AN INVESTIGATION OF THE ANTITUMOR-ACTIVITY AND BIODISTRIBUTION OF POLYMERIC MICELLAR PACLITAXEL

Purpose: To evaluate in vitro cytotoxicity, in vivo antitumour activit y and biodistribution of a novel polymeric (poly(DL-lactide)-block-met hoxy polyethylene glycol) micellar paclitaxel. Methods: Hs578T breast, SKMES non-small-cell lung, and HT-29 colon human tumour cells were ex posed, either for Ih or continuously, to conventionally formulated pac litaxel (Cremophor paclitaxel) or polymeric micellar paclitaxel. After a period of incubation, cytotoxicity was measured using a radiometric system. In the in vivo antitumour study, B6D2F1 mice, bearing P388 le ukaemia tumour intraperitoneally (i.p.), were treated with polymeric m icellar paclitaxel or Cremophor paclitaxel by i.p. injection. The numb er of deaths and body weights were recorded. In the biodistribution st udy, CD-1 mice were given micellar paclitaxel i.p. at a dose of 100 mg /kg. The mice were sacrificed after a given time and the organs were h arvested. Paclitaxel in the organs was extracted by acetonitrile and a nalysed using HPLC. Results: The polymeric micellar paclitaxel showed similar in vitro cytotoxicity to Cremophor paclitaxel against the tumo ur cell lines. The polymeric micellar formulation of paclitaxel produc ed a fivefold increase in the maximum tolerated dose (MTD) as compared with Cremophor paclitaxel when administered i.p. In addition, micella r paclitaxel was more efficacious in vivo when tested in the murine P3 88 leukaemia model of malignancy than Cremophor paclitaxel when both w ere administered i.p. at their MTDs. Micellar paclitaxel-treated anima ls had an increased survival time and, importantly, long-term survivor s (20% of those tested) were obtained only in the polymeric paclitaxel formulation group. Biodistribution studies indicated that a significa nt amount of paclitaxel could be detected in blood, liver, kidney, spl een, lung and heart of mice after i.p. dosing of the polymeric micella r paclitaxel formulation. Conclusion: These preliminary results indica te that polymeric micellar paclitaxel could be a clinically useful che motherapeutic formulation.