Effects of particle size and release property of paclitaxel-loaded nanoparticles on their peritoneal retention and therapeutic efficacy against mouse malignant ascites.

Malignant ascites accounts for abdominal pain, dyspnea and anorexia, all of which decrease quality of life in cancer patients. Intraperitoneal chemotherapy is a useful method for managing malignant ascites and nanoparticulate drug delivery system makes it more effective by increasing peritoneal retention of anti-cancer drugs. In this study, we prepared paclitaxel-loaded emulsions and liposomes with different particle sizes and drug release properties, and evaluated their peritoneal retention and therapeutic efficacy in Ehrlich's ascites carcinoma (EAC)-bearing mice. Liposomes with the size of 100 nm were rapidly absorbed from peritoneal cavity into blood after intraperitoneal injection into EAC-bearing mice, whereas 1000-nm liposomes were highly retained in peritoneal cavity. Accordingly, 1000 nm liposomes significantly prolonged survival time of EAC-bearing mice but did not inhibit the ascites accumulation because of too poor paclitaxel release. On the other hand, although peritoneal retention of emulsions themselves was similar irrespective of their sizes, 270-nm emulsions showed the higher PTX retention in ascites than other emulsions, and resulted in significantly prolonged survival time and lower accumulation of ascites in EAC-bearing mice. These results indicate that not only particle size but drug release property is one of key determinants of the biodisposition and therapeutic efficacy of intraperitoneally injected nanoparticulate PTX against malignant ascites.

Deeper penetration into tumor tissues and enhanced in vivo antitumor activity of liposomal paclitaxel by pretreatment with angiogenesis inhibitor SU5416.

The recently emerged concept of "vessel normalization" implies that judicious blockade of vascular endothelial growth factor (VEGF) signaling may transiently "normalize" the tumor vasculature, making it more suitable for tumor disposition of subsequently administered drugs. In this study, therefore, the effect of pretreatment with SU5416, a selective VEGF receptor-2 inhibitor, on tumor disposition and in vivo antitumor activity of polyethylene glycol (PEG)-modified liposomal paclitaxel (PL-PTX) was evaluated in Colon-26 solid tumor-bearing mice. To improve the solubility and in vivo disposition characteristics of SU5416, the inhibitor was formulated in PEGylated O/W emulsion (PE-SU5416). Pretreatment with PE-SU5416 significantly enhanced the in vivo antitumor effect of PL-PTX, although PE-SU5416 administration alone did not show any antitumor effect. Immunostaining for endothelial cells and pericytes demonstrated that the pretreatment with PE-SU5416 enhanced the pericyte coverage of the tumor vasculature. In addition, tumors treated with PE-SU5416 contained significantly smaller hypoxic regions compared with the nontreated control group, demonstrating that structural normalization of the tumor vasculature resulted in an improvement in tumor vessel functions, including oxygen supply. Furthermore, the pretreatment with PE-SU5416 increased the distribution of PEG liposomes and included PTX in the core region of the tumor, as well as conversely decreasing the ratio of their peripheral distribution. These results suggest that the structural and functional normalization of the tumor vasculature by the pretreatment with PE-SU5416 enabled liposomes to reach the deeper regions within tumor tissues, leading to more potent antitumor activity of PL-PTX.