (210 mg m À2 ), whether the so-called therapeutic window of NK105 is wider than that of conventional PTX should be determined in a future phases II or III trial, although the therapeutic window of NK105 appears to be wider than that of free PTX in mice experiments (Hamaguchi et al, 2005).…”

“…The hydrophobic inner core enables NK105 to entrap a sufficient amount of PTX. NK105 has a diameter of about 90 nm (Hamaguchi et al, 2005).…”

“…NK105 is a PTX-incorporating 'core-shell-type' polymeric micellar nanoparticle formulation (Hamaguchi et al, 2005). This particle can be injected intravenously without the use of Cremophor EL or ethanol as a vehicle.…”

“…These characteristics, which are unique to solid tumours, constitute the basis of the enhanced permeability and retention (EPR) effect (Matsumura and Maeda, 1986;Maeda et al, 2000;Duncan, 2003). The in vivo antitumour activity of NK105 was significantly more potent than that of free PTX, probably because of enhanced tumour exposure through the EPR effect (Hamaguchi et al, 2005).…”